Article

Angiotensin type 1a receptor signaling-dependent induction of vascular endothelial growth factor in stroma is relevant to tumor-associated angiogenesis and tumor growth

March 2005
Carcinogenesis 26(2):271-9

March 2005
26(2):271-9

DOI:10.1093/carcin/bgh324

Source
PubMed

Authors:

Shohei Yamashina

Kitasato University

Akiyoshi Fukamizu

university of tsukiuba

Show all 6 authorsHide

Angiotensin II is a multi-functional bioactive peptide and recent reports have suggested that angiotensin II is a proangiogenic growth factor. A retrospective cohort study revealed that angiotensin converting enzyme inhibitors decreased cancer risk, however, the precise mechanism is unknown. We hypothesized that endogenous angiotensin II plays a crucial role in tumor-associated angiogenesis. Tumors implanted in the subcutaneous tissue of wild-type mice developed intensive angiogenesis with vascular endothelial growth factor (VEGF) induction in tumor stroma. AT1a receptor (AT1a-R), but not AT1b receptor or AT2 receptor was expressed in tumor stroma and systemic administration of an AT1-R antagonist reduced tumor-associated angiogenesis and VEGF expression in tumor stroma. Angiotensin II up-regulates VEGF expression through the pathway including protein kinase C, AP-1 and NF-kappaB in fibroblasts, the major cellular component of tumor stroma. VEGF is a major determinant of tumor-associated angiogenesis in the present model, since angiogenesis was markedly reduced by either a VEGF neutralizing antibody or a VEGF receptor kinase inhibitor. Compared with the wild-type, tumor-associated angiogenesis was reduced in AT1a-R null mice, with reduced expression of VEGF in the stroma, and this reduction in AT1a-R null mice was not inhibited by an AT1-R antagonist. These suggest that host stromal VEGF induction by AT1a-R signaling is a key regulator of tumor-associated angiogenesis and tumor growth. AT1a-R signaling blockade may be a novel and effective therapeutic strategy against cancers.

Elucidating the Association Between the Upregulation of Angiotensin Type 1-Receptors and the Development of Gastrointestinal Malignancies

Article

Full-text available

Jun 2021

Mohammad Hassan Arjmand

The renin-angiotensin system (RAS) is a major regulator of body fluid hemostasis and blood pressure. Angiotensin type 1 receptors (AT1R) are one of the major components of this system and are widely expressed in different organs, including the gastrointestinal (GI) system. Very little known about the physiological roles of AT1R in GI tract but evidence has reported that local AT1Rs are upregulated in pathological conditions like GI malignancies and play role in stimulation of signaling pathways associated with GI cancers progression. AT1Rs axes signaling in tumor microenvironments stimulate inflammation and facilitate vascularization around the tumor cell to display invasive behavior. AT1Rs in stroma cells promote tumor-associated angiogenesis by upregulated of vessel endothelial growth factor (VEGF). Also, AT1Rs by the activation of molecular mechanisms such as PI3/Akt/NF-κB pathways increase the invasion of tumor cells. Experimental and clinical studies have reported that AT1R antagonists have beneficial influences by increasing the survival of patients with GI malignancies and reduction in the proliferation of GI cancer cell lines in vitro, and the growth and metastasis of tumors in vivo, therefore, AT1Rs antagonist have the potential for future anticancer strategies. This review focuses on the pathological roles of AT1Rs in GI malignancies.

The Angiotensin Receptor Blocker Losartan Suppresses Growth of Pulmonary Metastases via AT1R-Independent Inhibition of CCR2 Signaling and Monocyte Recruitment

Article

Apr 2019

Inflammatory monocytes have been shown to play key roles in cancer metastasis through promotion of tumor cell extravasation, growth, and angiogenesis. Monocyte recruitment to metastases is mediated primarily via the CCL2-CCR2 chemotactic axis. Thus, disruption of this axis represents an attractive therapeutic target for the treatment of metastatic disease. Losartan, a type I angiotensin II receptor (AT1R) antagonist, has been previously shown to have immunomodulatory actions involving monocyte and macrophage activity. However, the exact mechanisms accounting for these effects have not been fully elucidated. Therefore, we investigated the effects of losartan and its primary metabolite on CCL2-mediated monocyte recruitment and CCR2 receptor function using mouse tumor models and in vitro human monocyte cultures. We show, in this study, that losartan and its metabolite potently inhibit monocyte recruitment through the noncompetitive inhibition of CCL2-induced ERK1/2 activation, independent of AT1R activity. Studies in experimental metastasis models demonstrated that losartan treatment significantly reduced the metastatic burden in mice, an effect associated with a significant decrease in CD11b+/Ly6C+-recruited monocytes in the lungs. Collectively, these results indicate that losartan can exert antimetastatic activity by inhibiting CCR2 signaling and suppressing monocyte recruitment and therefore suggest that losartan (and potentially other AT1R blocker drugs) could be repurposed for use in cancer immunotherapy.

Chemoprevention with Enalapril and Aspirin in Men1(+/T) Knockout Mouse Model

Article

Full-text available

Jul 2018

Pancreatic neuroendocrine neoplasias (pNEN) are the most common cause of death in adult patients with multiple endocrine neoplasia type 1 (MEN1). So far, only few chemopreventive strategies (e.g. with somatostatin analogues) have been evaluated for MEN1 associated pNENs. In this experimental study on 75 Men1(+ /T) knockout mice, the effect of aspirin (n=25) and an inhibitor of angiotensin-I converting enzyme (enalapril, n=25) compared to controls (n=25) were evaluated as single chemopreventive strategies for pNENs after 6,9,12,15 and 18 months. After each study period, mice were sacrificed and the resected pancreata were evaluated by histopathological analysis, immunostaining, and real-time PCR. PNEN size and number was measured. Aspirin and enalapril lead to a pNEN size reduction of 80% (167518 µm2 vs 838876 µm2, p<0.001) and 79% (174758 µm2 vs 838876 µm2, p < 0.001) compared to controls. Furthermore, aspirin and enalapril treatment resulted in a significant reduction of the number of pNENs by 33%, (p= 0.04) and 41% (p= 0.002), respectively. The apoptosis marker caspase 3 revealed a higher positive expression in pNEN of treated Men1(+/T) mice. Immunostaining of VEGF in pNEN detected a down-regulation of its expression in treated Men1(+/T) mice compared to the control group. REL A transcript was significantly down-regulated in 18-months treated enalapril Men1(+/T) mice, but not in aspirin treated Men1(+/T) mice. There was no significant difference in Ki-67 index. Using a transgenic mouse model that imitates human MEN1, this study provides first evidence that aspirin and enalapril are effective chemopreventive agents for the progression of pNENs. .

Angiotensin II subtype 1a receptor signaling in resident hepatic macrophages induces liver metastasis formation

Article

Full-text available

Jun 2017
CANCER SCI

Liver metastases from colorectal cancer (CRC) are a clinically significant problem. The renin-angiotensin system (RAS) is involved in the tumor growth and metastases. This study was designed to evaluate the role of angiotensin II subtype receptor 1a (AT1a) in the formation of liver metastasis in CRC. A model of liver metastasis was made by intra-splenic injection of mouse colon cancer (CMT-93) into AT1a knockout mice (AT1aKO) and wild-type (C57BL/6) mice (WT). As compared with WT, the liver weight and liver metastatic rate were significantly lower in AT1aKO. The mRNA levels of CD31, transforming growth factor-beta1 (TGF-β1), and F4/80 were suppressed in AT1aKO as compared with WT. Double immunofluorescence analysis showed that the number of accumulated F4/80(+) cells expressing TGF-β1 in metastatic areas was higher in WT than in AT1aKO. AT1aKO bone marrow (BM) (AT1aKO-BM)→WT showed suppressed formation of liver metastasis as compared with WT-BM →WT. However, the formation of metastasis was further suppressed in WT-BM →AT1aKO as compared with AT1aKO-BM→WT. In addition, accumulated F4/80(+) cells in the liver metastasis were not BM-derived F4/80(+) cells, but mainly resident hepatic F4/80(+) cells, and these resident hepatic F4/80(+) cells were positive for TGF-β1. Angiotensin II enhanced TGF-β1 expression in Kupffer cells. Treatment of WT with clodronate liposomes suppressed liver metastasis by diminishing TGF-β1(+) F4/80(+) cells accumulation. The formation of liver metastasis correlated with collagen deposition in the metastatic area, which was dependent on AT1a signaling. These results suggested that resident hepatic macrophages induced liver metastasis formation by induction of TGF-β1 via AT1a signaling. This article is protected by copyright. All rights reserved.

Potensi Candesartan dalam Terapi COVID 19

Article

Full-text available

Feb 2022

Coronavirus disease 2019 (COVID-19) akibat severe acute respiratory syndrome coronavirus 2019 (SARS-CoV-2) menyebabkan kerusakan paru dan mortalitas bagi penderitanya. Di awal pandemi COVID-19, penggunaan obat antihipertensi RAS blocker diduga berperan dalam keluaran yang kurang baik pada pasien COVID-19 dengan hipertensi karena secara teoritis akan meningkatkan ekspresi ACE2 dan memperbanyak jalan masuk virus ke dalam organ. Beberapa penelitian terkini menyatakan sebaliknya. Studi preliminary menunjukkan penurunan mortalitas dan luaran kritis pasien dengan terapi ARB. Candesartan dalam studi in-vitro dapat mengurangi badai sitokin pada COVID-19 dan berpotensi mengurangi efek destruktif lain dari infeksi SARS-CoV-2. Candesartan dapat menekan inflamasi berlebih dan mengurangi stres oksidatif, sehingga berpotensi bermanfaat dalam terapi infeksi akut SARS-CoV-2. Candesartan juga bermanfaat mengurangi komplikasi jangka panjang, bermanfaat untuk fungsi paru dan organ-organ lainnya. Coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2019 (SARS-CoV-2) infection causes lung damage and mortality. At early COVID-19 pandemic stage, use of RAS blocker as antihypertensive drugs was discouraged because it potentially increases the expression of ACE2, therefore increase viral entry into organs. Nevertheless, recent researches suggests otherwise. Preliminary studies has shown reduction in mortality and critical outcomes of patients with ARB therapy. Candesartan in-vitro wasable to reduce cytokine storm in COVID-19 and potentially reduce other destructive effects of SARS-CoV-2 infection by surpressing excessive inflammation and reducing oxidative stress; potentially benefits acute treatment of SARS-CoV-2 infection. Candesartan also play a role in reducing long-term complications of the disease, improving lung function as well as other organs.

Prognostic impact of angiotensin-converting enzyme inhibitors and angiotensin receptors blockers in esophageal or gastric cancer patients with hypertension - a real-world study

Article

Full-text available

Apr 2022
BMC CANCER

Background Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are used in treating cardiovascular diseases. Previous studies indicated that ACEIs/ARBs may benefit cancer patients by inhibiting tumor angiogenesis and proliferation. The effect of ACEIs/ARBs on cancer survival in esophageal and gastric cancer is still unclear. This study is to investigate the association between ACEIs/ARBs usage and esophageal and gastric cancer prognosis. Methods This retrospective cohort study identified esophageal and gastric cancer patients during 2008–2016 from the Taiwan Cancer Registry, and obtained medication usage and follow-up information from the National Health Insurance Research Database and Death Registry. Analysis groups were defined as ACEIs/ARBs user or non-user based on the usage of ACEIs/ARBs within the 6 months after cancer diagnosis. The stabilized inverse probability of treatment weighting using propensity scores was applied to balance covariates between study groups. We also used Kaplan-Meier estimates and Cox regression to compare survival outcome and estimate hazard ratios (HRs). Results We identified 14,463 and 21,483 newly-diagnosed esophageal and gastric cancer patients during 2008–2016. ACEIs/ARBs users were associated with lower risk of cancer-specific mortality, although only significantly in gastric cancer (gastric: adjusted HR = 0.87, 95% CI = 0.78–0.97; esophageal: adjusted HR =0.88, 95% CI = 0.76–1.02). A better survival outcome was observed among patients who received higher cumulative defined daily dose of ACEIs/ARBs. Conclusions We found that using ACEIs/ARBs after cancer diagnosis were associated with lower risk of mortality. Our results add to the knowledge of the benefit of ACEIs/ARBs against mortality in individuals with esophageal/gastric cancer patients with hypertension.

Infection of Human Cells by SARS-CoV-2 and Molecular Overview of Gastrointestinal, Neurological, and Hepatic Problems in COVID-19 Patients

Article

Full-text available

Oct 2021

Citation: Rahban, M.; Stanek, A.; Hooshmand, A.; Khamineh, Y.; Ahi, S.; Kazim, S.N.; Ahmad, F.; Muronetz, V.; Samy Abousenna, M.; Zolghadri, S.; et al. Infection of Human Cells by SARS-CoV-2 and Molecular Abstract: The gastrointestinal tract is the body's largest interface between the host and the external environment. People infected with SARS-CoV-2 are at higher risk of microbiome alterations and severe diseases. Recent evidence has suggested that the pathophysiological and molecular mechanisms associated with gastrointestinal complicity in SARS-CoV-2 infection could be explained by the role of angiotensin-converting enzyme-2 (ACE2) cell receptors. These receptors are overexpressed in the gut lining, leading to a high intestinal permeability to foreign pathogens. It is believed that SARS-CoV-2 has a lesser likelihood of causing liver infection because of the diminished expression of ACE2 in liver cells. Interestingly, an interconnection between the lungs, brain, and gastrointestinal tract during severe COVID-19 has been mentioned. We hope that this review on the molecular mechanisms related to the gastrointestinal disorders as well as neurological and hepatic manifestations experienced by COVID-19 patients will help scientists to find a convenient solution for this and other pandemic events.

Infection of Human Cells by SARS-CoV-2 and Molecular Overview of Gastrointestinal, Neurological, and Hepatic Problems in COVID-19 Patients

Article

Full-text available

Oct 2021

The gastrointestinal tract is the body’s largest interface between the host and the external environment. People infected with SARS-CoV-2 are at higher risk of microbiome alterations and severe diseases. Recent evidence has suggested that the pathophysiological and molecular mechanisms associated with gastrointestinal complicity in SARS-CoV-2 infection could be explained by the role of angiotensin-converting enzyme-2 (ACE2) cell receptors. These receptors are overexpressed in the gut lining, leading to a high intestinal permeability to foreign pathogens. It is believed that SARS-CoV-2 has a lesser likelihood of causing liver infection because of the diminished expression of ACE2 in liver cells. Interestingly, an interconnection between the lungs, brain, and gastrointestinal tract during severe COVID-19 has been mentioned. We hope that this review on the molecular mechanisms related to the gastrointestinal disorders as well as neurological and hepatic manifestations experienced by COVID-19 patients will help scientists to find a convenient solution for this and other pandemic events.

Is RAS the Link Between COVID-19 and Increased Stress in Head and Neck Cancer Patients?

