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Tumorigenesis and the angiogenic switch
... The induction of tumor angiogenesis (the 'angiogenic switch') was found to represent a discrete and requisite step in the multistage development of certain tumor types [19][20][21] , leading to its incorporation as a qualitatively distinct hallmark of cancer 22 . The occurrence of a discrete angiogenic switch was initially demonstrated in RIP1-Tag2 (rat insulin promoter 1-T antigen 2) mice, a genetically engineered mouse model (GEMM) of pancreatic neuroendocrine tumorigenesis 23 . ...
... For example, activated BVs subtending increasingly aberrant epithelia were evident in the noninvasive stages of ductal carcinoma in situ in human breast cancer 26 and intraepithelial dysplasia in human cervical cancer 27 . Induction of angiogenesis may thus precede and allow the malignant progression of different tumor types [20][21][22] . The angiogenic switch was initially thought to depend on the de novo synthesis of proangiogenic factors 19 . ...
... However, a 'balance hypothesis' has since been proposed, suggesting that a biochemical equilibrium maintains BVs in a quiescent state. This equilibrium is disrupted during the angiogenic switch consequent to increased expression or bioavailability of angiogenesis inducers and/ or reduced expression or bioavailability of angiogenesis inhibitors 20,21 . ...
Research into the mechanisms and manifestations of solid tumor vascularization was launched more than 50 years ago with the proposition and experimental demonstrations that angiogenesis is instrumental for tumor growth and was, therefore, a promising therapeutic target. The biological knowledge and therapeutic insights forthcoming have been remarkable, punctuated by new concepts, many of which were not foreseen in the early decades. This article presents a perspective on tumor vascularization and its therapeutic targeting but does not portray a historical timeline. Rather, we highlight eight conceptual milestones, integrating initial discoveries and recent progress and posing open questions for the future.
... This limitation is critical as the "angiogenic switch" is hypothesized to occur in vivo in certain solid malignancies, like colon carcinoma, only after the tumors exceed diameters of 1-2 mm. [22,23] Additionally, in PDMS chips, the rectangular geometry of the channels in which EC are patterned prevents the faithful replication of physiological flow dynamics. ...
... The latter observation highlights the known dependence of tumor progression on angiogenesis. [22] To rule out that in absence of a vascular network the cells are deteriorating over time, a quantitative analysis of the whole bioreactor content was performed using flow cytometry. Excellent cell viability was found for both configurations ( Figure 5C). ...
... We initially hypothesized that modifying the tumors' position relative to the blood vessel could impact the formation of meaningful gradients of angiogenic factors, oxygen, and pH within the construct, which are known triggers for sprouting angiogenesis. [22] To this end, we adjusted the tumors' position relative to the bioprinted vascular-like structure. However, moving the tumor spheroids closer to the feeding vessel did not improve the formation of EC sprouts. ...
Advanced in vitro systems such as multicellular spheroids and lab‐on‐a‐chip devices have been developed, but often fall short in reproducing the tissue scale and self‐organization of human diseases. We here introduce a bio‐printed artificial tumor model with endothelial and stromal cells self‐organizing into perfusable and functional vascular structures. Our model uses 3D hydrogel matrices to embed multicellular tumor spheroids, allowing them to grow to mesoscopic scales and to interact with endothelial cells. We show that angiogenic multicellular tumor spheroids promote the growth of a vascular network, which in turn further enhances the growth of co‐cultivated tumor spheroids. The self‐developed vascular structure infiltrates the tumor spheroids, forms functional connections with the bioprinted endothelium, and can be perfused by erythrocytes and polystyrene microspheres. Moreover, cancer cells migrate spontaneously from the tumor spheroid through the self‐assembled vascular network into the fluid flow. Additionally, tumor type specific characteristics of desmoplasia, angiogenesis, and metastatic propensity are preserved between patient‐derived samples and tumors derived from this same material growing in our bioreactors. Overall, our modular approach opens up new avenues for studying tumor pathophysiology and cellular interactions in vitro, providing a platform for advanced drug testing while reducing the need for in vivo experimentation.
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... Angiogenesis has been determined to be involved in each stage of cancer, including tumorigenesis [9,10], progression [11], invasion, and metastasis [12,13]. VECs can affect tumor cells through direct intercellular contact, autocrine signaling, and parasitic cytokines [14]. ...
... For example, microRNAs and molecular chaperones are biologically active molecules carried by EVs. They directly or indirectly affect the initiation, cell proliferation, growth, and metastasis of gliomas [10,35]. Previous studies have found that breast cancer cell-derived EVs induce HUVEC generation through mir-210 [37] and mir-182-5p [27], thus enhancing migration, proliferation, and angiogenesis. ...
Vascular endothelial cells are closely related to tumor progression, and extracellular vesicles (EVs) play an important role in this process. EVs derived from breast cancer cells also affect the biological characteristics of human umbilical vein endothelial cells (HUVECs) to promote tumor progression. However, the mechanism remains unclear. In the present study, EVs derived from MDA-MB-231 and MCF-7 breast cancer cells were extracted at different concentrations (0, 10, 20, and 40 μg/ml). Specific concentrations of breast cancer cell line EVs (10, 20, and 40 μg/ml) significantly increased the proliferation, Colony formation, and migration of HUVECs (P < 0.05) compared to MDA-MB-231 and MCF-7 breast cancer cell-derived EVs. There was no significant difference in the expression levels of total JAK2 and STAT3 protein (P < 0.05), while the expression levels of P-JAK2 and P-STAT3 protein increased significantly (P < 0.05). In conclusion, EVs derived from breast cancer cells may promote the proliferation and migration of HUVECs by regulating the phosphorylation of the JAK2/STAT3 signaling pathway.
