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(a) Plasma cell infiltration in hypercellular bone marrow aspiration material (May Grunvald Giemsa; × 1000). (b) Plasma cell infiltration with significant mass in bone marrow biopsy material (H&E, × 400)
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Angiotensin converting enzyme (ACE) is a circulating enzyme that participates in the body's renin-angiotensin system (RAS) and is localized on the endothelial cell surface in the lung and other vascular beds. It catalyses the conversion of decapeptide angiotensin I to octapeptide angiotensin II. In the present study, we aimed to analyse the possibl...
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Background
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... The circulating renin-angiotensin-aldosterone system (RAAS) is primarily known for its pivotal role in regulating aldosterone secretion, blood pressure, cardiovascular homeostasis, fluid volume, and electrolyte balance [9][10][11]. Both angiotensin-convertingenzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are commonly used and regarded as safe therapies with few side effects [10]. ...
The chronic receipt of renin-angiotensin-aldosterone system (RAAS) inhibitors including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been assumed to be associated with a significant decrease in overall gynecologic cancer risks. This study aimed to investigate the associations of long-term RAAS inhibitors use with gynecologic cancer risks. A large population-based case-control study was conducted from claim databases of Taiwan’s Health and Welfare Data Science Center (2000–2016) and linked with Taiwan Cancer Registry (1979–2016). Each eligible case was matched with four controls using propensity matching score method for age, sex, month, and year of diagnosis. We applied conditional logistic regression with 95% confidence intervals to identify the associations of RAAS inhibitors use with gynecologic cancer risks. The statistical significance threshold was p < 0.05. A total of 97,736 gynecologic cancer cases were identified and matched with 390,944 controls. The adjusted odds ratio for RAAS inhibitors use and overall gynecologic cancer was 0.87 (95% CI: 0.85–0.89). Cervical cancer risk was found to be significantly decreased in the groups aged 20–39 years (aOR: 0.70, 95% CI: 0.58–0.85), 40–64 years (aOR: 0.77, 95% CI: 0.74–0.81), ≥65 years (aOR: 0.87, 95% CI: 0.83–0.91), and overall (aOR: 0.81, 95% CI: 0.79–0.84). Ovarian cancer risk was significantly lower in the groups aged 40–64 years (aOR: 0.76, 95% CI: 0.69–0.82), ≥65 years (aOR: 0.83, 95% CI: 0.75–092), and overall (aOR: 0.79, 95% CI: 0.74–0.84). However, a significantly increased endometrial cancer risk was observed in users aged 20–39 years (aOR: 2.54, 95% CI: 1.79–3.61), 40–64 years (aOR: 1.08, 95% CI: 1.02–1.14), and overall (aOR: 1.06, 95% CI: 1.01–1.11). There were significantly reduced risks of gynecologic cancers with ACEIs users in the groups aged 40–64 years (aOR: 0.88, 95% CI: 0.84–0.91), ≥65 years (aOR: 0.87, 95% CI: 0.83–0.90), and overall (aOR: 0.88, 95% CI: 0.85–0.80), and ARBs users aged 40-64 years (aOR: 0.91, 95% CI: 0.86–0.95). Our case-control study demonstrated that RAAS inhibitors use was associated with a significant decrease in overall gynecologic cancer risks. RAAS inhibitors exposure had lower associations with cervical and ovarian cancer risks, and increased endometrial cancer risk. ACEIs/ARBs use was found to have a preventive effect against gynecologic cancers. Future clinical research is needed to establish causality.
... исследовали уровень АПФ в сыворотке крови у больных с первично диагностированной множественной миеломой (n = 25) и у здоровых доноров из контрольной группы (n = 20). Уровни АПФ были достоверно выше у больных множественной миеломой (32,60 ± 20,26 Ед/л) по сравнению с донорами (15,35 ± 6,47 Ед/л) [44]. Экспрессия компонентов РАС была изучена методом количественной полимеразной цепной реакции у пациентов с хроническим миелолейкозом в момент диагностики, на 3, 6 и 12-й месяцы лечения иматинибом. ...