Article

Full-text available

Jul 2021

The COVID-19 pandemic emerged as a largely unexplained outbreak of pneumonia cases, in Wuhan City, China and rapidly spread across the world. By 11th March 2020, WHO declared it as a global pandemic. The resulting restrictions, to contain its spread, demanded a momentous change in the lifestyle of the general population as well as cancer patients. This augmented negative effects on the mental health of patients with head and neck cancer (HNC), who already battle with the stress of cancer diagnosis and treatment. The causative agent of COVID-19, SARS-CoV2, gains entry through the Angiotensin converting enzyme 2 (ACE2) receptor, which is a component of the Renin Angiotensin System (RAS). RAS has been shown to influence cancer and stress such that it can have progressive and suppressive effects on both. This review provides an overview of SARS-CoV2, looks at how the RAS provides a mechanistic link between stress, cancer and COVID-19 and the probable activation of the RAS axis that increase stress (anxiogenic) and tumor progression (tumorigenic), when ACE2 is hijacked by SARS-CoV2. The mental health crises brought about by this pandemic have been highlighted in many studies. The emerging links between cancer and stress make it more important than ever before to assess the stress burden of cancer patients and expand the strategies for its management.

Renin–Angiotensin–Aldosterone System and Immunomodulation: A State-of-the-Art Review

Article

Full-text available

Jul 2021

The renin–angiotensin system (RAS) has long been described in the field of cardiovascular physiology as the main player in blood pressure homeostasis. However, other effects have since been described, and include proliferation, fibrosis, and inflammation. To illustrate the immunomodulatory properties of the RAS, we chose three distinct fields in which RAS may play a critical role and be the subject of specific treatments. In oncology, RAS hyperactivation has been associated with tumor migration, survival, cell proliferation, and angiogenesis; preliminary data showed promise of the benefit of RAS blockers in patients treated for certain types of cancer. In intensive care medicine, vasoplegic shock has been associated with severe macro- and microcirculatory imbalance. A relative insufficiency in angiotensin II (AngII) was associated to lethal outcomes and synthetic AngII has been suggested as a specific treatment in these cases. Finally, in solid organ transplantation, both AngI and AngII have been associated with increased rejection events, with a regional specificity in the RAS activity. These elements emphasize the complexity of the direct and indirect interactions of RAS with immunomodulatory pathways and warrant further research in the field.

Transcriptional Regulation of Thrombin-Induced Endothelial VEGF Induction and Proangiogenic Response

Article

Full-text available

Apr 2021

Thrombin, the ligand of the protease-activated receptor 1 (PAR1), is a well-known stimulator of proangiogenic responses in vascular endothelial cells (ECs), which are mediated through the induction of vascular endothelial growth factor (VEGF). However, the transcriptional events underlying this thrombin-induced VEGF induction and angiogenic response are less well understood at present. As reported here, we conducted detailed promotor activation and signal transduction pathway studies in human microvascular ECs, to decipher the transcription factors and the intracellular signaling events underlying the thrombin and PAR-1-induced endothelial VEGF induction. We found that c-FOS is a key transcription factor controlling thrombin-induced EC VEGF synthesis and angiogenesis. Upon the binding and internalization of its G-protein-coupled PAR-1 receptor, thrombin triggers ERK1/2 signaling and activation of the nuclear AP-1/c-FOS transcription factor complex, which then leads to VEGF transcription, extracellular secretion, and concomitant proangiogenic responses of ECs.In conclusion, exposure of human microvascular ECs to thrombin triggers signaling through the PAR-1–ERK1/2–AP-1/c-FOS axis to control VEGF gene transcription and VEGF-induced angiogenesis. These observations offer a greater understanding of endothelial responses to thromboinflammation, which may help to interpret the results of clinical trials tackling the conditions associated with endothelial injury and thrombosis.

CCL5 production by fibroblasts through a local renin–angiotensin system in malignant melanoma affects tumor immune responses

Article

Full-text available

Jul 2021
J CANCER RES CLIN

PurposeTo enhance the antitumor effects of anti-programmed death-1 (PD-1) antibodies, it is important to reverse cancer-induced immunosuppression. We previously reported that a localized renin–angiotensin system in the tumor microenvironment inhibited tumor immunity via macrophages. In this study, we analyzed the underlying mechanism through which fibroblasts express tumor immunity influenced by the angiotensin receptor.Methods We used an angiotensin receptor inhibitor (ARB) to inhibit renin–angiotensin system. Furthermore, angiotensin receptors were knocked out from mice fibroblasts, which were then collected. The fibroblasts and a malignant melanoma were then transfused into a mouse model and tumor immunity response was analyzed.ResultsFibroblasts produced CC motif chemokine ligand 5 (CCL5) on renin–angiotensin system stimulation, and this production decreased after ARB administration. In mice with transplanted malignant melanoma, ARB administration resulted in decreased CCL5 concentration in the blood, increase in tumor-infiltrating T cells, decrease in regulatory T cells, as well as an increase in tumor antigen-specific T-cell responses. The mice in which the angiotensin receptor knockout fibroblasts and malignant melanoma were transplanted showed a similar decrease in CCL5 concentration and increased tumor antigen-specific T-cell responses. Furthermore, ARB and anti-PD-1 antibody were administered in combination, which resulted in significantly better tumor growth inhibition over monotherapy.Conclusion Inhibiting renin–angiotensin system restored the therapeutic efficacy of inhibited anti-PD-1 antibodies. Thus, this could be considered a valid approach to enhance the therapeutic efficacy of anti-PD-1 antibodies.

Effects of hypertension on cancer survival: A meta‐analysis

Article

Full-text available

Jan 2021

Background Hypertension is usually associated with increased cardiovascular mortality. Uncertainty exists about the possible role of hypertension as a poor prognostic factor for cancer‐specific mortality (CSM). To assess the association between pre‐existing hypertension and the risk of mortality and relapse after a diagnosis of cancer, we performed a systematic review and meta‐analysis of published studies. Methods PubMed, Scopus, Web of Science, the Cochrane Library, and EMBASE were searched from inception until May 2020, without language restrictions, for observational studies reporting the prognosis of patients with hypertension and cancer. The primary outcome of the study refers to CSM in hypertensive vs nonhypertensive patients, and secondary endpoints were overall mortality (OM) and progression or relapse‐free survival. The effect size was reported as hazard ratios (HRs) with 95% CIs. Results Mortality and relapse associated with hypertension in patients with various cancers were evaluated among 1 603 437 participants (n = 66 studies). Overall, diagnosis of cancer and hypertension was associated with an increased independent risk of OM (HR = 1.2 [95% CI, 1.13‐1.27], P < 0.01) and CSM (HR = 1.12 [95% CI, 1.04‐1.21], P < 0.01) but not of relapse (HR = 1.08 [95% CI, 0.98‐1.19], P = 0.14). Conclusions Among cancer patients, those with pre‐existing hypertension have a poorer outcome, probably due to multifactorial reasons. Adequate control of lifestyle, more intensive follow‐ups, monitoring for hypertension‐ and anticancer‐related cardiovascular complications, and establishing multidisciplinary cardio‐oncology units can be useful measures for reducing mortality and improving care in this setting.

Renin angiotensin system genes are biomarkers for personalized treatment of acute myeloid leukemia with Doxorubicin as well as etoposide

Article

Full-text available

Nov 2020
PLOS ONE

Despite the availability of various treatment protocols, response to therapy in patients with Acute Myeloid Leukemia (AML) remains largely unpredictable. Transcriptomic profiling studies have thus far revealed the presence of molecular subtypes of AML that are not accounted for by standard clinical parameters or by routinely used biomarkers. Such molecular subtypes of AML are predicted to vary in response to chemotherapy or targeted therapy. The Renin-Angiotensin System (RAS) is an important group of proteins that play a critical role in regulating blood pressure, vascular resistance and fluid/electrolyte balance. RAS pathway genes are also known to be present locally in tissues such as the bone marrow, where they play an important role in leukemic hematopoiesis. In this study, we asked if the RAS genes could be utilized to predict drug responses in patients with AML. We show that the combined in silico analysis of up to five RAS genes can reliably predict sensitivity to Doxorubicin as well as Etoposide in AML. The same genes could also predict sensitivity to Doxorubicin when tested in vitro . Additionally, gene set enrichment analysis revealed enrichment of TNF-alpha and type-I IFN response genes among sensitive, and TGF-beta and fibronectin related genes in resistant cancer cells. However, this does not seem to reflect an epithelial to mesenchymal transition per se. We also identified that RAS genes can stratify patients with AML into subtypes with distinct prognosis. Together, our results demonstrate that genes present in RAS are biomarkers for drug sensitivity and the prognostication of AML.

Impact of Gastrointestinal Symptoms in COVID-19: a Molecular Approach

Article

Full-text available

Dec 2020

The pandemic of novel coronavirus disease (COVID-19) caused by the Severe Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) creates an immense menace to public health worldwide. Currently, the World Health Organization (WHO) has recognized the novel coronavirus as the main cause of global pandemic. Patients infected with this virus generally show fever, nausea, and respiratory illness, while some patients also manifest gastrointestinal symptoms such as abdominal pain, vomiting, and diarrhea. Traces of SARS-CoV-2 RNA have been found in gastrointestinal cells. Further angiotensin converting enzyme 2 (ACE2) the known receptor for the virus is extensively expressed in these cells. This implies that gastrointestinal tract can be infected and can also present them as a replication site for SARS-CoV-2, but since this infection may lead to multiple organ failure, therefore identification of another receptor is a plausible choice. This review aims to provide comprehensive information about probable receptors such as sialic acid and CD147 which may facilitate the virus entry. Several potential targets are mentioned which can be used as a therapeutic approach for COVID-19 and associated GI disorders. The gut microbiomes are responsible for high levels of interferon-gamma which causes hyper-inflammation and exacerbates the severity of the disease. Briefly, this article highlights the gut microbiome's relation and provides potential diagnostic approaches like RDT and LC-MS for sensitive and specific identification of viral proteins. Altogether, this article reviews epidemiology, probable receptors and put forward the tentative ideas of the therapeutic targets and diagnostic methods for COVID-19 with gastrointestinal aspect of disease.

Influences of angiotensin I-converting enzyme gene insertion/deletion polymorphism on prostate cancer risk in Romania

Article

Full-text available

Dec 2019

ACE Inhibitor Therapy Does Not Influence the Survival Outcomes of Patients with Colorectal Liver Metastases Following Liver Resection

Article

Full-text available

Mar 2021

Background Angiotensin-converting enzyme (ACE) inhibitors have been shown to possibly influence the survival outcomes in certain cancers. The aim of this study was to evaluate the impact of ACE inhibitors on the outcomes of patients undergoing liver resection for colorectal liver metastases (CRLM). The secondary aim was to determine whether ACE inhibitors influenced histopathological changes in CRLM. Methods Patients treated with liver resection for CRLM over a 13-year period were identified from a prospectively maintained database. Data including demographics, primary tumour treatment, surgical data, histopathology analysis and clinical outcome were collated and analysed. Results A total of 586 patients underwent primary hepatic resections for CRLM during this period including 100 patients on ACE inhibitors. The median follow-up period was 23 (range: 12–96) months, in which 267 patients developed recurrent disease and 131 patients died. Independent predictors of disease-free survival on multivariate analysis included synchronous presentation, neoadjuvant chemotherapy, major liver resection, tumour size and number, extent of hepatic steatosis, R0 resection and presence of perineural invasion. Poorer overall survival was associated with neoadjuvant treatment, major liver resection, presence of multiple metastases, perineural invasion and positive resection margins on multivariate analysis. ACE inhibitors did not influence the survival outcome or histological presentation in CRLM. Conclusion The use of ACE inhibitors did not affect the survival outcome or tumour biology in patients with CRLM following liver resection.

The impact of Renin-angiotensin system blockers on lung cancers prognosis: A prisma-compliant systematic review and meta-analysis.

Article

Jan 2017

Comparative Experimental Studies of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers against Two Different Models of Angiogenesis

Article

Full-text available

May 2019

bjective: Angiogenesis, the formation of new capillary blood vessels. Wehave compared the effect of two Angiotensin-Converting Enzyme inhibitors(ACEIs) and two Angiotensin Receptor Blockers (ARBs) for its anti-angio-genic property to pinpoint their role in capillary growth. Methods: The anti-angiogenic activity of ACEIs (Lisinopril, Ramipril) and ARBs (Losartan, Val-sartan) were evaluated by in-ovo using and in-vivo methods by using chickembryo Chorioallantoic membrane (CAM) assay and sponge implantationmethod respectively. All the test drugs were tested at three dose level andSuramin was considered as standard. Before coming to the final conclu -sion various parameters were studied like angiogenic score, the numberof branching points and micro-vessels in CAM assay, whereas the deter -mination of Hb content, wet weight of the implants and VEGF was carriedout in sponge implantation model. Results: Among all the drugs Losartan,AT1R blocker has shown a promising anti-angiogenic effect against boththe models. Valsartan has also shown modest anti-angiogenic activity butnot as good as Losartan. Losartan has shown significant ( p<0.005) dose-dependent decrease in the number of blood vessels, new branching points,angiogenic score and the decrease in wet weight, Hb content and VEGFcontent in the implants compared to normal control group. There was nosignificant difference were observed in any of the parameters by ACEI.Conclusion: Losartan possesses a significant potential to inhibit angiogen-esis and this property could be useful in controlling metastasis in malignantcancerous tumors

ACE2 inhibits breast cancer angiogenesis via suppressing the VEGFa/VEGFR2/ERK pathway

Article

Full-text available

Dec 2019
J EXP CLIN CANC RES

Background Breast cancer angiogenesis is key for metastasis and predicts a poor prognosis. Angiotensin-converting enzyme 2 (ACE2), as a member of the renin-angiotensin system (RAS), was reported to restrain the progression of hepatocellular carcinoma (HCC) and non-small cell lung cancer (NSCLC) through inhibiting angiogenesis. However, the relationship between ACE2 and breast cancer angiogenesis remains unclear. Methods The prognosis and relative gene selection were analysed using the GEPIA, GEO, TCGA and STRING databases. ACE2 expression in breast cancer tissue was estimated by reverse transcription-quantitative polymerase chain reaction (qPCR). Breast cancer cell migration, proliferation and angiogenesis were assessed by Transwell migration, proliferation, tube formation, and wound healing assays. The expression of vascular endothelial growth factor A (VEGFa) was detected by qPCR and Western blotting. The phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2), mitogen-activated protein kinase 1/2 (MEK1/2), and extracellular signal-regulated protein kinase 1/2 (ERK1/2) was examined by Western blotting. Breast cancer metastasis and angiogenesis in vivo were measured using a zebrafish model. Results ACE2 was downregulated in breast cancer patients. Patients with higher ACE2 expression had longer relapse-free survival (RFS). In vitro, ACE2 inhibited breast cancer migration. Meanwhile, ACE2 in breast cancer cells inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, tube formation and migration. In the zebrafish model, ACE2 inhibited breast cancer cell metastasis, as demonstrated by analyses of the number of disseminated foci and the metastatic distance. Neo-angiogenesis was also decreased by ACE2. ACE2 downregulated the expression of VEGFa in breast cancer cells. Furthermore, ACE2 in breast cancer cells inactivated the phosphorylation of VEGFR2, MEK1/2, and ERK1/2 in HUVECs. Conclusions Our findings suggest that ACE2, as a potential resister to breast cancer, might inhibit breast cancer angiogenesis through the VEGFa/VEGFR2/ERK pathway. Trial registration Retrospectively registered. Electronic supplementary material The online version of this article (10.1186/s13046-019-1156-5) contains supplementary material, which is available to authorized users.