... As the tumor grows, it induces the formation of new blood vessels, which are structurally and functionally abnormal and characterized by tumor-specific ECs expressing unique markers and higher levels of growth factors and cytokines (102). Tumor-specific ECs secrete growth factors like VEGF, PDGF, and fibroblast growth factor-2 (FGF-2) to activate downstream signaling pathways involved in EC proliferation and migration, thus promoting angiogenesis in the TME (103)(104)(105). In addition, tumor-specific ECs contribute to tumor growth and progression by producing growth factors and cytokines that promote tumor cell survival and proliferation. ...
... Thus, the interplay between tumor angiogenesis and tumor growth highlights the importance of targeting tumorspecific ECs for effective cancer therapy. Tumor-specific ECs secrete growth factors, such as VEGF, PDGF, and FGF-2, which promote tumor cell survival and proliferation by binding to their corresponding receptors on tumor cells, such as VEGFR, PDGFR, and FGFR (103)(104)(105). Activation of these receptors leads to downstream signaling pathways, including the PI3K-Akt-mTOR and Raf-MEK-ERK pathways, which promote tumor cell survival, proliferation, and angiogenesis (106). ...
The development and differentiation of endothelial cells (ECs) are fundamental processes with significant implications for both health and disease. ECs, which are found in all organs and blood vessels, play a crucial role in facilitating nutrient and waste exchange and maintaining proper vessel function. Understanding the intricate signaling pathways involved in EC development holds great promise for enhancing vascularization, tissue engineering, and vascular regeneration. Hematopoietic stem cells originating from hemogenic ECs, give rise to diverse immune cell populations, and the interaction between ECs and immune cells is vital for maintaining vascular integrity and regulating immune responses. Dysregulation of vascular development pathways can lead to various diseases, including cancer, where tumor- specific ECs promote tumor growth through angiogenesis. Recent advancements in single-cell genomics and in vivo genetic labeling have shed light on EC development, plasticity, and heterogeneity, uncovering tissue-specific gene expression and crucial signaling pathways. This review explores the potential of ECs in various applications, presenting novel opportunities for advancing vascular medicine and treatment strategies.
... However, for tumors >1-2 mm, angiogenesis into the tumor is required. Angiogenesis is associated with tumor growth and distant metastasis, and angiogenic factors include VEGF, basic fibroblast growth factor, angiopoietin, hepatocyte growth factor, EGF and placental growth factor (16). The findings of the present study suggest that low-grade TETs, specifically thymoma types A and B1, express minimal VEGFR-2 expression levels. ...
... Drugs that inhibit angiogenesis can promote the tumor vasculature's restoration to normal operation. At the moment, scientists all around the world are focusing on tumor angiogenesis in the hopes of finding a cure for cancer [33]. In order to increase the efficacy of cancer therapy, new potent, target-specific cancer drugs are urgently required [34]. ...
Chemical, Material Sciences & Nano technology book series aims to bring together leading academic scientists, researchers and research scholars to exchange and share their experiences and research results on all aspects of Chemical, Material Sciences & Nano technology. The field of advanced and applied Chemical, Material Sciences & Nano technology has not only helped the development in various fields in Science and Technology but also contributes the improvement of the quality of human life to a great extent. The focus of the book would be on state-of-the-art technologies and advances in Chemical, Material Sciences & Nano technology and to provides a remarkable opportunity for the academic, research and industrial communities to address new challenges and share solutions.
... As tumours proliferate, they demand increased oxygen and nutrients, necessitating new blood vessel formation for sustained growth [21]. Recent studies have revealed a significant association between DANCR expression and tumour angiogenesis. ...
Cancer remains a leading cause of mortality and poses a substantial threat to public health. Studies have revealed that Long noncoding RNA DANCR is a cytoplasmic lncRNA whose aberrant expression plays a pivotal role in various cancer types. Within tumour biology, DANCR exerts regulatory control over crucial processes such as proliferation, invasion, metastasis, angiogenesis, inflammatory responses, cellular energy metabolism reprogramming, and apoptosis. By acting as a competitive endogenous RNA for miRNAs and by interacting with proteins and mRNAs at the molecular level, DANCR contributes significantly to cancer progression. Elevated DANCR levels have also been linked to heightened resistance to anticancer drugs. Moreover, the detection of circulating DANCR holds promise as a valuable biomarker for aiding in the clinical differentiation of different cancer types. This article offers a comprehensive review and elucidation of the primary functions and molecular mechanisms through which DANCR influences tumours.
... Tumor angiogenesis is initiated by an anagenesis switch which is upregulated by the balance between two key factors, proangiogenic and antiangiogenic factors (Bergers and Benjamin, 2003). The formation of new vasculature results from the action of proangiogenic factors overpowering the antiangiogenic factors. ...
Cancer is one of the most life-threating as well as deadly diseases with uncontrolled, uncoordinated cell division. Neoplasm is a mass of tumor cells that are not invasive but after it becomes malignant form, it is exceedingly difficult to eradicate. Cancer causation is mainly due to several factors such as genetic, occupational, way of life, chemical carcinogens, different artificial food additives, toxins, chronic infections of many pathogens, and other environmental factors. Notwithstanding, there is a massive range of cancer therapies, due to the many obstacles and resistance of the tumor cells it could not be able to get an efficient outcome. In past decades most of those therapies were focused on tumor cells alone. However, many documentations undoubtedly have shown that the tumor microenvironment has a greater influence on this complex localized disease. The tumor microenvironment consists of an enormous range of cells and non-cellular components. As a profitable nature, numerous studies have experimentally shown the efficiency of nanotechnology-based cancer therapies. The remodeling of the cancer microenvironment by nanoparticles (NP) is one efficacious strategy for the treatment of cancer. Most of them have shown enormous outcomes in-vivo and some of them are under preclinical trials. This review mainly focuses on a novel treatment that is associated with NP by targeting the remodeling angiogenesis of the tumor. Angiogenesis is the process of the emergence of new blood vessels from early blood vessels and it plays a major role in the pathologic and physiologic processes of cancer development. Therefore, the main objective of this review is the identification of strategies for cancer treatment mainly focusing on angiogenesis of the tumor microenvironment.