The renin-angiotensin system (RAS) has long been known as the endocrine system involved in the regulation of arterial pressure and waterelectrolyte balance. Local (tissue) RAS can influence cellular activity, tissue damage and regeneration. In the bone marrow there are active ligands of peptides, mediators, receptors and signaling pathways of the RAS. Local RAS can influence the growth, production, proliferation and differentiation of hematopoietic cells and participate in the regulation of both normal and pathological hematopoiesis. Angiotensin-converting enzyme (ACE) CD143 plays a key role in the classical RAS. After differentiation from hemangioblast, hematopoietic progenitor cells constantly express ACE in human embryonic, fetal and adult hematopoietic tissues, as well as at all stages of hematopoietic ontogeny. The ACE cleaves the C-terminal dipeptide and thus forms the octapeptide Angiotensin II. In addition to angiotensin II, ACE also regulates a group of biologically active peptides, such as substance P, ac-SDKP and angiotensin 1–7. Local RAS is also one of the most important components in the tumor microenvironment, affecting tumor growth and metastasis by autocrine and paracrine pathways, modulating numerous carcinogenic events such as angiogenesis, apoptosis, cell proliferation, immune responses, and extracellular matrix formation.The purpose of this review is to describe the known functions of local RAS in the hematopoiesis regulation. More detailed study of the RAS components mechanisms of action will expand therapy approaches in the neoplastic diseases and in bone marrow transplantation.
... Moreover another studies also demonstrated association of ACE with multiple myeloma and lung cancer [47] [48]. ...
Renin-Angiotensin System (RAS) is involved with hypertension and other cardiovascular diseases. However, the association of RAS components to cancer still causes suspicion. To try to clarify this, here we aimed to show this association for three important components: Angiotensin Converting Enzyme 1 (ACE1), Angiotensin Type 1 Receptor (AGTR1) and Angiotensin Type 2 Receptor (AGTR2). The first articles show that association of RAS components with cancer dates back to the 70's. ECA1 and AGTR1 have close association with cancer and ACE1 inhibitors or AGTR1 blockers are candidates to treatment of some tumors. Moreover, the action of AGTR2 is still controversial, but most studies show that the increased expression of AGTR2 can attack the cancer cells. In breast cancer, these components have also been widely studied and many works have shown that the correlation exists. Therefore specific target using these RAS components could be a beneficial, novel therapy to various tumors.
... The circulating renin-angiotensin system (RAS) is best known for its key role in regulating blood pressure, blood flow, fluid volume, and electrolyte balance [7][8][9]. In addition to these physiologic effects, recent trials have proposed the concept of a local tissue RAS in a variety of organ systems and its activation under tumoural conditions [10,11]. ...
Clinicopathologic and molecular studies have provided new insights and understanding on the pathological events during ovarian carcinogenesis. Moreover, angiotensin II-enhanced tumor cell invasion via type 1 angiotensin II receptor in ovarian cancer cell lines was recently demonstrated. It has been suggested that renin-angiotensin system (RAS) activity increases in diseases involving the female reproductive system. In the present study, we aimed to analyze the possible relationship between the levels of circulating angiotensin-converting enzyme (ACE), an important molecule of RAS, and ovarian cancer (OC).
This study was conducted in 41 epithelial OC patients (mean age 56.1 ± 10.2 years) and 19 healthy controls (mean age 53.4 ± 13.1 years). Clinical and laboratory features are summarized. Serum ACE and Ca-125 levels were measured using commercially available laboratory kits.
Serum ACE levels of epithelial OC patients and controls were 30.58 ± 13.37 and 14.15 ± 3.67, respectively. Serum ACE levels were significantly elevated in epithelial OC patients in comparison to healthy controls. Ca-125 levels of epithelial OC patients were also significantly elevated in epithelial OC patients. No correlation was observed between ACE levels and Ca-125 levels. In epithelial OC patients, serum ACE levels did not differ according to stages and pathologic subtypes of the patients.
Our results showed that serum ACE levels were increased in OC patients. Being an important component of RAS, circulating ACE might be associated with ongoing pathobiologic events in ovarian carcinogenesis. Therefore, targeting the RAS pathway could provide a future treatment strategy for this cancer type.
... In this study, CD34+MM hematopoietic cells also locally expressed RENIN, ANGTS, and ACE I mRNA, indicating the activity of RAS in myeloma-related progenitor cells. ACE activity was also linked to MM [43,44]. BM AGTR I expression levels of myeloma patients showed a positive correlation with their BM infiltration pattern and tumor load, indicated by serum β2 microglobulin levels [44]. ...