Liver Protective Effects of Renin-Angiotensin System Inhibition Have No Survival Benefits in Hepatocellular Carcinoma Induced By Repetitive Administration of Diethylnitrosamine in Mice

Article

Full-text available

Jun 2018

BACKGROUND Preclinical studies have demonstrated that renin-angiotensin system (RAS) signalling has strong tumour-promoting effects and RAS inhibition was associated with improvement in the overall survival in some cancer types including hepatocellular carcinoma (HCC). OBJECTIVE We aimed to investigate the effect of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-II-receptor blockers (ARBs) on the survival of mice with diethylnitrosamine (DEN) induced HCC. METHODS HCC was induced by weekly i.p. administration of DEN. Mice were treated with sorafenib (SO) (30 mg/kg), perindopril (PE) (1 mg/kg), fosinopril (FO) (2 mg/kg), losartan (LO) (10 mg/kg), PE (1 mg/kg) + SO (30 mg/kg), FO (2 mg/kg) + SO (30 mg/kg), or LO (10 mg/kg) + SO (30 mg/kg). Survival analysis was done using the Kaplan-Meier method, and the log-rank test was used for assessing the significance of difference between groups. RESULTS The administration of PE, FO and LO as monotherapy or as combined with SO resulted in marked improvement in the liver histologic picture with no impact on overall survival of mice. CONCLUSION Interfering the RAS either through the inhibition of ACE or the blockade of angiotensin II type 1 (AT1) receptors has similar effects on the liver of DEN-induced HCC mice and is not associated with longer survival due to detrimental effects of DEN on other organs. Hence, repetitive administration of DEN in such models of HCC is not suitable for mortality assessment studies.

Perindopril, Fosinopril and Losartan inhibited the progression of diethylnitrosamine-induced hepatocellular carcinoma in mice via the inactivation of nuclear transcription factor kappa-B

Article

May 2018
TOXICOL LETT

Hepatocellular carcinoma (HCC) is a major global health problem. Therapeutic interventions of HCC are still limited because of its complicated molecular pathogenesis. Many reports showed that renin-angiotensin system (RAS) contributes to the development of different types of malignancies. Therefore, the present study aimed to examine the effect of RAS inhibition using perindopril (1 mg/kg), fosinopril (2 mg/kg), or losartan (10 mg/kg) on diethylnitrosamine-induced HCC compared to sorafenib (30 mg/kg). The administration of RAS inhibitors resulted in improved liver function and histologic picture with a reduction in AFP levels. These effects found to be mediated through inactivation of NFкB pathway by the inhibition of NFĸB p65 phosphorylation at the Ser536 residue and inhibition of the phosphorylation-induced degradation of NFĸBia. Consequently, expression levels of cyclin D1 mRNA were significantly lowered. In addition, NFкB-induced TNF-α and TGF-β1 levels were reduced leading to lower levels of MMP-2 and VEGF. We concluded that RAS inhibition either through inhibiting the ACE or the blockade of AT1R has the same therapeutic benefit and that the tissue affinity of the ACEIs has no impact on its anti-tumor activity. These results suggest that ACEIs and ARBs can serve as promising candidates for further clinical trials in the management of HCC.

Involvement of local renin-angiotensin system in immunosuppression of tumor microenvironment

Article

Full-text available

Oct 2017

To improve the current cancer immunotherapies, strategies to modulate various immunosuppressive cells including myeloid derived suppressor cells (MDSCs) which were shown to be negative factors in the immune-checkpoint blockade therapy, need to be developed. In this study, we have evaluated the role of local renin–angiotensin system (RAS) in the tumor immune-microenvironment using murine models bearing tumor cell lines in which RAS was not involved in their proliferation and angiogenetic ability. Administration of angiotensin II receptor blockers (ARBs) to C57BL/6 mice bearing murine colon cancer cell line MC38 resulted in significant enhancement of tumor antigen gp70 specific T cells. ARB administration did not change the numbers of CD11b⁺ myeloid cells in tumors, but significantly reduced their T cell inhibitory ability along with decreased production of various immunosuppressive factors including interleukin (IL)-6, IL-10, VEGF, and arginase by CD11b⁺ cells in tumors. ARB also decreased expression of immunosuppressive factors such as chemokine ligand 12 and nitric oxide synthase 2 in cancer-associated fibroblasts (CAFs). Lastly, combination of ARB and anti-programmed death-ligand 1 (PD-L1) antibodies resulted in significant augmentation of anti-tumor effects in a CD8⁺ T cell-dependent manner. These results demonstrated that RAS is involved in generation of immunosuppressive tumor microenvironment caused by myeloid cells and fibroblasts, other than the previously shown proliferative and angiogenetic properties of cancer cells and macrophages, and that ARB can transform the immunosuppressive properties of MDSCs and CAFs and could be used in combination with PD-1/PD-L1 immune checkpoint blockade therapy.

Targeting the renin-angiotensin system to improve cancer treatment: Implications for immunotherapy

Article

Full-text available

Oct 2017

Renin-angiotensin system (RAS) inhibitors (RASi)—widely prescribed for the treatment of cardiovascular diseases—have considerable potential in oncology. The RAS plays a crucial role in cancer biology and affects tumor growth and dissemination directly and indirectly by remodeling the tumor microenvironment. We review clinical data on the benefit of RASi in primary and metastatic tumors and propose that, by activating immunostimulatory pathways, these inhibitors can enhance immunotherapy of cancer.

Angiotensin 1-7 inhibits angiotensin II-stimulated head and neck cancer progression

Article

Full-text available

Jun 2017
EUR J ORAL SCI

Angiotensin II (Ang II) is the product of the proteolytic action of angiotensin-converting enzyme (ACE) on the precursor peptide, angiotensin I (Ang I). In addition to its vasoactive properties, Ang II is able to stimulate angiogenesis and act as a mitogen, promoting cellular proliferation. Recently, evidence has emerged that Ang II is also able to promote tumour invasion, a key step in the metastatic cascade, although the mechanisms by which it does so remain largely obscure. Here we show that Ang II is able to promote the invasion and migration of head and neck squamous cell carcinoma (HNSCC) cells both in an autocrine manner and by triggering stromal tumour-paracrine interactions. The effects of Ang II on autocrine and paracrine signalling pathways are mediated by angiotensin receptor 1 (AT1 R) and inhibited by angiotensin 1-7 (Ang 1-7), a peptide produced from Ang II by the action of angiotensin-converting enzyme 2 (ACE2). These data are the first to demonstrate a role for the renin-angiotensin system in oral carcinogenesis and raise the possibility of utilizing AT1 R receptor antagonists and/or Ang 1-7 as novel therapeutic agents for HNSCC.

Cancer Stem Cells in Moderately Differentiated Lip Squamous Cell Carcinoma Express Components of the Renin–Angiotensin System

Article

Full-text available

Jun 2017

Aim We investigated the expression of the renin–angiotensin system (RAS) by cancer stem cell (CSC) subpopulations we have identified in moderately differentiated lip squamous cell carcinoma (MDLSCC). Method Ten MDLSCC samples underwent 3,3-diaminobenzidine (DAB) and immunofluorescent immunohistochemical (IHC) staining for (pro)renin receptor (PRR), angiotensin-converting enzyme (ACE), angiotensin II receptor 1 (ATIIR1), and receptor 2 (ATIIR2). NanoString analysis and Western blotting (WB) were performed on six MDLSCC samples for gene and protein expression, respectively. Results IHC staining showed expression of PRR, ATIIR1, and ATIIR2 on cells within the tumor nests (TNs) and the stroma. ACE was localized to the microvessels within the stroma. WB detected PRR, ACE, and ATIIR2. NanoString analysis confirmed gene expression of PRR, ACE, and ATIIR1. Conclusion Components of the RAS: PRR, ATIIR1, and ATIIR2 are expressed on two CSC subpopulations in MDLSCC, one within the TNs and the other within the stroma. The endothelium of the microvessels within the stroma expresses ACE.

Angiotensin II type 2 receptor promotes apoptosis and inhibits angiogenesis in bladder cancer

Article

Full-text available

Jun 2017
J Exp Clin Canc Res

Background Bladder cancer (BCa) is the ninth most common form of cancer in the world. There is a continuing need not only for improving the accuracy of diagnostic markers but also for the development of new treatment strategies. Recent studies have shown that the renin-angiotensin system (RAS), which include the angiotensin type 1 (AT1R), type 2(AT2R), and Mas receptors, play an important role in tumorigenesis and may guide us in meeting those needs. Results In this study, we first observed that AT1R and Mas expression levels were significantly upregulated in BCa specimens while AT2R was significantly downregulated. Viral vector mediated overexpression of AT2R induced apoptosis and dramatically suppressed BCa cell proliferation in vitro, suggesting a therapeutic effect. Investigation into the mechanism revealed that the overexpression of AT2R increases the expression levels of caspase-3, caspase-8, and p38 and decreases the expression level of pErk. AT2R overexpression also leads to upregulation of 2 apoptosis-related genes (BCL2A1, TNFSF25) and downregulation of 8 apoptosis-related genes (CASP 6, CASP 9, DFFA, IGF1R, PYCARD, TNF, TNFRSF21, TNFSF10, NAIP) in transduced EJ cells as determined by PCR Array analysis. In vivo, we observed that AT2R overexpression caused significant reduction in xenograft tumors sizes by downregulation VEGF and induction of apoptosis. Conclusions Taken together, the data suggest that AT1R, AT2R or Mas could be used as a diagnostic marker of BCa and AT2R is a promising novel target gene for BCa gene therapy.

Use of inhibitors of the renin–angiotensin system is associated with longer survival in patients with hepatocellular carcinoma

Article

Nov 2017

Background: Inhibition of the renin-angiotensin system (RAS) was associated with longer survival in patients with different solid malignancies. Objective: The objective of this study was to investigate the effect of RAS inhibitor (RASi) treatment (angiotensin-converting enzyme inhibitors or angiotensin-II-receptor blockers) on survival of patients with hepatocellular carcinoma (HCC). Methods: Patients diagnosed with HCC and Child-Pugh A between 1992 and 2013 who received sorafenib, experimental therapy, or best supportive care were eligible for the Vienna cohort. The Mainz cohort included patients with HCC and Child-Pugh A who received sorafenib treatment between 2007 and 2016. The association between RASi and overall survival (OS) was evaluated in univariate and multivariate analyses. Results: In the Vienna cohort, 43 of 156 patients received RASi for hypertension. RASi treatment was associated with longer OS (11.9 vs. 6.8 months (mo); p = 0.014) and remained a significant prognostic factor upon multivariate analysis (HR = 0.6; 95% CI 0.4-0.9; p = 0.011). In subgroup analysis, patients treated with sorafenib plus RASi had better median OS (19.5 mo) compared to those treated with either sorafenib (10.9 mo) or RASi (9.7 mo) alone (p = 0.043). The beneficial effect of RASi on survival was confirmed in the Mainz cohort (n = 76). Conclusion: RAS inhibition is associated with longer survival in HCC patients with Child-Pugh class A.

Influence of Tumor Microenvironment on the Distribution and Elimination of Nano-formulations

Article

Jun 2016
CURR DRUG METAB

Objective: To give an in-depth overview about the tumor and its surrounding microenvironment influencing distribution and elimination of nanoformulations. Mehtods: This up-to-date review will summarize the microenvironmental components and their influence on the various factors related to nanoformulations and tumor which affect the penetration, distribution, regulation and clearance of nanoformulations from the tumor cells. Results of recent advances in miroenvironmental tuning with nanoformulations will be evaluated mechanistically. In addition, those natures of tumors involving enhanced cancer therapy will be discussed. Finally, strategies of nanoparticulate design and decoration to achieve efficient drug delivery are presented. Results: Development of tumor is facilitated by its surrounding microenvironment and is regulated by different extra and intracellular components. Drug-loaded nanoformulations are mainly administered via oral and parenteral routes which reach tumor cells via different mechanisms. Chemotherapeutics get diffused from circulation into the surrounding microenvironment which latter get internalized into the cellular interstial area by passive diffusion mechanism due to virtue of size, charge, and pegylation effects, or by ligands and receptor mediated, or through enhanced permeability and retention effects through leaky apertures. Due to mildly acidic environment and hypoxic interstial environment, the influx of nanoformulations is hindered. The metabolites of the nanoformulations get diffused out from the tumor cells as a results of high interstial fluid pressure and get cleared either via liver or via renal execration. Conclusion: Well-understanding tumoral microenvironments which significantly affect distribution and elimination of nanoformulations is essential for engineering delivery systems with superior anti-tumoral effect.

Heart failure pharmacotherapy and cancer: pathways and pre-clinical/clinical evidence

Article

Full-text available

Mar 2024

Heart failure (HF) patients have a significantly higher risk of new-onset cancer and cancer-associated mortality, compared to subjects free of HF. While both the prevention and treatment of new-onset HF in patients with cancer have been investigated extensively, less is known about the prevention and treatment of new-onset cancer in patients with HF, and whether and how guideline-directed medical therapy (GDMT) for HF should be modified when cancer is diagnosed in HF patients. The purpose of this review is to elaborate and discuss the effects of pillar HF pharmacotherapies, as well as digoxin and diuretics on cancer, and to identify areas for further research and novel therapeutic strategies. To this end, in this review, (i) proposed effects and mechanisms of action of guideline-directed HF drugs on cancer derived from pre-clinical data will be described, (ii) the evidence from both observational studies and randomized controlled trials on the effects of guideline-directed medical therapy on cancer incidence and cancer-related outcomes, as synthetized by meta-analyses will be reviewed, and (iii) considerations for future pre-clinical and clinical investigations will be provided.

An angiotensin system inhibitor (Losartan) potentiates anti-tumor efficacy of cisplatin in a murine model of non-small cell lung cancer

Article

Full-text available

Feb 2024

Objective Previous studies have demonstrated synergistic antitumor effects of angiotensin system inhibition (ASI) combined with cisplatin therapy in pancreatic cancer. This study examines whether or not synergistic antitumor effects occur with combination ASI and cisplatin treatment in lung cancer, and whether or not ASI-induced changes in epithelial-mesenchymal transition play a role in the mechanism of this antitumor phenomenon. Methods A set of lung cancer cell lines representing a spectrum of epithelial to mesenchymal phenotypes were identified and characterized. Response of epithelial-mesenchymal transition markers to losartan was characterized. Cell culture models of lung cancer were next treated with losartan, cisplatin, or combination of both. Markers of epithelial-mesenchymal transition or surrogates of other signaling pathways (AKT, Stat3, and programmed death-ligand), and cell viability were quantified. Findings were confirmed in both allogenic and syngeneic in vivo murine flank tumor models. Results Losartan treatment significantly increased E-cadherin and reduced vimentin in human lung cancer cell lines. Combination treatment with losartan and cisplatin enhanced epithelial markers, reduced mesenchymal markers, inhibited promesenchymal signaling mediators, and reduced cell viability. Findings were confirmed in vivo in a murine flank tumor model with transition from mesenchymal to epithelial phenotype and reduced tumor size following combination losartan and cisplatin treatment. Conclusions Combination losartan and cisplatin treatment attenuates the epithelial-mesenchymal transition pathway and enhances the cytotoxic effect of chemotherapy with in vitro and in vivo models of non–small cell lung cancer. This study suggests an important role for ASI therapy in the treatment of lung cancer.