... Altogether, the balance between these two classes of molecules is of utmost significance for angiogenesis capacity and tumor control. If this balance is disrupted, favoring the pro-angiogenic side, the "angiogenic switch'' occurs (Bergers and Benjamin, 2003). This results in circulating endothelial progenitors (CEP) recruitment which are able to promote angiogenesis. ...
Metronomic chemotherapy (MCT), characterized by the continuous administration of chemotherapeutics at a lower dose without prolonged drug-free periods, has garnered significant attention over the last 2 decades. Extensive evidence from both pre-clinical and clinical settings indicates that MCT induces distinct biological effects than the standard Maximum Tolerated Dose (MTD) chemotherapy. The low toxicity profile, reduced likelihood of inducing acquired therapeutic resistance, and low cost of MCT render it an attractive chemotherapeutic regimen option. One of the most prominent aspects of MCT is its anti-angiogenesis effects. It has been shown to stimulate the expression of anti-angiogenic molecules, thereby inhibiting angiogenesis. In addition, MCT has been shown to decrease the regulatory T-cell population and promote anti-tumor immune response through inducing dendritic cell maturation and increasing the number of cytotoxic T-cells. Combination therapies utilizing MCT along with oncolytic virotherapy, radiotherapy or other chemotherapeutic regimens have been studied extensively. This review provides an overview of the current status of MCT research and the established mechanisms of action of MCT treatment and also offers insights into potential avenues of development for MCT in the future.
... GSEA analysis was performed on these genes and results showed that angiogenesis, epithelial-mesenchymal transition (EMT), inflammatory response, and myogenesis were enriched in up-regulated genes in High HP group (Fig. 3D). These terms have been demonstrated to be associated with tumor progress [6,[47][48][49]. Finally, we investigated the potential relationship between HPscore and patients' response to clinical treatments based on the chemotherapy response data from TCGA. ...
Bladder cancer is a prevalent malignancy with high mortality rates worldwide. Hypoxia is a critical factor in the development and progression of cancers. However, whether and how hypoxia-related genes (HRGs) could affect the development and the chemotherapy response of bladder cancer is still largely unexplored. This study comprehensively explored the complex molecular landscape associated with hypoxia in bladder cancer by analyzing 260 hypoxia genes based on transcriptomic and genomic data in 411 samples. Employing the 109 dysregulated hypoxia genes for consensus clustering, we delineated two distinct bladder cancer clusters characterized by disparate survival outcomes and distinct oncogenic roles. We defined a HPscore that was correlated with a variety of clinical features, including TNM stages and pathologic grades. Tumor immune landscape analysis identified three immune clusters and close interactions between hypoxia genes and the various immune cells. Utilizing a network-based method, we defined 129 HRGs exerting influence on apoptotic processes and critical signaling pathways in cancer. Further analysis of chemotherapy drug sensitivity identified potential drug–target HRGs. We developed a Risk Score model that was related to the overall survival of bladder cancer patients based on doxorubicin-target HRGs: ACTG2, MYC, PDGFRB, DHRS2, and KLRD1. This study not only enhanced our understanding of bladder cancer at the molecular level but also provided promising avenues for the development of targeted therapies, representing a significant step toward the identification of effective treatments and addressing the urgent need for advancements in bladder cancer management.
... Pathological angiogenesis is a hallmark of cancer and can occur at any stage of the disease [36]. Tumor angiogenic activity is closely linked to prognosis, and the development of anti-angiogenic drugs could not only be used for cancer treatment but also aid in preventing tumor recurrence and metastasis [37]. Elucidating the molecular mechanisms underlying TPL's anti-angiogenic effects would facilitate the development and application of related drugs. ...
Triptolide (TPL) is a compound sourced from Tripterygium wilfordii Hook. F., a traditional Chinese medicinal herb recognized for its impressive anti-inflammatory, anti-angiogenic, immunosuppressive, and antitumor qualities. Notwithstanding its favorable attributes, the precise mechanism through which TPL influences tumor cells remains enigmatic. Its toxicity and limited water solubility significantly impede the clinical application of TPL. We offer a comprehensive overview of recent research endeavors aimed at unraveling the antitumor mechanism of TPL in this review. Additionally, we briefly discuss current strategies to effectively manage the challenges associated with TPL in future clinical applications. By compiling this information, we aim to enhance the understanding of the underlying mechanisms involved in TPL and identify potential avenues for further advancement in antitumor therapy.
... Tumor angiogenesis is a complex process in which multiple cells and cytokines are involved [24]. The interactions between tumor cells and endothelial cells (ECs) influence tumor angiogenesis [25].VEGF is one of the most critical regulatory factors of tumor angiogenesis and promotes tumor progression, making it a key target of anticancer therapy in various malignant tumors [26][27][28]. We discovered that TMEM9 knockdown inhibited the expression and secretion of VEGF in LUAD cells. ...
Abnormal Transmembrane protein 9 ( TMEM9 ) expression has been identified in various human tumors. However, the prognostic potential and mechanistic role of TMEM9 in lung adenocarcinoma (LUAD) remain unclear. Here, we first found a significant upregulation of TMEM9 in LUAD tissues, and TMEM9 expression was positively correlated with microvessel density (MVD), T stage, and clinical stage. Survival analysis demonstrated TMEM9 was an independent indicator of poor prognosis in LUAD patients. In addition, downregulation of TMEM9 suppressed tumor growth and metastasis in vitro and in vivo models, and reduced HUVEC proliferation, migration, and tube formation in a cancer cell/HUVEC coculture model. Furthermore, TMEM9 upregulated VEGF expression, and VEGF -neutralizing antibodies reversed HUVEC angiogenesis and cancer cell migration ability caused by overexpression of TMEM9 . In contrast, recombinant VEGF (r VEGF ) abolished the inhibitory effect of TMEM9 -knockdown LUAD cells on HUVEC angiogenesis and tumor cell migration. Moreover, we showed that TMEM9 upregulated VEGF expression by activating the mitogen-activated protein kinase/extracellular signal-regulated kinase/ STAT3 ( MEK / ERK / STAT3 ) pathway. Together, our study provides mechanistic insights into the role of TMEM9 in LUAD and highlights the potential of targeting the TMEM9 / MEK / ERK / STAT3 / VEGF pathway as a novel therapy for preventing LUAD progression.