Objective: The prominent functions of the local renin-angiotensin system (RAS) in primitive hematopoiesis further support the hypothesis that local autocrine bone marrow RAS could also be active in neoplastic hematopoiesis. The aim of this study is to examine critical RAS elements in normal CD34+ hematopoietic stem cells and multiple myeloma (MM)-related progenitor cells.
Materials and Methods: The study group comprised the total bone marrow cells (CBM) of 10 hematologically normal people, the CD34+ stem cell samples (CD34+CBM) of 9 healthy donors for allogeneic peripheral stem cell transplantation, and the CD34+ stem cell samples (CD34+MM) of 9 MM patients undergoing autologous peripheral stem cell transplantation. We searched for the gene expression of the major RAS components in healthy hematopoietic cells and myeloma cells by quantitative real-time polymerase chain reaction analysis.
Results: RENIN, angiotensinogen (ANGTS), and angiotensin converting enzyme-I (ACE I) mRNA expression levels of CBM were significantly higher than those in myeloma patients (p=0.03, p=0.002, and p=0.0008, respectively). Moreover, RENIN and ANGTS mRNA expression levels were significantly higher in CD34+ stem cell samples of healthy allogeneic donors compared to those in myeloma patients (p=0.001 and p=0.01). However, ACE I expression levels were similar in CD34+CBM and CD34+MM hematopoietic cells (p=0.89).
Conclusion: Although found to be lower than in the CBM and CD34+CBM hematopoietic cells, the local RAS components were also expressed in CD34+MM hematopoietic cells. This point should be kept in mind while focusing on the immunobiology of MM and the processing of autologous cells during the formation of transplantation treatment protocols.
... In addition, there is an emerging evidence showing the existence of RAS components in the bone marrow microenvironment [42], and the functional and pharmacological experiments have demonstrated that RAS regulates bone marrow stromal cells, and stem cells, thus involving haematopoiesis and tissue regeneration by progenitor cells [42][43][44]. Whether there is a role of bone marrow RAS in bone metabolism and there are any interactions of the RAS between bone marrow and bone tissue itself still need to be further investigated. ...
... In addition, there is an emerging evidence showing the existence of RAS components in the bone marrow microenvironment [42], and the functional and pharmacological experiments have demonstrated that RAS regulates bone marrow stromal cells, and stem cells, thus involving haematopoiesis and tissue regeneration by progenitor cells [42][43][44]. Whether there is a role of bone marrow RAS in bone metabolism and there are any interactions of the RAS between bone marrow and bone tissue itself still need to be further investigated. ...
Metabolic bone disorder is usually caused by abnormalities of minerals and hormones metabolism. Recently, it has been proved by several studies that the renin-angiotensin system (RAS) in local bone tissue is directly involved in bone metabolism. Activation of skeletal RAS plays an important role in bone metabolic disorders. Based on in vitro, in vivo, and clinical studies, this review explains the roles of RAS in bone metabolism and also covers the potential approaches and beneficial effects of RAS inhibition on bone health. Differential strategies for inhibiting RAS can be employed to maintain bone health, which are attributed primarily to the reduced level of angiotensin II (AngII) and suppressed stimulation of the AngII signaling pathway. The use of renin inhibitors, angiotensin-converting enzyme inhibitors, and AngII receptor blockers either individually or in combination with each other could have promising results in fighting bone metabolic disorders associated with other cardiovascular diseases as well as independent bone injuries.
... 6 ACE is expressed in a wide range of tissues including skin, vascular endothelium and immune cells. [7][8][9][10][11] Plasma and tissue concentration of ACE are determined by the ACE gene (chromosome 17q23). 12 The ACE gene has functional insertion/deletion (I/D) polymorphism of a 287 bp Alu sequence within intron 16. 13 ACE DD carriers have higher local levels of ACE than those with the ID and II genotypes. ...
The relationship between the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and psoriasis has previously been studied mainly in Caucasians and only once in Asians. The aim of this study is to evaluate the association between the ACE I/D polymorphism and the risk of psoriasis in a Chinese population.