Angiotensin-converting enzyme

Chapter

Jan 2024

The renin-angiotensin-aldosterone system (RAAS) signaling pathways and cancer: foes versus allies

Article

Full-text available

Oct 2023
Canc Cell Int

The renin-angiotensin-aldosterone system (RAAS), is an old system with new fundamental roles in cancer biology which influences cell growth, migration, death, and metastasis. RAAS signaling enhances cell proliferation in malignancy directly and indirectly by affecting tumor cells and modulating angiogenesis. Cancer development may be influenced by the balance between the ACE/Ang II/AT1R and the ACE2/Ang 1–7/Mas receptor pathways. The interactions between Ang II/AT1R and Ang I/AT2R as well as Ang1-7/Mas and alamandine/MrgD receptors in the RAAS pathway can significantly impact the development of cancer. Ang I/AT2R, Ang1-7/Mas, and alamandine/MrgD interactions can have anticancer effects while Ang II/AT1R interactions can be involved in the development of cancer. Evidence suggests that inhibitors of the RAAS, which are conventionally used to treat cardiovascular diseases, may be beneficial in cancer therapies. Herein, we aim to provide a thorough description of the elements of RAAS and their molecular play in cancer. Alongside this, the role of RAAS components in sex-dependent cancers as well as GI cancers will be discussed with the hope of enlightening new venues for adjuvant cancer treatment. Graphical abstract

Effect of extensive artery isolation during robotic-assisted partial nephrectomy on blood pressure of patients with poorly controlled hypertension: a preliminary study

Article

Full-text available

Oct 2022
INT UROL NEPHROL

Purpose To investigate whether extensive renal artery isolation during robotic-assisted partial nephrectomy (RAPN) for renal cell carcinoma (RCC) affects blood pressure (BP) of patients with poorly controlled hypertension. Methods We included 60 patients diagnosed with poorly controlled hypertension who underwent RAPN by an experienced surgeon. The renal artery of the treated kidney was sufficiently isolated. Systolic BP (SBP), diastolic BP (DBP) and antihypertensive medication information were obtained at baseline and 3- and 6-month follow-up after surgery. Primary endpoints were changes in BP, and medications. Predictors of SBP reduction at 3 months were assessed by multivariable logistic regression. Results All 60 RAPN procedures were successful, with no major intra- or postoperative complications. Mean SBP and DBP decreased significantly at 3 months after surgery (SBP, −7.8 ± 6.3 mmHg, P < 0.001; DBP, −4.2 ± 6.4 mmHg, P = 0.01). SBP and DBP did not differ between 3- and 6-month follow-up. The mean number of BP medications prescribed was lower at 3 months than baseline (1.7 ± 1.0 vs 2.1 ± 1.0, P = 0.016). The only significant predictor of SBP reduction at 3 months was baseline SBP. Conclusions Renal denervation with extensive renal artery isolation during RAPN may improve BP control among patients with poorly controlled hypertension in short term.

Salvianolic acid B, a new type I IRE1 kinase inhibitor, abrogates AngII‐induced angiogenesis by interacting with IRE1 in its active conformation

Article

Sep 2022

Angiotensin II (AngII)‐mediated pathological angiogenesis is one of the important factors promoting the progression of atherosclerosis, tumour metastasis, and diabetic retinopathy. Here, we first demonstrated that salvianolic acid B (Sal B) attenuated AngII‐induced angiogenesis by downregulating the IRE1/ASK1/JNK/p38MAPK signalling pathway and protected vascular endothelial cells from hypoxia‐induced damage. These pharmacological consequences could be ascribed to the unique interactions between Sal B and the ATP‐binding cavity of IREIα, leading to bi‐directional roles of IRE1 kinase and endonuclease activity; this may possibly be one of the essential mechanisms of the bi‐directional regulation of angiogenesis in different conditions. Moreover, our results indicated that IRE1 was a novel anti‐angiogenesis target and type I IRE1 kinase inhibitor (e.g., Sal B, APY29) and might be a potentially eligible low‐toxicity drug for treating AngII‐mediated pathological angiogenesis.

Effect of angiotensin II pathway inhibitors on post-surgical adhesion band formation: a potential repurposing of old drugs

Article

Aug 2022
INJURY

Background : In this study we investigated the therapeutic potential of angiotensin II pathway inhibitors in attenuating post-surgical adhesion band formation in tendon injury. Method : We assigned 30 Wistar albino rats to 5 groups, including negative control, positive control, sham, Telmisartan- and Enalapril-treated groups (n=6). Telmisartan and Enalapril at a dose of 10 mg/kg were administered intraperitoneally for 21 days. Hematoxylin-Eosin, and Masson's trichrome staining were used to measure the inflammatory cell accumulation and collagen deposition in the Achilles tendon tissue sections. Oxidative stress markers were analyzed in tissue samples by spectrophotometric methods. Properties of Achilles tendon adhesions were compared based on Tang and Ishiyama scoring systems in the presence and absence of angiotensin II pathway inhibitors. Results : Telmisartan and Enalapril reduced severity, length, and density of surgical-induced tendon adhesion at site of injury (***p < 0.001). Our results showed that administration of angiotensin II pathway inhibitors decreased infiltration of inflammatory cells to the injured area (*p < 0.05) and suppressed inflammation by regulating oxidative stress markers including MDA (***p < 0.001), total thiol (***p < 0.001), CAT (***p < 0.001), and SOD (***p < 0.001), in post-operative Achilles tendon tissues. Significant lower collagen deposition and formation of fibrotic tissues was seen in Telmisartan- and Enalapril-treated groups as detected by Masson's trichrome staining which correlated with a decrease in quantity (**p < 0.01) and grading of fibrosis score (***p < 0.001), in adhesive tissues. Moreover, inhibition of angiotensin II pathway could also ameliorate mechanical properties including ultimate load (***p < 0.001), and ultimate stress (*p < 0.05) in injured Tendons. Conclusion : Our results showed that ssuppression of inflammation and fibrosis are two mechanisms by which Telmisartan and Enalapril elicit potent protective responses post Achilles tendon injuries.

Angiotensin-converting Enzyme Inhibitors and Angiotensin Receptor Blockers as Potential Therapeutic Options for Pancreatic Cancer

Article

May 2022

The renin–angiotensin system (RAS) has been reported to have a role in carcinogenesis, and therefore it may be of value as a potential therapeutic target in inhibiting tumor growth. It has been shown that inhibition of RAS via angiotensin I-converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor (ARBs) inhibitors may have a protective effect against several malignancies. Here we provide an overview on the potential value of RAS pathway and targeting via ACE/ARB inhibitors in pancreatic cancer. Whilst the potential role of RAS as a target for the treatment of pancreatic cancer has been reported, the use of candesartan with gemcitabine failed to improve outcomes in pancreatic cancer. Another study of 1–3 years using ARB was found to reduce the risk of pancreatic cancer. In line with these trials, there have been others demonstrating that the ARBs in combination with gemcitabine might improve clinical outcomes in patients with advanced pancreatic cancer. Prospective trials are warranted to investigate this hypothesis.

Survival impact of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists in head and neck cancer

Article

Jul 2021
HEAD NECK-J SCI SPEC

Background: Preclinical evidence suggests a link between the renin-angiotensin system and oncogenesis. We aimed to explore the impact of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) in head and neck cancer (HNC). Methods: Over 5000 patients were identified from the Surveillance, Epidemiology, and End Results-Medicare linked dataset and categorized according to ACEi and ARB and diagnoses of chronic kidney disease (CKD) or hypertension (HTN). Overall survival (OS) and cancer-specific survival (CSS) were compared using Cox multivariable regression (MVA), expressed as hazard ratios (HR) with 95% confidence intervals (95%CI). Results: No significant MVA associations for OS or CSS were found for ACEi. Compared to patients with CKD/HTN taking ARB, those with CKD/HTN not taking ARB experienced worse OS (HR 1.28, 95%CI 1.09-1.51, p = 0.003) and CSS (HR 1.23, 95%CI 1.00-1.50, p = 0.050). Conclusions: ARB usage is associated with improved OS and CSS among HNC patients with CKD or HTN.

Interação entre SARS-COV-2 e o sistema Renina Angiotensina

Article

Full-text available

Jan 2021

Inhibition of Angiotensin II Type I Pathway Reduced Tumor Growth and Ameliorates Fibrosis/inflammation Associated with Colorectal Cancer

Preprint

Full-text available

Jul 2020

Dysregulation of the angiotensin-II Type-I receptor (AT1R) and its pathway was reported to associate with poor-prognosis in several malignancies, including colorectal-cancer (CRC). We have explored the therapeutic-potential of targeting AT1R using valsartan, and its pharmacological-interaction with Fluorouracil (5-FU) in CRC. Anti-proliferative function was evaluated in 2-/3-dimensional cells and in vivo models. Anti-proliferative, anti-migratory, apoptotic function and effect on cell-cycle was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), wound-healing test, and Fluorescence-activated cell sorting (FACS), respectively, while gene-expression was determined at mRNA/protein levels. By histogical analysis and measuring of oxidative/antioxidant markers, we evaluated the anti-inflammatory properties of valsartan. Valsartan suppressed cell-growth and impacted the anti-tumor-activities of 5-FU by apoptosis-induction. Valsartan inhibited the cells migration by perturbation of Matrix metalloproteinase (MMP1). Furthermore, valsartan inhibited tumor-growth and metastasis, and this was more notable in valsartan/5-FU combination-treated-group. The mechanism was plausible to be via the induction of Reactive-oxygen-species (ROS) and down-regulation of Superoxide-dismutase (SOD), thiol/catalase (CAT) as well as Vascular endothelial growth factor (VEGF) and Transforming growth factor beta (TGF-β). Valsartan may protect cells against intestinal fibrosis by modulation of pro-fibrotic and pro-inflammatory components include fibronectin, Interleukin) IL-1β (, Tumor necrosis factor alpha) TNF-α (, Interferon gamma) INF-γ (, and Monocyte Chemotactic Protein 1 (MCP-1). Our findings demonstrated that targeting the AT1R receptor may inhibit tumor-growth and ameliorate fibrosis and inflammation associated with CRC via modulation of AT1 and TGF-β pathways.

Heart failure as interstitial cancer: emergence of a malignant fibroblast phenotype

Article

Nov 2019

A prolonged state of left ventricular pressure overload, commonly caused by hypertension and aortic valve disease, promotes remodelling of the myocardium that can progress to heart failure with preserved ejection fraction (HFpEF). In animal models, a major factor driving progression from pressure-overload hypertrophy (POH) to HFpEF is the activation and proliferation of an abnormal fibroblast phenotype that is resistant to apoptosis, degrades normal stromal matrix and is replaced with a fibrotic matrix structure. A similar fibroblast phenotype has been identified in the stroma of solid cancers. This cancer-associated fibroblast drives tumour growth and invasion. The proliferation and expansion of these abnormal fibroblast populations in both HFpEF and cancer contribute to progression of disease. In early-phase clinical trials, chemotherapeutic agents targeting cancer-associated fibroblasts had antitumour properties. In this Perspectives article, we postulate that, because the abnormal fibroblast populations in POH and cancer have identical characteristics, chemotherapeutic agents targeting the POH-related fibroblast might attenuate the development of myocardial fibrosis, a pathophysiological hallmark of HFpEF. These agents must be designed to target the abnormal fibroblasts with high specificity because many classes of chemotherapeutic drugs can themselves cause myocardial dysfunction and heart failure. In this Perspectives article, Oatmen and colleagues propose that, because abnormal fibroblast populations present in pressure-overload hypertrophy and cancer have similar molecular features, chemotherapeutic agents might be effective in preventing the progression of pressure-overload hypertrophy to heart failure with preserved ejection fraction.

Therapeutic Targeting of Cancer Stem Cells in Human Glioblastoma by Manipulating the Renin-angiotensin System

Preprint

Full-text available

Sep 2019

Patients with glioblastoma (GB), a highly aggressive brain tumor, have a median survival of 14.6 months following neurosurgical resection with adjuvant chemoradiotherapy. Quiescent GB cancer stem cells (CSCs) invariably cause local recurrence. These GB CSCs that can be identified by embryonic stem cell markers express components of the renin-angiotensin system and are associated with circulating CSCs. Despite the presence of circulating CSCs, GB rarely develops distant metastasis outside the central nervous system. This paper reviews the current literature on GB growth inhibition in relation to CSCs, circulating CSCs, the RAS and the novel therapeutic approach by repurposing drugs that target the renin-angiotensin system to improve overall symptom-free survival and maintain quality of life.

Therapeutic Targeting of Cancer Stem Cells via Modulation of the Renin-Angiotensin System

Article

Full-text available

Aug 2019

Cancer stem cells (CSCs) are proposed to be the cells that initiate tumorigenesis and maintain tumor development due to their self-renewal and multipotency properties. CSCs have been identified in many cancer types and are thought to be responsible for treatment resistance, metastasis, and recurrence. As such, targeting CSCs specifically should result in durable cancer treatment. One potential option for targeting CSCs is by manipulation of the renin-angiotensin system (RAS) and pathways that converge on the RAS with numerous inexpensive medications currently in common clinical use. In addition to its crucial role in cardiovascular and body fluid homeostasis, the RAS is vital for stem cell maintenance and differentiation and plays a role in tumorigenesis and cancer prevention, suggesting that these roles may converge and result in modulation of CSC function by the RAS. In support of this, components of the RAS have been shown to be expressed in many cancer types and have been more recently localized to the CSCs in some tumors. Given these roles of the RAS in tumor development, clinical trials using RAS inhibitors either singly or in combination with other therapies are underway in different cancer types. This review outlines the roles of the RAS, with respect to CSCs, and suggests that the presence of components of the RAS in CSCs could offer an avenue for therapeutic targeting using RAS modulators. Due to the nature of the RAS and its crosstalk with numerous other signaling pathways, a systems approach using traditional RAS inhibitors in combination with inhibitors of bypass loops of the RAS and other signaling pathways that converge on the RAS may offer a novel therapeutic approach to cancer treatment.

Antihypertensive therapy with angiotensin II receptor blockers and risk of cancer

Article

Oct 2012

Elena Baranova

The article reviews available up-to-date knowledge from randomized trials, observational trials and metaanalyses about the problem of risk of cancer as a possible complication of angiotensin II receptor blockers therapy.

The Renin-Angiotensin System in the Breast

Chapter

Mar 2007

The relationship between the endocrine system and cancer, it can be fairly said, was first identified in the breast, and has since been most extensively studied in this tissue. The early demonstration that breast cancer cell growth was regulated by oestrogen, and proof of the beneficial effects of surgical removal of the sources of oestrogen, led to the development of anti-oestrogen drugs, exemplified by tamoxifen, and more recently, the aromatase inhibitors, that have been remarkably successful (Barnes et al 2004; Howell et al 2004; Jones et al 2004). It is this success, perhaps, that has overshadowed the substantial (and long established) evidence that regulation of breast tissue, and particularly breast epithelial tissue growth and function, is multifactorial, and many hormones and growth factors areinvolved(Haagensen1986;Dicksonet al1992;Hansenet al2000;Tucker2000; Pollard 2001; Goffin et al 2002; Singer et al 2003; Lamote et al 2004; Nicolini et al 2006; see also Wysolmerski and van Houten, 2002). This particularly comes to the fore when tumours that are non-responsive to tamoxifen, or do not contain oestrogen receptors, are studied. In these, growth factors and their receptors have been targeted for drug development, and this in turn reflects the fairly long-held recognition that several of the proto-oncogenes have functions connected with the growth factors, their receptors, or the intracellular signalling mechanisms that they activate (Ross et al 2004; Bianco et al 2005; Hynes et al 2005; Pal et al 2005; Zhang et al 2005). Yet there remain still further possibilities.