... Tumor angiogenesis is a complex process, subject to regulation by a balance between pro-angiogenic and antiangiogenic factors within a solid tumor [10,11]. When the equilibrium tilts toward pro-angiogenic factors, ECs are stimulated to proliferate and migrate towards the tumor, forming new blood vessels. ...
Sustained angiogenesis stands as a hallmark of cancer. The intricate vascular tumor microenvironment fuels cancer progression and metastasis, fosters therapy resistance, and facilitates immune evasion. Therapeutic strategies targeting tumor vasculature have emerged as transformative for cancer treatment, encompassing anti-angiogenesis, vessel normalization, and endothelial reprogramming. Growing evidence suggests the dynamic regulation of tumor angiogenesis by infiltrating myeloid cells, such as macrophages, myeloid-derived suppressor cells (MDSCs), and neutrophils. Understanding these regulatory mechanisms is pivotal in paving the way for successful vasculature-targeted cancer treatments. Therapeutic interventions aimed to disrupt myeloid cell-mediated tumor angiogenesis may reshape tumor microenvironment and overcome tumor resistance to radio/chemotherapy and immunotherapy.
... 16,17 The persistence of microscopic tumor deposits independent of VEGF-driven neovasculature has been hypothesized to explain the weak activity of VEGFdirected therapies in the setting of minimal residual disease. 18,19 Whereas 76% of patients in the study have had disease recurrence, only 28% of patients have died (Fig 3). Although the study was not powered to assess OS, there was a trend toward inferior survival for the pazopanib arm (P two-sided 5 .012), ...
PURPOSE
Patients with no evidence of disease (NED) after metastasectomy for renal cell carcinoma are at high risk of recurrence. Pazopanib is an inhibitor of vascular endothelial growth factor receptor and other kinases that improves progression-free survival in patients with metastatic RCC (mRCC). We conducted a randomized, double-blind, placebo-controlled multicenter study to test whether pazopanib would improve disease-free survival (DFS) in patients with mRCC rendered NED after metastasectomy.
PATIENTS AND METHODS
Patients with NED after metastasectomy were randomly assigned 1:1 to receive pazopanib 800 mg once daily versus placebo for 52 weeks. The study was designed to observe an improvement in DFS from 25% to 45% with pazopanib at 3 years, corresponding to 42% reduction in the DFS event rate.
RESULTS
From August 2012 to July 2017, 129 patients were enrolled. The study was unblinded after 83 DFS events (92% information). The study did not meet its primary end point. An updated analysis at 60.5-month median follow-up from random assignment (95% CI, 59.3 to 71.0) showed that the 3-year DFS was 27.4% (95% CI, 17.9 to 41.7) for pazopanib and 21.9% (95% CI, 13.3 to 36.2) for placebo. Hazard ratio (HR) for DFS was 0.90 ([95% CI, 0.60 to 1.34]; P one-sided = .29) in favor of pazopanib. Three-year overall survival (OS) was 81.9% (95% CI, 72.7 to 92.2) for pazopanib and 91.4% (95% CI, 84.4 to 98.9) for placebo. The HR for OS was 2.55 (95% CI, 1.23 to 5.27) in favor of placebo ( P two-sided = .012). Health-related quality-of-life measures deteriorated in the pazopanib group during the treatment period.
CONCLUSION
Pazopanib did not improve DFS as the primary end point compared with blinded placebo in patients with mRCC with NED after metastasectomy. In addition, there was a concerning trend favoring placebo in OS.
... Glioblastoma, like other solid tumors, relies on blood supply by specialized vascular structures to meet the increased metabolic demands [39,41,65,66] and vasculature, in brain tumors, correlates with their aggressive phenotype [65,66]. In the complex glioblastoma landscape, several mechanisms drive vasculogenesis: (1) the recruitment of circulating endothelial progenitor cells into the vascular architecture of brain tumor [67,68]; (2) the lining of tumor vessels and tumor cells [68]; (3) a process of transdifferentiation where cancer stem-like cells differentiate into endothelial cells [69]. Here we reported that GM/ABX-treated mice exhibit increased CD34 + CD31 + vascularlike structure in the tumor core. ...
In recent years, several studies described the close relationship between the composition of gut microbiota and brain functions, highlighting the importance of gut-derived metabolites in mediating neuronal and glial cells cross-talk in physiological and pathological condition. Gut dysbiosis may affects cerebral tumors growth and progression, but the specific metabolites involved in this modulation have not been identified yet. Using a syngeneic mouse model of glioma, we have investigated the role of dysbiosis induced by the administration of non-absorbable antibiotics on mouse metabolome and on tumor microenvironment. We report that antibiotics treatment induced: (1) alteration of the gut and brain metabolome profiles; (2) modeling of tumor microenvironment toward a pro-angiogenic phenotype in which microglia and glioma cells are actively involved; (3) increased glioma stemness; (4) trans-differentiation of glioma cells into endothelial precursor cells, thus increasing vasculogenesis. We propose glycine as a metabolite that, in ABX-induced dysbiosis, shapes brain microenvironment and contributes to glioma growth and progression.