The study population consisted of 668 psoriasis patients and 668 matched control subjects. The ACE I/D gene polymorphism was analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).
The frequency of the ACE II genotype (odds ratio (OR) = 1.32, 95% confidence interval (CI) = 1.06, 1.63; P = 0.01) and I allele (OR = 1.25, 95% CI = 1.06, 1.48; P = 0.01) in patients with psoriasis was significantly higher than that in the control group. And the D allele frequency in patients with psoriasis was significantly lower (OR = 0.80, 95% CI = 0.68, 0.95; P = 0.01) than that in the control group. When stratified by family history, the frequency of the DD genotype was marginally significantly lower in patients with a positive family history of psoriasis (familial psoriasis) than in those with negative (sporadic psoriasis) (OR = 0.47, 95% CI = 0.23, 0.97; P = 0.04). When stratified by onset of the disease, type of psoriasis and the severity of psoriasis, no statistically significant result was observed.
Our study suggested that the ACE II genotype and I allele might confer susceptibility to psoriasis in a Chinese population.
... ACE-expressing macrophages in the lymph nodes of patients Hodgkin's disease have been detected [118]. ACE activity was also linked to multiple myeloma [119,120]. ACE hyperfunction results in faster hydrolysis of the AcSDKP peptide, which in turn decreases in BM tissues, allowing HSCs to enter the S-stage of the cell cycle [4,16,34]. The plasma concentration of AcSDKP, a reversible negative regulator of the proliferation of normal haematopoietic stem cells, is physiologically regulated by ACE [14][15][16]121]. ...
The locally active ligand peptides, mediators, receptors and signalling pathways of the haematopoietic BM (bone marrow) autocrine/paracrine RAS (renin-angiotensin system) affect the essential steps of definitive blood cell production. Haematopoiesis, erythropoiesis, myelopoiesis, formation of monocytic and lymphocytic lineages, thrombopoiesis and other stromal cellular elements are regulated by the local BM RAS. The local BM RAS is present and active even in primitive embryonic haematopoiesis. ACE (angiotensin-converting enzyme) is expressed on the surface of the first endothelial and haematopoietic cells, forming the marrow cavity in the embryo. ACE marks early haematopoietic precursor cells and long-term blood-forming CD34+ BM cells. The local autocrine tissue BM RAS may also be active in neoplastic haematopoiesis. Critical RAS mediators such as renin, ACE, AngII (angiotensin II) and angiotensinogen have been identified in leukaemic blast cells. The local tissue RAS influences tumour growth and metastases in an autocrine and paracrine fashion via the modulation of numerous carcinogenic events, such as angiogenesis, apoptosis, cellular proliferation, immune responses, cell signalling and extracellular matrix formation. The aim of the present review is to outline the known functions of the local BM RAS within the context of primitive, definitive and neoplastic haematopoiesis. Targeting the actions of local RAS molecules could represent a valuable therapeutic option for the management of neoplastic disorders.
The regular functioning of the human body is the result of interactions between numerous organs and biological systems, with the Renin-Angiotensin System (RAS) playing a crucial role in maintaining homeostasis for human existence. Though RAS is mainly known for regulation of blood pressure, however, its role in cancer development and progression has been emerging nowadays wherein this system was found to promote angiogenesis and inflammation in tumor niche. RAS comprises of numerous elements, of which angiotensin converting enzyme (ACE) is of utmost significance which converts angiotensin I (ATI) to angiotensin II (ATII), which then undergoes downstream signaling via binding to AT receptors. This signaling aids in hematopoiesis and the associated malignancies like leukemia, myeloma and lymphoma. ACE and the downstream signaling cascades upregulation could be seen in cancer models which are linked to the activation of multiple signaling events involving NF-κB, PI3K, MAPK, etc. The importance of RAS in hematological malignancies led to the exploration of RAS inhibitors for the cancer treatment. There are certain categories of RAS inhibitors which include ACE inhibitors, Angiotensin receptor blockers or renin inhibitors which have been tested in vitro either alone or in combination for therapeutics of various cancers including hematological malignancies. The local RAS and its association with cancer might opens up new avenues for investigation and development of novel therapies for hematological malignancies.KeywordsRenin-angiotensin systemCancerTherapeuticsHematological malignanciesSignalingACEACE inhibitors