Synergistic suppression of tumor angiogenesis by co-delivering of VEGF targeted siRNA and candesartan mediated by functionalized carbon nanovectors

Article

Jun 2017

Single-walled carbon nanotubes (SWNTs) with unique physicochemical properties have exhibited promising biomedical applications as drug/gene carrier. In this study, polyethyleneimine (PEI) modified SWNT conjugates linked with candesartan (CD) were developed to deliver vascular endothelial growth factor (VEGF) targeted siRNA (siVEGF) for synergistic and targeted treatment of tumor angiogenesis. The characterization results revealed that SWNT-PEI-CD conjugates were successfully synthesized, and exhibited desirable dispersibility and superior stability. Confocal laser scanning microscopy (CLSM) and Flow cytometry (FCM) results showed that SWNT-PEI-CD/siVEGF complexes could achieve high cell uptake and speciﬁc intracellular distribution of siRNA in AT1R overexpressed PANC-1 cells. Strong downregulation of VEGF was also verified by qRT-PCR, ELISA and Western blot in complexes treated PANC-1 cells. In vitro angiogenesis assay showed that SWNT-PEI-CD/siVEGF complexes highly inhibited tube formation of HUVECs. Furthermore, in vivo observation in PANC-1 xenografted nude mice demonstrated that SWNT-PEI-CD/siVEGF complexes exhibited significant distribution at tumor site and caused obvious inhibition of tumor growth and tumor associated angiogenesis repression induced by drug combo of CD and siVEGF. Finally, WST-1 assay indicated that SWNT-PEI-CD possessed low cytotoxicity and hemolysis test showed good biocompatibility of SWNT-PEI-CD. And hematological and histological analyses confirmed that SWNT-PEI-CD/siVEGF complexes did not cause any obvious toxic effects to blood and major organs. These findings suggested that the SWNT-PEI-CD/siVEGF co-delivery system with tumor targeting specificity, improved endosomal escaping property and collaboration of angiogenesis inhibition could be a prospective method for efficient tumor anti-angiogenic therapy.

Significance of a gallbladder wall blood flow analysis by Doppler ultrasonography in the diagnosis of gallbladder cancer

Article

Jun 2009

We reviewed the maximal blood flow velocity (Vmax) in the gallbladder wall (cystic artery) using Doppler ultrasonography in 46 patients (cancer N=14, benign N=32). The Vmax of cancer (45.0±13.2 cm/s) was significantly higher than that observed for chronic cholecystitis, polyps or ADM (adenomyomatosis) (p<0.01). An ROC analysis showed a Vmax cut-off value of 35.2 cm/s, while the sensitivity was 85.7% and the specificity was 88.2%. The histological findings clarified the fibrous hyperplastic change in the intraarterial membrane of the basal area lying under the cancer nest. This alteration was not found in the non-cancer areas, polyps or ADM. These results suggested that stenotic change of the artery may cause an increase in the blood flow velocity. In conclusion, a blood flow analysis makes it possible to directly evaluate cancerous changes in the preoperative examination.

Evaluation of beta-blockers and survival among hypertensive patients with renal cell carcinoma

Article

Sep 2016

Objectives: Beta-blocker use is associated with improved survival for multiple nonurologic malignancies. Our objective was to evaluate the association between beta-blocker use and survival among surgically managed hypertensive patients with clear-cell renal cell carcinoma (ccRCC). Methods: Hypertensive patients with ccRCC treated with either radical or partial nephrectomy between 2000 and 2010 were identified from our Nephrectomy Registry. Beta-blocker use within 90 days before surgery was identified. The associations between beta-blocker use and risk of disease progression, death from renal cell carcinoma (RCC), and all-cause mortality were assessed using Cox proportional hazards regression models. Results: In total, 913 hypertensive patients were identified who underwent either partial or radical nephrectomy for ccRCC. Of these, 104 (11%) had documented beta-blocker use within 90 days before surgery. At last follow-up (median 8.2y among survivors), 258 patients showed progression (median 1.6y following surgery), and 369 patients had died (median 4.1y following surgery), including 138 who died of RCC. After adjusting for PROG (progression-free survival) and SSIGN (cancer-specific survival) scores, beta-blocker use was not significantly associated with the risk of disease progression (hazard ratio [HR] = 0.94; 95% CI: 0.61-1.47; P = 0.80) or the risk of death from RCC (HR = 0.74; 95% CI: 0.38-1.41; P = 0.35). Similarly, on multivariable analysis adjusting for clinicopathologic features, there was not a significant association between beta-blocker use and the risk of all-cause mortality (HR = 0.83; 95% CI: 0.59-1.16; P = 0.27). Conclusions: Beta-blocker use for hypertension within 90 days before surgery was not associated with the risk of progression, death from RCC, or death from any cause.

The effect of angiotensin system inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) on cancer recurrence and survival: a meta-analysis

Article

May 2016

To assess the current evidence on the potential benefit of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) on cancer recurrence and survival, we comprehensively searched PubMed, Embase, and the Cochrane Library from their inception to April 2013. Two authors screened out duplicates and independently reviewed the eligibility of each study. We included comparative studies comparing the use and nonuse of ACEIs or ARBs in cancer patients. Primary outcomes were disease-free survival (DFS) and overall survival. We included 11 studies with 4964 participants in the final analysis. The meta-analysis showed that the use of ACEIs or ARBs resulted in a significant improvement in DFS [hazard ratio (HR) 0.60; 95% confidence interval (CI) 0.41-0.87; P=0.007)] and overall survival (HR 0.75; 95% CI 0.57-0.99; P=0.04). Even when cancer stage was classified into low (I/II) or high (III/IV), DFS improvement was applied to both low stage (HR 0.56; 95% CI 0.32-0.96; P=0.04) and high stage (HR 0.59; 95% CI 0.37-0.94; P=0.03). Analysis according to cancer type showed benefits in urinary tract cancer (HR 0.22), colorectal cancer (HR 0.22), pancreatic cancer (HR 0.58), and prostate cancer (HR 0.14), but not in breast cancer and hepatocellular cancer. This meta-analysis provides evidence that the use of ACEIs or ARBs in cancer patients can lead to a 40 and 25% reduction in the risk of cancer recurrence and mortality.

Anticorps anti-VEGF: un emploi universel

Chapter

Jan 2008

Les très nombreux travaux menés depuis les années soixante sur le rôle de ľangiogenèse dans les cancers ont permis ďaboutir à des traitements ciblant ce processus physiopathologique (1, 2).

Evidence for the importance of angiotensin II type 1 receptor in ischemia-induced angiogenesis

Article

Full-text available

Mar 2002
J CLIN INVEST

The role of the renin-angiotensin system (RAS) in angiogenesis is little known. Here, we show that the angiotensin II (ATII) type 1 (AT1) receptor plays an important role in ischemia-induced angiogenesis. Well-developed collateral vessels and angiogenesis were observed in wild-type (WT) mice in response to hindlimb ischemia, whereas these responses were reduced in ATII type 1a receptor knockout (AT1a -/-) mice. Ischemia-induced angiogenesis was also impaired in WT mice treated with the AT1 receptor blocker TCV-116. These effects were not due to reduced systemic blood pressure (SBP), because hydralazine treatment preserved angiogenesis in WT mice although it reduced SBP to a level similar to that of AT1a -/- mice. Infiltration of inflammatory mononuclear cells (MNCs), including macrophages and T lymphocytes, was suppressed in the ischemic tissues of AT1a -/- mice compared with WT mice. Double immunofluorescence staining revealed that infiltrated macrophages and T lymphocytes expressed VEGF, and the expression of VEGF and monocyte chemoattractant protein-1 was also decreased in AT1a -/-. Finally, the impaired angiogenesis in AT1a -/- mice was rescued by intramuscular transplantation of MNCs obtained from WT mice, further indicating the importance of MNC infiltration in ischemia-induced angiogenesis. Thus, the ATII-AT1 receptor pathway promotes early angiogenesis by supporting inflammatory cell infiltration and angiogenic cytokine expression.

Influence of angiotensin system on endothelial and smooth muscle cell migration

Article

Full-text available

Aug 1990

The blood vessel wall's response to injury is an important determinant of luminal size and vessel function. The physiologic migration of endothelial cells from the edges of a wound and the pathophysiologic migration of medial smooth muscle cells into the intima are two important components of the vessel wall's response to injury. The influence of the angiotensin system on endothelial and smooth muscle cell migration have not been examined. In the present study, the influence of angiotensin system components on bovine aortic endothelial cell (BAEC) and bovine aortic smooth muscle cell (BASMC) migration after release of cultured cell monolayers from contact inhibition was determined. The angiotensin-converting enzyme (ACE) inhibitor lisinopril increased BAEC migration 41% +/- 3% (P less than 0.001), as did the specific angiotensin II antagonist sar1, ile8-angiotensin II (SAR) (41% +/- 3% (P less than 0.001). Exogenous angiotensin I and angiotensin II did not affect BAEC migration. Exogenous angiotensin II abolished the effect of lisinopril on BAEC migration. Lisinopril increased cell-associated u-plasminogen activator (u-PA) 23% +/- 3% (P less than 0.001) in migrating BAEC and angiotensin II abolished this increase. SAR increased u-PA 33% +/- 0% (P less than 0.001). In contrast, these agents had the opposite effect on smooth muscle cells. Angiotensin II increased smooth muscle cell migration 40% +/- 3% (P less than 0.001), and this effect was abolished by SAR. Angiotensin II also increased cell-associated u-PA 83% +/- 7% (P less than 0.001) in migrating BASMC. The increase in BAEC migration with inhibition of endothelial cell angiotensin II stimulation, either with lisinopril or SAR, also was associated with an increase in cell-associated u-PA. These results indicate that lisinopril interrupts an autocrine pathway in endothelial cells, in which endothelial cell-derived angiotensin I is converted to angiotensin II by ACE, and imply that angiotensin-converting enzyme inhibitors in vivo would act to reduce vessel wall injury by directly increasing the rate of endothelial cell wound closure; by increasing the antithrombotic tendency of the endothelium via enhanced u-PA; and indirectly, by decreasing production of angiotensin II and thereby the rate of smooth muscle cell migration into the intima.

Single-Step Method Of RNA Isolation By Acid Guanidinium Thiocyanate-Phenol-Chlorform Extraction

Article

Full-text available

May 1987

A new method of total RNA isolation by a single extraction with an acid guanidinium thiocyanate-phenol-chloroform mixture is described. The method provides a pure preparation of undegraded RNA in high yield and can be completed within 4 h. It is particularly useful for processing large numbers of samples and for isolation of RNA from minute quantities of cells or tissue samples.

Angiotensin II Type 1a Receptor-deficient Mice with Hypotension and Hyperreninemia

Article

Full-text available

Sep 1995

Angiotensin (AT) II, the bioactive octapeptide in the renin-angiotensin system that plays a key role in cardiovascular homeostasis, exerts its multiple effects through the different types of AT receptors, AT1a, AT1b, and AT2. Previously, we showed chronic hypotension in angiotensinogen (the precursor of AT)-deficient mice and a dramatic increase in renin mRNA levels in its kidney, but it remains unclear which types of AT receptors regulate the blood pressure and renin gene expression. In order to elucidate the physiological roles of AT1a receptor, we generated mutant mice with a targeted replacement of the AT1a receptor loci by the lacZ gene. In the heterozygous mutant mice, the strong lacZ staining was found in the glomerulus and juxtaglomerular apparatus of the renal cortex, which coincided with that of the signals detected by in situ hybridization. Chronic hypotension was observed in the heterozygous and homozygous mutant mice, with 10 and 22 mm Hg lower systolic blood pressure, respectively, than that of wild-type littermates. Both the levels of renin mRNA in the kidney and plasma renin activity were markedly increased only in the homozygous mutant mice. These results demonstrated that an AT1a-mediated signal transduction pathway is, at least in part, involved in the regulation of blood pressure and renin gene expression.

The mouse gene for vascular endothelial growth factor. Genomic structure, definition of the transcriptional unit, and characterization of transcriptional and post-transcriptional regulatory sequences

Article

Full-text available

Mar 1996

We describe the genomic organization and functional characterization of the mouse gene encoding vascular endothelial growth factor (VEGF), a polypeptide implicated in embryonic vascular development and postnatal angiogenesis. The coding region for mouse VEGF is interrupted by seven introns and encompasses approximately 14 kilobases. Organization of exons suggests that, similar to the human VEGF gene, alternative splicing generates the 120-, 164-, and 188-amino acid isoforms, but does not predict a fourth VEGF isoform corresponding to human VEGF. Approximately 1.2 kilobases of 5′-flanking region have been sequenced, and primer extension analysis identified a single major transcription initiation site, notably lacking TATA or CCAT consensus sequences. The 5′-flanking region is sufficient to promote a 7-fold induction of basal transcription. The genomic region encoding the 3′-untranslated region was determined by Northern and nuclease mapping analysis. Investigation of mRNA sequences responsible for the rapid turnover of VEGF mRNA (mRNA half-life, <1 h) (Shima, D. T., Deutsch, U., and D'Amore, P. A.(1995) FEBS Lett. 370, 203-208) revealed that the 3′-untranslated region was sufficient to trigger the rapid turnover of a normally long-lived reporter mRNA in vitro. These data and reagents will allow the molecular and genetic analysis of mechanisms that control the developmental and pathological expression of VEGF.

Chymase as a proangiogenic factor. A possible involvement of chymase-angiotensin-dependent pathway in the hamster sponge angiogenesis model

Article

Full-text available

Mar 2000

We investigated the profound involvement of chymase, an alternative angiotensin II-generating enzyme, in angiogenesis using a hamster sponge implant model. In vivo transfection of human pro-chymase cDNA or a direct injection of purified chymase into the sponges implanted resulted in marked increment of hemoglobin contents in the sponge granuloma tissues, demonstrating that chymase has an ability to elicit angiogenesis and is a potent angiogenic factor. Daily injection of basic fibroblast growth factor into the sponges implanted also induced angiogenesis, which was suppressed by the treatment with chymostatin, an inhibitor of chymase, or TCV-116, an antagonist of angiotensin II (Ang II) type 1 receptor. Expression of chymase mRNA and production of Ang II in the granuloma tissues were enhanced by the stimulation with basic fibroblast growth factor. Chymase activity in the sponge granulomas increased in parallel with the rise in hemoglobin contents, and mast cells observed in the granuloma tissues were positively stained with anti-chymase antibody. Exogenous administration not only of Ang II but of angiotensin I (Ang I) directly into the sponges could enhance angiogenesis. Chymostatin inhibited the angiogenesis induced by Ang I but not Ang II, suggesting the presence of a chymase-like Ang II-generating activity in the sponge granulomas. Our results may suggest a potential ability of chymase to promote angiogenesis through the local chymase-dependent and angiotensin-converting enzyme-dependent Ang II generating system in pathophysiological angiogenesis.