... Thus, angiogenesis induction represents one of the key cancer hallmarks that are shared by all types of cancer [9,10]. Angiogenesis is tightly regulated through the balance between stimulatory (proangiogenic) and inhibitory (antiangiogenic) signals, a phenomenon known as the angiogenic switch [11]. This switch is considered "on" when the proangiogenic signals overpower those of the antiangiogenic signals [12]. ...
VEGFR2 and FAK signaling pathways are interconnected and have synergistic effects on tumor angiogenesis, growth, and metastasis. Thus, instead of the conventional targeting of each of these proteins individually with a specific inhibitor, the present work aimed to discover novel dual inhibitors targeting both VEGFR2 and FAK exploiting their association. To this end, receptor-based pharmacophore modeling technique was opted to generate 3D pharmacophore models for VEGFR2 and FAK type II kinase inhibitors. The generated pharmacophore models were validated by assessing their ability to discriminate between active and decoy compounds in a pre-compiled test set of VEGFR2 and FAK active compounds and decoys. ZINCPharmer web tool was then used to screen the ZINC database purchasable subset using the validated pharmacophore models retrieving 42,616 hits for VEGFR2 and 28,475 hits for FAK. Subsequently, they were filtered using various filters leaving 13,023 and 6,832 survived compounds for VEGFR2 and FAK, respectively, with 124 common compounds. Based on molecular docking simulations, thirteen compounds were found to satisfy all necessary interactions with VEGFR2 and FAK kinase domains. Thus, they are predicted to have a possible dual VEGFR2/FAK inhibitory activity. Finally, SwissADME web tool showed that compound ZINC09875266 is not only promising in terms of binding pattern to our target kinases, but also in terms of pharmacokinetic properties.
... Pericytes are tightly connected to ECs and this interaction enables pericytes to control dynamic growth, migration, and phenotype acquisition of ECs via the release of Notch3, VEGF, angiopoietin 1, PDGF-BB, etc. (Gaengel et al., 2009;Lee et al., 2010). Following the release of pro-angiogenesis factors, the physical connection of pericytes to the vascular surface is loosened and thus ECs enter the proliferation state (Yancopoulos et al., 2000;Bergers and Benjamin, 2003). While pericytes are recruited to the abluminal surface of vessels during the maturation of vessel structure. ...
The vasculature system is composed of a multiplicity of juxtaposed cells to generate a functional biological barrier between the blood and tissues. On the luminal surface of blood vessels, endothelial cells (ECs) are in close contact with circulating cells while supporting basal lamina and pericytes wrap the abluminal surface. Thus, the reciprocal interaction of pericytes with ECs is a vital element in the physiological activity of the vascular system. Several reports have indicated that the occurrence of pericyte dysfunction under ischemic and degenerative conditions results in varied micro and macro-vascular complications. Emerging evidence points to the fact that autophagy, a conserved self-digestive cell machinery, can regulate the activity of several cells like pericytes in response to various stresses and pathological conditions. Here, we aim to highlight the role of autophagic response in pericyte activity and angiogenesis potential following different pathological conditions.
... Cell-cycle disruption can cause tumor dormancy, or it can result from a powerful balanced scenario where the start of apoptosis balances cell growth. Both during the onset of cancer formation and throughout the remission stage following the completion of anticancer therapy, tumors might recommence their progression from persisting residual illness [87]. Three key mechanisms by which MCT promotes tumor dormancy are immune surveillance, angiogenesis suppression, and programmed cell death of malignant cells [32].Immune surveillance enables the immune system to monitor, recognize, and eliminate nascent tumor cells. ...
Cancer represents a significant global health and economic burden due to its high mortality rates. While effective in some instances, traditional chemotherapy often falls short of entirely eradicating various types of cancer. It can cause severe side effects due to harm to healthy cells. Two therapeutic approaches have risen to the forefront to address these limitations: metronomic chemotherapy (MCT) and drug repurposing. Metronomic chemotherapy is an innovative approach that breaks from traditional models. It involves the administration of chemotherapeutic regimens at lower doses, without long drug-free intervals that have previously been a hallmark of such treatments. This method offers a significant reduction in side effects and improved disease management. Simultaneously, drug repurposing has gained considerable attraction in cancer treatment. This approach involves utilizing existing drugs, initially developed for other therapeutic purposes, as potential cancer treatments. The application of known drugs in a new context accelerates the timeline from laboratory to patient due to pre-existing safety and dosage data. The intersection of these two strategies gives rise to a novel therapeutic approach named ‘Metronomics.’ This approach encapsulates the benefits of both MCT and drug repurposing, leading to reduced toxicity, potential for oral administration, improved patient quality of life, accelerated clinical implementation, and enhanced affordability. Numerous clinical studies have endorsed the efficacy of metronomic chemotherapy with tolerable side effects, underlining the potential of Metronomics in better cancer management, particularly in low- and middle-income countries. This review underscores the benefits and applications of metronomic chemotherapy and drug repurposing, specifically in the context of breast cancer, showcasing the promising results of pre-clinical and clinical studies. However, we acknowledge the necessity of additional clinical investigations to definitively establish the role of metronomic chemotherapy in conjunction with other treatments in comprehensive cancer management.
... Abnormal angiogenesis allows the extravasation of plasma proteins, establishing a provisional matrix, necessary for the migration of activated endothelial cells. Basement membrane and extracellular matrix are degraded locally by metalloproteases, allowing the underlying endothelial cells to migrate following the trail of the angiogenic stimulus into the perivascular space [61]. Another study [62], not originally designed to look for retinal pathophysiological mechanisms but for the microvascular damage in diabetes, obtained results that fit again in demonstrating that sEVs from adipocytes obtained in a high glucose environment, were able to damage retina microvascular endothelial cells via a LINC00968/miR-361-5p/TRAF3 signaling pathway [62]. ...
This review focuses on the role of small extracellular vesicles in the pathophysiological mechanisms of retinal degenerative diseases. Many of these mechanisms are related or modulated by the oxidative burden of the retinal cells. It has been recently demonstrated that cellular communication in the retina involves extracellular vesicles and that their rate of release and cargo features might be affected by the cellular environment and in some instances also mediated by autophagy. The fate of these vesicles is diverse, and could end up in the circulation and be used as markers, or target neighbour cells modulating gene and protein expression and eventually also angiogenesis. Neovascularization in the retina promotes vision loss in diseases such as diabetic retinopathy and age-related macular degeneration. The importance of micro RNAs, either as small extracellular vesicles’ cargo or free circulating, on the regulation of retinal angiogenesis is also discussed.
... Angiogenesis factors (AFs) consist of anti-angiogenic and pro-angiogenic factors to maintain a delicate balance in angiogenesis. However, tumors are characterized by a disruption of this balance and induce activate angiogenesis of equilibrium, which acts as a condition for growth and metastasis [14,15]. Treatments for metastatic RCC have been revolutionized by antiangiogenic targeted therapy [16,17]. ...
Background
Clear cell renal cell carcinoma (ccRCC), the most common type of RCC, typically produces no symptoms initially. Patients with ccRCC are at increased risk of developing advanced metastatic disease due to the absence of dependable and effective prognostic biomarkers. Therefore, it is particularly urgent to find optimal stratification of patients with ccRCC to distinguish the clinical benefits of different malignant degrees. Angiogenesis has a profound impact on the malignant behavior of renal cancer cells, and anti-angiogenic drugs have been applied to metastatic renal cancer patients. Moreover, immune function dysregulation is also a significant factor in tumorigenesis. We aim to construct a predictive model that combines angiogenesis and immune-related genes (AIRGs) to aid clinicians in predicting ccRCC prognosis.
Methods
We gathered transcriptome and clinicopathology data from two datasets, the E-MTAB-1980 dataset and the Cancer Genome Atlas (TCGA). We utilized consensus clustering to find new molecular subgroups. A predictive model for the prognosis of angiogenesis-immune-associated genes (AIRGs) was conducted by the lasso and multivariate Cox regression analysis. The signature's predictive ability was then tested in different datasets. Meticulous scrutiny and comprehensive assessment were undertaken, both internally and externally, to establish the prognostic model. Analyses of immunogenomics were carried out to examine the relationship between risk scores and clinical/immune features, including immune cell infiltration, genomic alterations, and response to targeted and immunotherapy therapy.
Results
Our prognostic signature, comprising 4 AIRGs, stood as an independent prognostic factor for ccRCC, while risk scores emerged as a novel indicator for forecasting overall survival. Risk scores exhibited significant associations with various immunophenotypic factors, such as oncogenic pathways, antitumor response, different immune cell infiltration, antitumor immunity, and response to targeted and immunotherapy therapy.
Conclusions
AIRGs-based prognostic prediction model could effectively predict immunotherapy responses and survival outcomes of ccRCC.
Veterinary oncology has experienced significant evolution over the last few decades, with chemotherapy being currently applied to several neoplasms with therapeutic success. Traditionally, chemotherapy protocols are based on classic cytostatic drugs under the concept of maximum tolerated dose (MTD), which has been associated with a greater risk of toxicity and resistance. Thus, new therapeutic alternatives have emerged, such as metronomic chemotherapy (MC), introducing a new paradigm in cancer treatment. MC consists of administering low doses of chemotherapy drugs continuously over a long period of time, modulating the tumour microenvironment (TME) due to the combination of cytotoxic, antiangiogenic and immunomodulatory effects. This multi-targeted therapy has been described as a treatment option in several canine and feline cancers since 2007, with positive results already published in the literature, particularly in mammary carcinomas and soft tissue sarcomas in dogs. The aim of this review article is to describe the current knowledge about the use of MC in small animal oncology, with emphasis on its mechanisms of action, the most commonly used drugs and clinical outcome.
Transient left ventricular dysfunction (TLVD), a temporary condition marked by reversible impairment of ventricular function, remains an underdiagnosed yet significant contributor to morbidity and mortality in clinical practice. Unlike the well-explored atherosclerotic disease of the epicardial coronary arteries, the diverse etiologies of TLVD require greater attention for proper diagnosis and management. The spectrum of disorders associated with TLVD includes stress-induced cardiomyopathy, central nervous system injuries, histaminergic syndromes, various inflammatory diseases, pregnancy-related conditions, and genetically determined syndromes. Furthermore, myocardial infarction with non-obstructive coronary arteries (MINOCA) origins such as coronary artery spasm, coronary thromboembolism, and spontaneous coronary artery dissection (SCAD) may also manifest as TLVD, eventually showing recovery. This review highlights the range of ischemic and non-ischemic clinical situations that lead to TLVD, gathering conditions like Tako-Tsubo Syndrome (TTS), Kounis syndrome (KS), Myocarditis, Peripartum Cardiomyopathy (PPCM), and Tachycardia-induced cardiomyopathy (TIC). Differentiation amongst these causes is crucial, as they involve distinct clinical, instrumental, and genetic predictors that bode different outcomes and recovery potential for left ventricular function. The purpose of this review is to improve everyday clinical approaches to treating these diseases by providing an extensive survey of conditions linked with TLVD and the elements impacting prognosis and outcomes.