Host cyclooxygenase-2 modulates carcinoma growth

Article

Full-text available

Jul 2000

Cyclooxygenase-2 (COX-2; Ptgs2) acts as a tumor promoter in rodent models for colorectal cancer, but its precise role in carcinogenesis remains unclear. We evaluated the contribution of host-derived COX-1 and COX-2 in tumor growth using both genetic and pharmacological approaches. Lewis lung carcinoma (LLC) cells grow rapidly as solid tumors when implanted in C57BL/6 mice. We found that tumor growth was markedly attenuated in COX-2(-/-), but not COX-1(-/-) or wild-type mice. Treatment of wild-type C57BL/6 mice bearing LLC tumors with a selective COX-2 inhibitor also reduced tumor growth. A decrease in vascular density was observed in tumors grown in COX-2(-/-) mice when compared with those in wild-type mice. Because COX-2 is expressed in stromal fibroblasts of human and rodent colorectal carcinomas, we evaluated COX-2(-/-) mouse fibroblasts and found a 94% reduction in their ability to produce the proangiogenic factor, VEGF. Additionally, treatment of wild-type mouse fibroblasts with a selective COX-2 inhibitor reduced VEGF production by 92%.

The Angiotensin-I-converting Enzyme Inhibitor Perindopril Suppresses Tumor Growth and Angiogenesis: Possible Role of the Vascular Endothelial Growth Factor

Article

Full-text available

May 2001

Angiotensin-I converting enzyme (ACE) inhibitor is used widely as an antihypertensive agent, and it has been suggested recently that it decreases the risk of cancer (A. F. Lever et al., Lancet, 352: 179-184, 1998). In this study, we examined the effect of several ACE inhibitors and angiotensin-II type 1 receptor (AT(1)-R) antagonists on tumor development and angiogenesis in a murine hepatocellular carcinoma model. Among ACE inhibitors, perindopril appeared to be a potent inhibitor of tumor development and angiogenesis, whereas AT(1)-R antagonists did not exert such an inhibitory effect. The inhibitory effect of perindopril was achieved even on established tumors. The level of the potent angiogenic factor, vascular endothelial growth factor (VEGF), in the tumor was significantly suppressed by perindopril. In vitro studies showed that perindopril-derived active form, perindoprilat, suppressed the endothelial cell tubule formation. Perindoprilat treatment also significantly inhibited VEGF mRNA expression in BNL-HCC cells in vitro. These results showed that the ACE inhibitor perindopril inhibited tumor development and angiogenesis independent from AT(1)-R blockage, and that VEGF alternation may be involved in the mechanism of this inhibitory effect. Because perindopril is widely used in clinical practice, it may represent an effective new strategy for anticancer therapy.

Evidence for the importance of angiotensin II type 1 receptor in ischemia-induced angiogenesis

Article

Full-text available

Apr 2002

The role of the renin-angiotensin system (RAS) in angiogenesis is little known. Here, we show that the angiotensin II (ATII) type 1 (AT1) receptor plays an important role in ischemia-induced angiogenesis. Well-developed collateral vessels and angiogenesis were observed in wild-type (WT) mice in response to hindlimb ischemia, whereas these responses were reduced in ATII type 1a receptor knockout (AT1a(-/-)) mice. Ischemia-induced angiogenesis was also impaired in WT mice treated with the AT1 receptor blocker TCV-116. These effects were not due to reduced systemic blood pressure (SBP), because hydralazine treatment preserved angiogenesis in WT mice although it reduced SBP to a level similar to that of AT1a(-/-) mice. Infiltration of inflammatory mononuclear cells (MNCs), including macrophages and T lymphocytes, was suppressed in the ischemic tissues of AT1a(-/-) mice compared with WT mice. Double immunofluorescence staining revealed that infiltrated macrophages and T lymphocytes expressed VEGF, and the expression of VEGF and monocyte chemoattractant protein-1 was also decreased in AT1a(-/-). Finally, the impaired angiogenesis in AT1a(-/-) mice was rescued by intramuscular transplantation of MNCs obtained from WT mice, further indicating the importance of MNC infiltration in ischemia-induced angiogenesis. Thus, the ATII--AT1 receptor pathway promotes early angiogenesis by supporting inflammatory cell infiltration and angiogenic cytokine expression.

Adenylate Cyclase/Protein Kinase A Signaling Pathway Enhances Angiogenesis Through Induction of Vascular Endothelial Growth Factor In Vivo

Article

Full-text available

Dec 2001

We previously reported that endogenous prostaglandins (PGs) may increase cAMP facilitated angiogenesis through the induction of vascular endothelial growth factor (VEGF) in rat sponge implantation models. In the present experiment, we tested whether or not adenylate cyclase / protein kinase A (AC/PKA)-dependent VEGF induction enhanced angiogenesis in this model. Topical daily injections of 8-bromo-cAMP enhanced angiogenesis in a dose-dependent manner. Forskolin, an activator of AC, also facilitated angiogenesis as did amrinone, an inhibitor of phosphodiesterase. VEGF induction was confirmed by the increased levels in the fluids in the sponge matrix after topical injection of 8-bromo-cAMP. Immunohistochemical investigation further revealed the VEGF-expressed cells in the sponge granulation tissues to be fibroblasts, and the intensity of positive reactions was enhanced by 8-bromo-cAMP, forskolin and amrinone. Angiogenesis without topical injections of the above compounds was suppressed by SQ22,536, an inhibitor for AC, or H-89, an inhibitor for PKA, with concomitant reductions in VEGF levels. Daily topical injections of neutralizing antibody or anti-sense oligonucleotide against VEGF significantly suppressed angiogenesis. PGE2-induced angiogenesis was suppressed with SQ22,536 or H-89. These results suggested that AC/PKA-dependent induction of VEGF certainly enhanced angiogenesis and that pharmacological tools for controlling this signaling pathway may be able to facilitate the management of conditions involving angiogenesis.

Angiotensin II Angiogenic Effect In Vivo Involves Vascular Endothelial Growth Factor- and Inflammation-Related Pathways

Article

Full-text available

Jun 2002

Although accumulating lines of evidence indicate the proangiogenic role of angiotensin II (Ang II), little is known about the molecular mechanisms associated with such an effect. This study aimed to identify molecular events involved in Ang II-induced angiogenesis in the Matrigel model in mice. C57Bl/6 female mice received a subcutaneous injection of either Matrigel or Matrigel with Ang II (10(-7) M) alone, with Ang II and an AT1 receptor antagonist (candesartan, 10(-6) M), or with Ang II and AT2 receptor antagonist (PD123319, 10(-6) M). After 14 days, angiogenesis was assessed in the Matrigel-plug by histological evaluation and cellular counting. Ang II increased by 1.9-fold the number of cells within the Matrigel (p < 0.01 versus control). Immunohistological analysis revealed the presence of macrophages, endothelial and smooth muscle cells, and the development of vascular-like structure. Such an angiogenic effect was associated with an increase in vascular endothelial growth factor (VEGF) (1.5-fold, p < 0.01), endothelial nitric oxide (eNOS) (1.7-fold, p < 0.01), and cyclooxygenase-2 (1.4-fold, p < 0.05) protein levels measured by Western blotting. Conversely, Ang II treatment did not affect MMP-9 and MMP-2 activity, assessed by zymography. Blockade of AT1 receptor completely prevented the Ang II-induced angiogenesis and protein regulations, whereas that of AT2 was ineffective. Administration of VEGF neutralizing antibody (2.5 microg ip twice a week) and cyclooxygenase-2 selective inhibitor (nimesulide, 30 mg/L) also hampered Ang II proangiogenic effect. In addition, Ang II-induced cell ingrowth was impaired by treatment with nitric oxide synthase inhibitor (L-NAME, 10 mg/kg/day) and in eNOS-deficient mice. Therefore, in an in vivo model, Ang II induced angiogenesis through AT1 receptor, which involved activation of VEGF/eNOS-related pathway and of the inflammatory process.

Inflammation and Cancer

Article

Full-text available

Dec 2002

Recent data have expanded the concept that inflammation is a critical component of tumour progression. Many cancers arise from sites of infection, chronic irritation and inflammation. It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration. In addition, tumour cells have co-opted some of the signalling molecules of the innate immune system, such as selectins, chemokines and their receptors for invasion, migration and metastasis. These insights are fostering new anti-inflammatory therapeutic approaches to cancer development.

Host Prostaglandin E2-EP3 Signaling Regulates Tumor-Associated Angiogenesis and Tumor Growth

Article

Full-text available

Feb 2003

Nonsteroidal antiinflammatories are known to suppress incidence and progression of malignancies including colorectal cancers. However, the precise mechanism of this action remains unknown. Using prostaglandin (PG) receptor knockout mice, we have evaluated a role of PGs in tumor-associated angiogenesis and tumor growth, and identified PG receptors involved. Sarcoma-180 cells implanted in wild-type (WT) mice formed a tumor with extensive angiogenesis, which was greatly suppressed by specific inhibitors for cyclooxygenase (COX)-2 but not for COX-1. Angiogenesis in sponge implantation model, which can mimic tumor-stromal angiogenesis, was markedly suppressed in mice lacking EP3 (EP3−/−) with reduced expression of vascular endothelial growth factor (VEGF) around the sponge implants. Further, implanted tumor growth (sarcoma-180, Lewis lung carcinoma) was markedly suppressed in EP3−/−, in which tumor-associated angiogenesis was also reduced. Immunohistochemical analysis revealed that major VEGF-expressing cells in the stroma were CD3/Mac-1 double-negative fibroblasts, and that VEGF-expression in the stroma was markedly reduced in EP3−/−, compared with WT. Application of an EP3 receptor antagonist inhibited tumor growth and angiogenesis in WT, but not in EP3−/−. These results demonstrate significance of host stromal PGE2-EP3 receptor signaling in tumor development and angiogenesis. An EP3 receptor antagonist may be a candidate of chemopreventive agents effective for malignant tumors.

Combination antiangiogenesis therapy with marimastat, captopril and fragmin in patients with advanced cancer

Article

Full-text available

Aug 2004

Marimastat, low molecular weight heparins and captopril have antiangiogenic activity in vitro and in animal models. We studied the safety and efficacy of the combination of these drugs in patients with advanced cancer. In all, 50 patients were enrolled. Captopril was given orally at a dose of 50 mg bd daily. Fragmin was administered as a daily subcutaneous injection of 200 units kg(-1) for the first 28 days and 5000 units thereafter. Marimastat was given at 10 mg bd orally. Serum, plasma and urinary angiogenic factors were measured at baseline and after 1 month of treatment. Inhibition of release of tumour necrosis factor alpha (TNF-alpha) from peripheral lymphocytes was used as a surrogate pharmacodynamic end point. There was one case of haemorrhagic stroke and one upper gastrointestinal haemorrhage. The commonest toxicity was myalgia. One of 10 patients with renal cancer had a partial response, and three patients had a prolonged period of stable disease. The treatment significantly inhibited phytohaemagglutinin (PHA)-stimulated TNF-alpha release from patient's lymphocytes. The combination of marimastat, fragmin and captopril is well tolerated and has in vivo activity. Inhibition of PHA-stimulated TNF-alpha release from lymphocytes is a surrogate pharmacodynamic marker of metalloprotease inhibition.

Enalapril to Prevent Cardiac Function Decline in Long-Term Survivors of Pediatric Cancer Exposed to Anthracyclines

Article

Full-text available

Apr 2004

To determine whether an angiotensin-converting enzyme (ACE) inhibitor, enalapril, prevents cardiac function deterioration (defined using maximal cardiac index [MCI] on exercise testing or increase in left ventricular end-systolic wall stress [LVESWS]) in long-term survivors of pediatric cancer. This was a randomized, double-blind, controlled clinical trial comparing enalapril to placebo in 135 long-term survivors of pediatric cancer who had at least one cardiac abnormality identified at any time after anthracycline exposure. There was no difference in the rate of change in MCI per year between enalapril and placebo groups (0.30 v 0.18 L/min/m(2); P =.55). However, during the first year of treatment, the rate of change in LVESWS was greater in the enalapril group than in the placebo group (-8.59 v 1.85 g/cm(2); P =.033) and this difference was maintained over the study period, resulting in a 9% reduction in estimated LVESWS by year 5 in the enalapril group. Six of seven patients removed from random assignment to treatment because of cardiac deterioration were initially treated with placebo (P =.11), and one has died as a result of heart failure. Side effects from enalapril included dizziness or hypotension (22% v 3% in the placebo group; P =.0003) and fatigue (10% v 0%; P =.013). Enalapril treatment did not influence exercise performance, but did reduce LVESWS in the first year; this reduction was maintained over the study period. Any theoretical benefits of LVESWS reduction in this anthracycline-exposed population must be weighed against potential side effects from ACE inhibitors when making treatment decisions.

Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vi

Article

Jan 1993
NATURE

Angiotensin-ll-lnduced Angiogenesis in Sponge Implants in Mice

Article

Jan 1996
J VASC RES

Stimulators of angiogenesis hold potential in promoting the development of collateral circulation in ischaemic tissue and accelerating wound healing, but promote pathological vasoformation in angiogenesis-dependent diseases (solid tumours, atherosclerosis). The renin-angiotensin system is implicated in both beneficial angiogenesis and pathological vascular growth. We investigated the angiogenic activity of angiotensin II (All) in a sponge implant model in mice; this peptide enhanced angiogenesis, as well as glycosaminoglycan (GAG, chondroitin sulfate proteoglycan) and protein synthesis in sponge matrix in mice in a dose-dependent fashion. Extensive angiogenesis was achieved with All (1 μg), which gave no significant increase in wet weight and protein and only a small effect on GAG. In the implants treated with All (2 μg) no further increase in angiogenesis was observed, whereas a marked effect was shown in wet weight (326 ± 15 vs. 424 ± 27 mg), total protein (18 ± 1 vs. 25 ± 1 μg/ww) and GAG(98 ± 10 vs. 160 ± 13 ng/ww). The local blood flow has been determined by measuring the washout rate of 133Xe injected into the implants, correlated with histological evidence of vessel growth. This model of angiogenesis has allowed sequential studies of fibrovascular tissue infiltration simultaneously with histological and biochemical parameters of angiogenesis.

Upregulation of vascular endothelial growth factor by angiotensin II in rat heart endothelial cells

Article

Feb 1998
Biochim Biophys Acta

Vascular endothelial growth factor (VEGF) is a potent mitogen for endothelial cells and a vascular permeability factor. In this study we found that the addition of angiotensin II (AII) to rat heart endothelial cells induced VEGF mRNA production. VEGF mRNA levels reached a plateau within 2 h after the addition of AII and decreased after 4 h. The induction was superinduced by cycloheximide and blocked by actinomycin D. Losartan, an AT1 receptor antagonist, abolished the induction of VEGF mRNA by AII, whereas PD 123319, an AT2 receptor antagonist, had no effect on VEGF mRNA induction. H7, a protein kinase C inhibitor, blocked the induction. RT-PCR experiments showed two mRNA species (VEGF 120 and VEGF 164) in these cells and both species were stimulated by AII. Transient transfection experiment showed that VEGF promoter activity was increased 2.2-fold upon AII stimulation. Electrophoretic mobility shift assay revealed an enhanced binding of transcription factors AP-1 and NF-kappa B. Immunoblot analysis showed that the amount of secreted VEGF was elevated in the medium 8 h after AII stimulation. Our results demonstrate for the first time that the upregulation of VEGF by AII may play a significant role in AII-induced hyperpermeability.

What Is the Evidence That Tumors Are Angiogenesis Dependent?