Extracellular vesicles (EVs) have recently received increasing attention as essential mediators of communication between tumor cells and their microenvironments. Tumor-associated macrophages (TAMs) play a proangiogenic role in various tumors, especially head and neck squamous cell carcinoma (HNSCC), and angiogenesis is closely related to tumor growth and metastasis. This research focused on exploring the mechanisms by which EVs derived from TAMs modulate tumor angiogenesis in HNSCC. Our results indicated that TAMs infiltration correlated positively with microvascular density in HNSCC. Then we collected and identified EVs from TAMs. In the microfluidic chip, TAMs derived EVs significantly enhanced the angiogenic potential of pHUVECs and successfully induced the formation of perfusable blood vessels. qPCR and immunofluorescence analyses revealed that EVs from TAMs transferred miR-21-5p to endothelial cells (ECs). And targeting miR-21-5p of TAMs could effectively inhibit TAM-EVs induced angiogenesis. Western blot and tube formation assays showed that miR-21-5p from TAM-EVs downregulated LATS1 and VHL levels but upregulated YAP1 and HIF-1α levels, and the inhibitors of YAP1 and HIF-1α could both reduce the miR-21-5p enhanced angiogenesis in HUVECs. The in vivo experiments further proved that miR-21-5p carried by TAM-EVs promoted the process of tumor angiogenesis via YAP1/HIF-1α axis in HNSCC. Conclusively, TAM-derived EVs transferred miR-21-5p to ECs to target the mRNA of LATS1 and VHL, which inhibited YAP1 phosphorylation and subsequently enhanced YAP1-mediated HIF-1α transcription and reduced VHL-mediated HIF-1α ubiquitination, contributing to angiogenesis in HNSCC. These findings present a novel regulatory mechanism of tumor angiogenesis, and miR-21-5p/YAP1/HIF-1α might be a potential therapeutic target for HNSCC.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00018-024-05210-6.
In European countries, nearly 10% of all hospital admissions are related to respiratory diseases, mainly chronic life-threatening diseases such as COPD, pulmonary hypertension, IPF or lung cancer. The contribution of blood vessels and angiogenesis to lung regeneration, remodeling and disease progression has been increasingly appreciated. The vascular supply of the lung shows the peculiarity of dual perfusion of the pulmonary circulation (vasa publica), which maintains a functional blood-gas barrier, and the bronchial circulation (vasa privata), which reveals a profiled capacity for angiogenesis (namely intussusceptive and sprouting angiogenesis) and alveolar-vascular remodeling by the recruitment of endothelial precursor cells. The aim of this review is to outline the importance of vascular remodeling and angiogenesis in a variety of non-neoplastic and neoplastic acute and chronic respiratory diseases such as lung infection, COPD, lung fibrosis, pulmonary hypertension and lung cancer.
Plant-based natural products provide a strong background to evaluate, predict the novel class of compounds having anti-cancer properties, as well as to explore their potential mechanism mechanisms of action. Due to the huge cost and time utilization in the traditional drug development approaches, bioinformatics plays a major role to facilitate drug discovery with less cost and time strategies. Several bioinformatics-based approaches being used recently to screen as well as to characterize the potential plant-based compounds can be used to treat several types of cancer. Some of the computational approaches are target identification, screening of compounds molecular docking, molecular dynamics simulations, QSAR analysis, pharmacophore modeling, and ADMET (absorption, distribution, metabolism, excretion, and toxicity). This chapter describes specific computational methods being used currently to screen and characterize different plant-based anti-cancer molecules by taking examples from the recent literature and discussing their advantages and limitations.
The tumor microenvironment is a highly complex and dynamic mixture of cell types, including tumor, immune and endothelial cells (ECs), soluble factors (cytokines, chemokines, and growth factors), blood vessels and extracellular matrix. Within this complex network, ECs are not only relevant for controlling blood fluidity and permeability, and orchestrating tumor angiogenesis but also for regulating the antitumor immune response. Lining the luminal side of vessels, ECs check the passage of molecules into the tumor compartment, regulate cellular transmigration, and interact with both circulating pathogens and innate and adaptive immune cells. Thus, they represent a first-line defense system that participates in immune responses. Tumor-associated ECs are involved in T cell priming, activation, and proliferation by acting as semi-professional antigen presenting cells. Thus, targeting ECs may assist in improving antitumor immune cell functions. Moreover, tumor-associated ECs contribute to the development at the tumor site of tertiary lymphoid structures, which have recently been associated with enhanced response to immune checkpoint inhibitors (ICI). When compared to normal ECs, tumor-associated ECs are abnormal in terms of phenotype, genetic expression profile, and functions. They are characterized by high proliferative potential and the ability to activate immunosuppressive mechanisms that support tumor progression and metastatic dissemination. A complete phenotypic and functional characterization of tumor-associated ECs could be helpful to clarify their complex role within the tumor microenvironment and to identify EC specific drug targets to improve cancer therapy. The emerging therapeutic strategies based on the combination of anti-angiogenic treatments with immunotherapy strategies, including ICI, CAR T cells and bispecific antibodies aim to impact both ECs and immune cells to block angiogenesis and at the same time to increase recruitment and activation of effector cells within the tumor.
Tumors have high requirements in terms of nutrients and oxygen. Angiogenesis is the classical mechanism for vessel formation. Tumoral vascularization has the function of nourishing the cancer cells to support tumor growth. Vasculogenic mimicry, a novel intratumoral microcirculation system, alludes to the ability of cancer cells to organize in three-dimensional (3D) channel-like architectures. It also supplies the tumors with nutrients and oxygen. Both mechanisms operate in a coordinated way; however, their functions in breast cancer stem-like cells and their regulation by microRNAs remain elusive. In the present study, we investigated the functional role of microRNA-204 (miR-204) on angiogenesis and vasculogenic mimicry in breast cancer stem-like cells. Using flow cytometry assays, we found that 86.1% of MDA-MB-231 and 92% of Hs-578t breast cancer cells showed the CD44+/CD24− immunophenotype representative of cancer stem-like cells (CSCs). The MDA-MB-231 subpopulation of CSCs exhibited the ability to form mammospheres, as expected. Interestingly, we found that the restoration of miR-204 expression in CSCs significantly inhibited the number and size of the mammospheres. Moreover, we found that MDA-MB-231 and Hs-578t CSCs efficiently undergo angiogenesis and hypoxia-induced vasculogenic mimicry in vitro. The transfection of precursor miR-204 in both CSCs was able to impair the angiogenesis in the HUVEC cell model, which was observed as a diminution in the number of polygons and sprouting cells. Remarkably, miR-204 mimics also resulted in the inhibition of vasculogenic mimicry formation in MDA-MB-231 and Hs-578t CSCs, with a significant reduction in the number of channel-like structures and branch points. Mechanistically, the effects of miR-204 were associated with a diminution of pro-angiogenic VEGFA and β-catenin protein levels. In conclusion, our findings indicated that miR-204 abrogates the angiogenesis and vasculogenic mimicry development in breast cancer stem-like cells, suggesting that it could be a potential tool for breast cancer intervention based on microRNA replacement therapies.