Article

Feb 1990

JJ Folkman

Angiotensin II stimulates angiogenesis in the chorio-allantoic membrane of the chick embryo

Article

Apr 1991
EUR J PHARMACOL

Angiotensin II was applied daily in doses of 67 or 670 ng to a section of the chick embryo chorio-allantoic membrane from day 7 to day 14 after fertilization of the eggs. During this one-week period, it caused a significant, dose-dependent increase in the vascular density index. The increase obtained with 670 ng daily was comparable to that after daily administration of 1.7 micrograms adenosine, a known stimulator of angiogenesis. The data suggest a possible role for angiotensin II as a mediator of vascular growth.

Paquet J-L, Baudouin-Legros M, Brunelle G, Meyer PAngiotensin II-induced proliferation of aortic myocytes in spontaneously hypertensive rats. J Hypertens 8: 565-572

Article

Jul 1990

In order to determine whether the morphological modifications observed in arterial media of spontaneously hypertensive rats (SHR) could be induced by an abnormal response of the smooth muscle cells to vasoactive agents, we studied the action of angiotensin (Ang) II on cultured aortic smooth muscle cells from both SHR and Wistar-Kyoto rats (WKY). Under our experimental conditions, Ang II exerts a mitogenic action on SHR cells, whereas its effect is very weak on WKY cells. Phospholipase C activation and c-fos and c-myc proto-oncogene expressions induced by Ang II are considerably enhanced in SHR cells, and these abnormalities may be linked to an increased number of Ang II receptors.

Renin-like activity in ovarian follicular fluid

Article

Sep 1985
FERTIL STERIL

Angiogenesis is a feature of ovarian follicle and corpus luteum development. Ovarian homogenates and follicular fluid (FF) contain factors that stimulate new vessel formation. Because the renin-angiotensin system has been shown to facilitate angiogenesis, renin activity was measured in FF and plasma from 20 normal, ovulatory women who were undergoing in vitro fertilization and were therefore stimulated with human menopausal gonadotropin/human chorionic gonadotropin. Serum estradiol (E2) and FF E2 and progesterone (P) were also determined and correlated with FF and plasma renin activity. FF renin activity was significantly higher than plasma renin activity (55.8 +/- 7.9 versus 3.8 +/- 0.7 ng of angiotensin I/ml/hour, P less than 0.001). Positive correlations were found between FF E2 and renin activity (r = 0.53, P less than 0.05). There was also a correlation between plasma renin activity and serum E2 (r = 0.69, P less than 0.05). No correlation was present between FF P and renin activity. The high renin-like activity present in FF after stimulation with gonadotropins could be involved in the mechanism of angiogenesis and may play an important role in events related to reproductive processes.

Angiotensin II Activates Na/H Exchange and Stimulates Growth in Cultured Vascular Smooth Muscle Cells

Article

Jan 1989
J Hypertens Suppl

Angiotensin II (Ang II) stimulated the growth of cultured vascular smooth muscle cells in a dose-dependent manner; a small but significant increase being seen at 10(-9) mol/l, whereas 10(-5) mol/l produced a 166% increase compared with control cells. Saralasin blocked the Ang II-mediated increase in cell number. Amiloride-sensitive Na+-H+ exchange was characterized (Km = 18 mmol/l, Vmax = 0.27 pH units/30 s) in cell monolayers using the fluorescent probe biscarboxyethylcarboxy fluorescein. Angiotensin II (10(-7) mol/l) produced a small overall net intracellular alkalinization. Raising intracellular pH via Na+-H+ activation might be one of the ways in which Ang II increases cell growth.

Folkman J. Tumor angiogenesis: Therapeutic implications. N Engl J Med 285: 1182-1186

Article

Dec 1971

Judah Folkman

This article has no abstract; the first 100 words appear below. THE growth of solid neoplasms is always accompanied by neovascularization. This new capillary growth is even more vigorous and continuous than a similar outgrowth of capillary sprouts observed in fresh wounds or in inflammation.¹ Many workers have described the association between growing solid malignant tumors and new vessel growth.²³⁴⁵⁶ However, it has not been appreciated until the past few years that the population of tumor cells and the population of capillary endothelial cells within a neoplasm may constitute a highly integrated ecosystem. In this ecosystem the mitotic index of the two cell populations may depend upon each other. Tumor cells . . . Supported by a grant (5 RO1 CA08185–06) from the National Cancer Institute, a grant from the American Cancer Society, National Chapter (IC-28), and gifts from the Merck Company and the Alza Corporation. Source Information From the Department of Surgery, Children's Hospital Medical Center and Harvard Medical School, Boston, Massachusetts 02115.

Kim HJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara NInhibition of vascular endothelial growth factor induced angiogenesis suppresses tumor growth in-vivo. Nature (Lond) 362: 841-844

Article

May 1993

The development of new blood vessels (angiogenesis) is required for many physiological processes including embryogenesis, wound healing and corpus luteum formation. Blood vessel neoformation is also important in the pathogenesis of many disorders, particularly rapid growth and metastasis of solid tumours. There are several potential mediators of tumour angiogenesis, including basic and acidic fibroblast growth factors, tumour necrosis factor-alpha and transforming factors-alpha and -beta. But it is unclear whether any of these agents actually mediates angiogenesis and tumour growth in vivo. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen and an angiogenesis inducer released by a variety of tumour cells and expressed in human tumours in situ. To test whether VEGF may be a tumour angiogenesis factor in vivo, we injected human rhabdomyosarcoma, glioblastoma multiforme or leiomyosarcoma cell lines into nude mice. We report here that treatment with a monoclonal antibody specific for VEGF inhibited the growth of the tumours, but had no effect on the growth rate of the tumour cells in vitro. The density of vessels was decreased in the antibody-treated tumours. These findings demonstrate that inhibition of the action of an angiogenic factor spontaneously produced by tumour cells may suppress tumour growth in vivo.

Patterns and Emerging Mechanisms of the Angiogenic Switch during Tumorigenesis

Article

Sep 1996
CELL

We wish to thank Jeff Arbeit, Karen Smith-McCune, Noel Weidner, Ella Bossy-Wetzel, and Christine Jolicoeur for providing the tissue sections used to prepare Figure 3Figure 3; Noel Bouck, Karen Smith-McCune, David Olson, Dowdy Jackson, and Jeff Arbeit for comments on the manuscript; and Wendy Gee and Terry Schoop of BioMed Arts (San Francisco) for artwork. The work from the authors' laboratories reviewed herein was supported by grants from the National Cancer Institute.

Comparative studies of the angiogenic activity of vasoactive intestinal peptide, endothelins-1 and - 3 and angiotensin II in rat sponge mode

Article

Mar 1996

The angiogenic activity of four vasoactive peptides with a range of vasodilator and vasoconstrictor properties, i.e. vasoactive intestinal peptide (VIP), endothelin‐1, endothelin‐3 and angiotensin II, were investigated in a rat sponge model. Neovascularization was assessed by the ¹³³ Xe clearance technique and confirmed by histological studies. Daily doses of the vasodilator peptide, VIP (1000 pmol), caused intense neovascularization, but a lower dose (10 pmol) produced no apparent effect. However, the lower dose of VIP, when given with a subthreshold dose of interleukin‐1α (0.3 pmol), produced an angiogenic response similar to that seen with the higher dose of VIP. The neovascular response induced by co‐administration of VIP and interleukin‐1α was inhibited by simultaneous administration of 100 pmol VIP (10–28), a specific VIP receptor antagonist. In contrast, daily doses of 10, 100 or 1000 pmol endothelin‐3 (a mixed vasoconstrictor and vasodilator with more marked vasodilator activity) or of 100 or 1000 pmol endothelin‐1 (also with mixed activity but with much more pronounced vasoconstrictor response) produced no apparent effect on sponge‐induced angiogenesis. The vasoconstrictor peptide, angiotensin II, in daily doses of 1000 pmol, caused an intense neovascularization like VIP but lower doses of angiotensin II (10 or 100 pmol) produced no apparent effect. The lowest dose of angiotensin II (10 pmol) when administered with the subthreshold dose of interleukin‐1α (0.3 pmol) had no effect on the basal neovascular response in the sponges. The angiotensin II‐induced neovascular response was inhibited by co‐administration of 100 nmol of the specific AT 1 receptor antagonist, losartan, but not by the AT 2 receptor antagonist, PD 123319. These data show that VIP and angiotensin II possess angiogenic activity. However, endothelin‐1 and endothelin‐3 had no activity at the doses used. Thus the angiogenic response is not related to local vasoconstriction or vasodilatation in the sponges. The blockade of VIP‐ and angiotensin II‐induced angiogenesis at the receptor level suggests that receptor modulation could provide a strategy for the management of angiogenic diseases.

Angiotensin-II-induced angiogenesis in sponge implants in mice

Article

Nov 1996

Stimulators of angiogenesis hold potential in promoting the development of collateral circulation in ischaemic tissue and accelerating would healing, but promote pathological vasoformation in angiogenesis-dependent diseases (solid tumours, atherosclerosis). The renin-angiotensin system is implicated in both beneficial angiogenesis and pathological vascular growth. We investigated the angiogenic activity of angiotensin II (AII) in a sponge implant model in mice; this peptide enhanced angiogenesis, as well as glycosaminoglycan (GAG, chondroitin sulfate proteoglycan) and protein synthesis in sponge matrix in mice in a dose-dependent fashion. Extensive angiogenesis was achieved with AII (1 microgram), which gave no significant increase in wet weight and protein and only a small effect on GAG. In the implants treated with AII (2 micrograms) no further increase in angiogenesis was observed, whereas a marked effect was shown in wet weight (326 +/- 15 vs. 424 +/- 27 mg), total protein (18 +/- 1 vs. 25 +/- 1 micrograms/ww) and GAG (98 +/- 10 vs. 160 +/- 13 ng/ww). The local blood flow has been determined by measuring the washout rate of 133Xe injected into the implants, correlated with histological evidence of vessel growth. This model of angiogenesis has allowed sequential studies of fibrovascular tissue infiltration simultaneously with histological and biochemical parameters of angiogenesis.

Tumor-host interactions in the gallbladder suppress distal angiogenesis and tumor growth: involvement of transforming growth factor beta1

Article

Nov 1999

Angiogenesis inhibitors produced by a primary tumor can create a systemic anti-angiogenic environment and maintain metastatic tumor cells in a state of dormancy. We show here that the gallbladder microenvironment modulates the production of transforming growth factor (TGF)-beta1, a multifunctional cytokine that functions as an endogenous anti-angiogenic and anti-tumor factor in a cranial window preparation. We found that a wide variety of human gallbladder tumors express TGF-beta1 irrespective of histologic type. We implanted a gel impregnated with basic fibroblast growth factor or Mz-ChA-2 tumor in the cranial windows of mice without tumors or mice with subcutaneous or gallbladder tumors to study angiogenesis and tumor growth at a secondary site. Angiogenesis, leukocyte-endothelial interaction in vessels and tumor growth in the cranial window were substantially inhibited in mice with gallbladder tumors. The concentration of TGF-beta1 in the plasma of mice with gallbladder tumors was 300% higher than that in the plasma of mice without tumors or with subcutaneous tumors. In contrast, there was no difference in the plasma levels of other anti- and pro-angiogenic factors. Treatment with neutralizing antibody against TGF-beta1 reversed both angiogenesis suppression and inhibition of leukocyte rolling induced by gallbladder tumors. TGF-beta1 also inhibited Mz-ChA-2 tumor cell proliferation. Our results indicate that the production of anti-angiogenesis/proliferation factors is regulated by tumor-host interactions.

Angiotensin II and Retinal Pericytes Migration

Article

Dec 1999

Angiotensin II (Ang II) appears to participate in the regulation of neovascularization processes in the retina. Migration of perimural cells such as pericytes plays a key role in regulation of angiogenesis. We hypothesize that Ang II stimulates migration of retina pericytes. For this we studied the effects of Ang II on migration of bovine retinal pericytes using modified Boyden chambers and collagen IV-covered polyester membranes. Ang II stimulated migration of pericytes by 54.8 +/- 9.7% (n = 10, p < 0.001). This effect was blocked by an AT(1) receptor antagonist (Losartan) but not by an AT(2) receptor antagonist (PD123319). We determined using checkerboard assays (n = 3) that Ang II induces migration of pericytes by chemotaxis (gradient-dependent), in opposition to chemokinesis (nondirected). Thus, Ang II via its AT(1) receptor acts as a chemotactic factor and stimulates migration of retina microvascular pericytes. This effect may contribute to Ang II-induced regulation of neovascularization processes in the retina.

Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases

Article

Apr 2000

A growing body of evidence supports the notion that angiotensin II (Ang II), the central product of the renin-angiotensin system, may play a central role not only in the etiology of hypertension but also in the pathophysiology of cardiovascular and renal diseases in humans. In this review, we focus on the role of Ang II in cardiovascular and renal diseases at the molecular and cellular levels and discuss up-to-date evidence concerning the in vitro and in vivo actions of Ang II and the pharmacological effects of angiotensin receptor antagonists in comparison with angiotensin-converting enzyme inhibitors. Ang II, via AT(1) receptor, directly causes cellular phenotypic changes and cell growth, regulates the gene expression of various bioactive substances (vasoactive hormones, growth factors, extracellular matrix components, cytokines, etc.), and activates multiple intracellular signaling cascades (mitogen-activated protein kinase cascades, tyrosine kinases, various transcription factors, etc.) in cardiac myocytes and fibroblasts, vascular endothelial and smooth muscle cells, and renal mesangial cells. These actions are supposed to participate in the pathophysiology of cardiac hypertrophy and remodeling, heart failure, vascular thickening, atherosclerosis, and glomerulosclerosis. Furthermore, in vivo recent evidence suggest that the activation of mitogen-activated protein kinases and activator protein-1 by Ang II may play the key role in cardiovascular and renal diseases. However, there are still unresolved questions and controversies on the mechanism of Ang II-mediated cardiovascular and renal diseases.

Angiotensin II-Stimulated Vascular Endothelial Growth Factor Expression in Bovine Retinal Pericytes

Article

May 2000
INVEST OPHTH VIS SCI

Angiotensin II (AII) has been shown to play a role in many vascular diseases. In the study described, the effect of AII on vascular endothelial growth factor (VEGF) expression and related intracellular signaling mechanism was investigated in bovine retinal microcapillary pericytes. Cultured bovine retinal microvascular endothelial cells and pericytes were prepared. VEGF expression was determined by Northern blot analysis and immunoprecipitation assay. Cell proliferation was assessed by DNA content growth assay. Reporter gene studies were performed to identify the AII responsible transcription-activating region of VEGF gene. Angiotensin II induced a significant increase in VEGF mRNA in a time- and dose-dependent manner. Angiotensin II type I receptor antagonist inhibited this effect. Angiotensin II activates the transcription of VEGF gene without changing the mRNA half-life, and the AII responsible region was found in the 5'-flanking region of the VEGF gene. Angiotensin II also increased the expression of c-fos and c-jun mRNA, and antisense oligonucleotides against c-Fos blocked the AII-induced VEGF mRNA expression. The conditioned media of AII-stimulated pericyte cultures had a growth-promoting effect on endothelial cells, and this effect was inhibited almost completely by VEGF neutralizing antibody. These findings suggest that AII might induce angiogenic activity through a paracrine function of VEGF in retinal microvascular cells.

Cyclo-oxygenase enhances basic fibroblast growth factor-induced angiogenesis through induction of vascular endothelial growth factor in rat sponge models

Article

Jul 2000

Angiogenesis is reportedly enhanced by prostaglandins (PGs). In the present study, we investigated whether or not cyclo-oxygenase (COX)-2 mediated angiogenesis in chronic and proliferate granuloma. In rat sponge implants, angiogenesis was gradually developed over a 14-day experimental period as granuloma formed. This angiogenesis was enhanced by topical injections of human recombinant basic fibroblast growth factor (bFGF). In sponge granuloma, mRNA of COX-1 was constitutively expressed, whereas that of COX-2 was increased with neovascularization in parallel with that of vascular endothelial growth factor (VEGF). Topical injections of bFGF increased the expression of COX-2 mRNA. bFGF-stimulated angiogenesis was inhibited by indomethacin or selective COX-2 inhibitors, NS-398, nimesulide, and JTE-522. The levels of PGE2 and 6-keto-PGF1α in the sponge granuloma were increased with bFGF 13 fold and 9 fold, respectively, and these levels were markedly reduced by NS-398. The expression of VEGF mRNA in the granuloma was also enhanced by bFGF, and was reduced by NS-398. Topical injections of PGE2 and beraprost sodium, a PGI2 analogue, increased the expression of VEGF mRNA, with angiogenesis enhancement. The enhanced angiogenesis by bFGF was significantly inhibited by topical injections of VEGF anti-sense oligonucleotide. These results suggested that COX-2 may enhance bFGF-induced neovascularization in sponge granuloma by PG-mediated expression of VEGF, and that a COX-2 inhibitor would facilitate the management of conditions involving angiogenesis. British Journal of Pharmacology (2000) 130, 641–649; doi:10.1038/sj.bjp.0703327

Chymase mediates mast cell-induced angiogenesis in hamster sponge granulomas

Article

Aug 2000
EUR J PHARMACOL

We investigated the contribution of mast cell chymase in mast cell-dependent angiogenesis using the hamster sponge-implant model, where angiogenesis in the granulation tissue surrounding the subcutaneously implanted sponge was evaluated by measuring the hemoglobin content. Daily local injection of compound 48/80 (3-100 microg/site/day), a potent mast cell activator, induced formation of granulomas and angiogenesis in time- and dose-dependent manners. This angiogenic response was inhibited by chymase inhibitors including chymostatin (> or = 1 nmol/site/day), soybean trypsin inhibitor (SBTI; > or = 1.4 nmol/site/day) and lima bean trypsin inhibitor (LBTI; > or = 3.3 nmol/site/day), but not by a tryptase inhibitor like leupeptin (> or = 700 nmol/site/day). Although pyrilamine (> or = 2,580 nmol/site/day), a histamine H1 receptor antagonist, and protamine (300 microg/site/day) also inhibited angiogenesis, these effects were much less pronounced than those by chymase inhibitors. Furthermore, antigen-induced angiogenesis in hamsters pre-sensitized with ovalbumin was also inhibited by the chymase inhibitors by 60-70%. Our results suggest that chymase is a major mediator in mast cell-mediated angiogenesis.

Gupta RA, Dubois RNColorectal cancer prevention and treatment by inhibition of Cox-2. Nature Rev Cancer 1: 11-21

Article

Nov 2001
NAT REV CANCER

Population-based studies have established that long-term intake of non-steroidal anti-inflammatory drugs (NSAIDs), compounds that inhibit the enzymatic activity of cyclooxygenase (COX), reduces the relative risk for developing colorectal cancer. These studies led to the identification of a molecular target, COX-2, that is involved in tumour promotion during colorectal cancer progression. Recent studies in humans indicate that therapy with specific COX-2 inhibitors might be an effective approach to colorectal cancer prevention and treatment.

Blockade of angiotensin AT1a receptor signaling reduces tumor growth, angiogenesis, and metastasis

Article

Jul 2002

It was reported that angiotensin II stimulates angiogenesis in vivo, and angiotensin-converting enzyme (ACE) inhibitors inhibit angiogenesis. We found that an AT1-receptor (AT1-R) antagonist, TCV-116, inhibited tumor growth, tumor-associated angiogenesis, and metastasis in a murine model. Tumor growth of Sarcoma 180 (S-180) cells and of fibrosarcoma (NFSA) cells was strongly inhibited by administration of TCV-116 in the diet at a dose of approximately 100 mg/kg/day. This reduction was accompanied with a marked reduction in tumor-associated angiogenesis. The same treatment also reduced the lung metastasis of intravenously injected Lewis lung carcinoma cells. These effects of TCV-116 were equivalent to those of the ACE inhibitor, lisinopril. In S-180 and NFSA tumor tissues, ACE and AT1a receptor (AT1a-R) mRNAs were expressed when assessed with RT-PCR. AT1b receptor and AT2 receptor, however, were not detected. Immunoreactive AT1-R was detected mainly on the neovascularized vascular endothelial cells in which expression was reduced by TCV-116 and lisinopril. These results suggested that TCV-116 inhibits the angiogenesis, growth, and metastasis of tumors highly dependent on AT1a-R blockade. Blockade of AT1a-R signaling may therefore become an effective novel strategy for tumor chemoprevention.

Suppressed Angiogenesis in Kininogen-Deficiencies

Article

Aug 2002

We investigated whether the kinin-generating system enhanced angiogenesis in chronic and proliferative granuloma and in tumor-surrounding stroma. In rat sponge implants, angiogenesis was gradually developed in normal Brown Norway Kitasato rats (BN-Ki). The development of angiogenesis was significantly suppressed in kininogen-deficient Brown Norway Katholiek rats (BN-Ka). The angiogenesis enhanced by basic fibroblast growth factor was also significantly less marked in BN-Ka than in BN-Ki. Naturally occurring angiogenesis was significantly suppressed by B(1) or B(2) antagonist. mRNA of vascular endothelial growth factor was more highly expressed in the granulation tissues in BN-Ki than in BN-Ka. Daily topical injections of aprotinin, but not of soy bean trypsin inhibitor, suppressed angiogenesis. Daily topical injections of low-molecular weight kininogen enhanced angiogenesis in BN-Ka. Topical injections of serum from BN-Ki, but not from BN-Ka, also facilitated angiogenesis in BN-Ka. FR190997, a nonpeptide mimic of bradykinin, promoted angiogenesis markedly, with concomitant increases in vascular endothelial growth factor mRNA. Angiogenesis in the granulation tissues around the implanted Millipore chambers containing Walker-256 cells was markedly more suppressed in BN-Ka than in BN-Ki. Our results suggest that endogenous kinin generated from the tissue kallikrein-kinin system enhances angiogenesis in chronic and proliferative granuloma and in the stroma surrounding a tumor. Thus, the agents for the kinin-generating system and/or kinin receptor signaling may become useful tools for controlling angiogenesis.

Significance of Vascular Endothelial Cell Growth Factor Up-Regulation Mediated via a Chymase-Angiotensin-Dependent Pathway during Angiogenesis in Hamster Sponge Granulomas

Article

Oct 2002

Chymase is a serine protease responsible for local production of angiotensin (Ang) II from its precursor Ang I in several species, including humans, dogs, and hamsters. We have previously reported that chymase facilitates angiogenesis in sponge granulation tissues via local production of Ang II. Herein, we report the significance of vascular endothelial growth factor (VEGF) up-regulation mediated by Ang II during angiogenesis in hamster sponge granulomas. Treatment of granulation tissues with an anti-VEGF neutralizing antibody or antisense oligomers against VEGF mRNA significantly reduced Ang II-induced angiogenesis, supporting a significant role for VEGF during angiogenesis. In cultured fibroblasts prepared from granulation tissues, VEGF mRNA was up-regulated in response to Ang II within 2 h and this enhanced expression was abolished in the presence of an Ang II type 1 receptor-selective antagonist, an inhibitor of nuclear factor-kappaB activation, or an activator protein-1 inhibitor. To study the significance of local production of Ang II by chymase, we examined the effects of chymostatin on in vivo angiogenesis. We found that chymostatin markedly inhibited both up-regulation of VEGF mRNA and angiogenesis in granulation tissues treated by compound 48/80 or basic fibroblast growth factor. Our results suggest that Ang II directly acts on fibroblasts in granulation tissue to up-regulate VEGF mRNA and thereby induce angiogenesis. Furthermore, a chymase-Ang II-VEGF pathway may operate in granulation tissue as the primary mediator of angiogenesis.

Mantovani A, Sozzani S, Locati M, Allavena P, Sica AMacrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23: 549-555

Article

Dec 2002
TRENDS IMMUNOL

Mononuclear phagocytes are versatile cells that can express different functional programs in response to microenvironmental signals. Fully polarized M1 and M2 (or alternatively activated) macrophages are the extremes of a continuum of functional states. Macrophages that infiltrate tumor tissues are driven by tumor-derived and T cell-derived cytokines to acquire a polarized M2 phenotype. These functionally polarized cells, and similarly oriented or immature dendritic cells present in tumors, have a key role in subversion of adaptive immunity and in inflammatory circuits that promote tumor growth and progression.

Angiotensin II Receptor Types 1A, 1B, and 2 in Murine Neuroblastoma Neuro‐2a Cells

Article

Mar 2003

In this study, the mouse neuroblastoma cell line Neuro-2a was analyzed for expression of angiotensin II receptors. Reverse-transcriptase polymerase chain reaction (RT-PCR) showed that Neuro-2a cells express mRNA of angiotensin II (AngII) receptor subtypes AT1A, AT1B, and AT2. Analysis of Neuro-2a cells by Western blotting revealed AT1 and AT2 receptor protein expression. The predominant molecular weights were determined to be 50.4 kDa for the AT1 receptor and 62.4 kDa for the AT2 receptor. Observation of AT1 and AT2 receptor localization within Neuro-2a cells using immunocytochemistry showed distribution similar to other G-protein coupled receptors with diffuse distribution in the cytosol, perinuclear enrichment and accumulation of receptors on the outer cellular periphery with extension into the neurites. Furthermore, we observed InsP3 formation following AngII induction that could be abolished in presence of the AT1A receptor antagonist losartan. The results clearly show expression of the AngII receptor types AT1A and AT2 in the Neuro-2a cell line. We conclude that Neuro-2a cells represent an interesting model cell line for study of mechanisms that control the interplay between these receptors.

Prostanoid signalling relevant to tumor growth and angiogenesis

Article

Nov 2003
TRENDS PHARMACOL SCI

Non-steroidal anti-inflammatory drugs (NSAIDs) that inhibit the cyclooxygenases (COXs) and suppress prostaglandin (PG) synthesis have been used widely as anti-inflammatory, antipyretic and analgesic agents. Recent epidemiological studies have established that the long-term intake of NSAIDs reduces the risk of colorectal cancer. Despite the efficacy of NSAIDs as anticancer agents, the precise mechanism(s) of their protective effect remain(s) unknown. A wide range of mechanisms have been proposed to account for the antitumor actions of NSAIDs, some of which are unrelated to the inhibition of COX activity and subsequent PG formation. However, recent results from knockout mice indicate that prostanoid receptor signaling enhances tumor-associated angiogenesis and tumor growth. Here, we discuss the significance of PGE2 signaling via prostanoid receptors, such as EP3 receptors, on the host stroma but not on tumor cells themselves. Agents that block these receptor signaling events are promising novel therapeutic tools for malignant tumors.

COX-2/VEGF-Dependent Facilitation of Tumor-Associated Angiogenesis and Tumor Growth in vivo

Article

Nov 2003

Nonsteroidal anti-inflammatory drugs are known to suppress the occurrence and progression of malignancies such as colorectal cancers. However, the precise mechanism of these actions remains unknown. We have evaluated the role of an inducible cyclo-oxygenase (COX-2) in tumor-associated angiogenesis and tumor growth, and identified the downstream molecules involved using a ddy mouse model of sponge angiogenesis, which mimics tumor angiogenesis and is COX-2 and vascular endothelial growth factor (VEGF) dependent. In this model, VEGF expression was down-regulated by selective COX-2 inhibition with NS-398. To find out the involvement of COX-2/VEGF pathway in tumor-associated angiogenesis, we estimated angiogenesis occurring around implanted Millipore chambers containing sarcoma-180 (S-180) cells or Lewis lung carcinoma cells. Daily oral administration of NS-398 or of aspirin, a nonselective COX inhibitor, suppressed angiogenesis seen around the Millipore chambers. S-180 cells implanted in ddy mice formed substantial tumors with extensive angiogenesis markedly suppressed by aspirin and COX-2 inhibitors NS-398 and JTE522, but not by mofezolac, an inhibitor of constitutive COX-1. Tumor-associated angiogenesis was also significantly suppressed by a neutralizing antibody against VEGF. S-180 tumor growth in the subcutaneous tissues was also suppressed by aspirin, COX-2 selective inhibitors, and the VEGF antibody, but not by the COX-1 inhibitor. These results demonstrate that the inhibition of the COX-2/VEGF-dependent pathway was effective in tumor-associated angiogenesis, tumor growth, and tumor metastasis.

Angiotensin II subtype 1A (AT1A) receptors in the rat sensory vagal complex: Subcellular localization and association with endogenous angiotensin

Article

Feb 2003
NEUROSCIENCE

Angiotensin II (Ang II) type 1 (AT1) receptors are prevalent in the sensory vagal complex including the nucleus tractus solitarii (NTS) and area postrema, each of which has been implicated in the central cardiovascular effects produced by Ang II. In rodents, these actions prominently involve the AT1A receptor. Thus, we examined the electron microscopic dual immunolabeling of antisera recognizing the AT1A receptor and Ang II to determine interactive sites in the sensory vagal complex of rat brain. In both the area postrema and adjacent dorsomedial NTS, many somatodendritic profiles were dually labeled for the AT1A receptor and Ang II. In these profiles, AT1A receptor-immunoreactivity was often seen in the cytoplasm beneath labeled portions of the plasma membrane and in endosome-like granules as well as Golgi lamellae and outer nuclear membranes. In addition, AT1A receptor labeling was detected on the plasma membrane and in association with cytoplasmic membranes in many small axons and axon terminals. These terminals were morphologically heterogeneous containing multiple types of vesicles and forming either inhibitory- or excitatory-type synapses. In the area postrema, AT1A receptor labeling also was detected in many non-neuronal cells including glia, capillary endothelial cells and perivascular fibroblasts that were less prevalent in the NTS. We conclude that in the rat sensory vagal complex, AT1A receptors are strategically positioned for involvement in modulation of the postsynaptic excitability and intracrine hormone-like effects of Ang II. In addition, these receptors have distributions consistent with diverse roles in regulation of transmitter release, regional blood flow and/or vascular permeability.

Prostanoid receptor signaling relevant to tumor growth and angiogenesisFujita et al. 278 by guest on June 6, 2013 http://carcin.oxfordjournals.org/ Downloaded from 35 Cyclooxygenase regulates angiogenesis induced by colon cancer cells

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M Majima
H Amano
I Hayashi

Majima,M., Amano,H. and Hayashi,I. (2003) Prostanoid receptor signaling relevant to tumor growth and angiogenesis. Trends Pharmacol. Sci., 24, 524--529. M.Fujita et al. 278 by guest on June 6, 2013 http://carcin.oxfordjournals.org/ Downloaded from 35. Tsujii,M., Kawano,S., Tsuji,S., Sawaoka,H., Hori,M. and DuBois,R.N. (1998) Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell, 93, 705--716.

Angiotensin type 1a receptor signaling-dependent induction of vascular endothelial growth factor in stroma is relevant to tumor-associated angiogenesis and tumor growth

Abstract

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