This review focuses on the role of small extracellular vesicles in the pathophysiological mechanisms of retinal degenerative diseases. Many of these mechanisms are related to or modulated by the oxidative burden of retinal cells. It has been recently demonstrated that cellular communication in the retina involves extracellular vesicles and that their rate of release and cargo features might be affected by the cellular environment, and in some instances, they might also be mediated by autophagy. The fate of these vesicles is diverse: they could end up in circulation being used as markers, or target neighbor cells modulating gene and protein expression, or eventually, in angiogenesis. Neovascularization in the retina promotes vision loss in diseases such as diabetic retinopathy and age-related macular degeneration. The importance of micro RNAs, either as small extracellular vesicles’ cargo or free circulating, in the regulation of retinal angiogenesis is also discussed.
Previously, we demonstrated that the expression of THBS1 is increased in esophageal squamous cell carcinoma (ESCC) tissues and is correlated with lymph node metastasis and poor prognosis, indicating that THBS1 might be a candidate oncogene in ESCC. In this study, we future studied the specific role of THBS1 in ESCC and its molecular mechanism. Silencing THBS1 expression resulted in inhibition of cell migration and cell invasion of ESCC cells, the decrease of colony formation and proliferation. Tube formation of human umbilical vein endothelial cells (HUVECs) in vitro was decreased when cultured with conditioned medium from THBS1‐silenced cells. The expression of CD31, a marker for blood vessel endothelial cells, was decreased in tumor tissues derived from THBS1‐silenced tumors in vivo. Silencing THBS1 leaded the decreased of hypoxia‐inducible factor‐1α (HIF‐1α), HIF‐1β, and VEGFA protein. The expression of p‐ERK and p‐AKT were declined in HUVECs following incubation with conditioned medium from THBS1‐silenced ESCC cells compared conditioned medium from control cells. Furthermore, the treatment with bevacizumab boosted the decrease of the p‐ERK and p‐AKT levels in HUVECs incubated with the conditioned medium from THBS1‐silenced ESCC cells. THBS1 silencing combined with bevacizumab blocked VEGF, inhibited to the tube formation, colony formation and migration of HUVECs, which were superior to that of bevacizumab alone. We presumed that THBS1 can enhance HIF‐1/VEGF signaling and subsequently induce angiogenesis by activating the AKT and ERK pathways in HUVECs, resulting in bevacizumab resistance. THBS1 would be a potential target in tumor antiangiogenesis therapies.
Simple Summary
Breast cancer, the second-leading cause of mortality among women worldwide, is often diagnosed through invasive tissue sampling. This method may not fully represent the tumor’s overall physiology, potentially leading to suboptimal treatment strategies and tumor recurrence. A non-invasive approach using MRI to quantify the hypoxic environment within the tumor could significantly enhance the accuracy of breast-cancer-subtype prediction. Our study introduces non-invasive imaging markers for hypoxia and related angiogenesis, utilizing hyperoxic-blood-oxygen-level-dependent (BOLD)-MRI and intravoxel-incoherent-motion (IVIM)-MRI techniques. These markers correlate with microvessel density and maturity as assessed by histology, enabling the distinction between the less aggressive luminal A and the more aggressive triple-negative breast cancers.
Abstract
Tumor neoangiogenesis is an important hallmark of cancer progression, triggered by alternating selective pressures from the hypoxic tumor microenvironment. Non-invasive, non-contrast-enhanced multiparametric MRI combining blood-oxygen-level-dependent (BOLD) MRI, which depicts blood oxygen saturation, and intravoxel-incoherent-motion (IVIM) MRI, which captures intravascular and extravascular diffusion, can provide insights into tumor oxygenation and neovascularization simultaneously. Our objective was to identify imaging markers that can predict hypoxia-induced angiogenesis and to validate our findings using multiplexed immunohistochemical analyses. We present an in vivo study involving 36 female athymic nude mice inoculated with luminal A, Her2+, and triple-negative breast cancer cells. We used a high-field 9.4-tesla MRI system for imaging and subsequently analyzed the tumors using multiplex immunohistochemistry for CD-31, PDGFR-β, and Hif1-α. We found that the hyperoxic-BOLD-MRI-derived parameter ΔR2* discriminated luminal A from Her2+ and triple-negative breast cancers, while the IVIM-derived parameter fIVIM discriminated luminal A and Her2+ from triple-negative breast cancers. A comprehensive analysis using principal-component analysis of both multiparametric MRI- and mpIHC-derived data highlighted the differences between triple-negative and luminal A breast cancers. We conclude that multiparametric MRI combining hyperoxic BOLD MRI and IVIM MRI, without the need for contrast agents, offers promising non-invasive markers for evaluating hypoxia-induced angiogenesis.
β-Caryophyllene (BCP), a bicyclic sesquiterpene that is a component of the essential oils of various spice and food plants, has been described as a selective CB2 cannabinoid receptor agonist. In the present study, the effect of BCP on angiogenesis was investigated. It was found that conditioned media (CM) from BCP-treated hypoxic A549 lung cancer cells exhibited a concentration-dependent inhibitory effect on human umbilical vein endothelial cell (HUVEC) tube formation induced by CM from vehicle-treated hypoxic A549 cells. There was an associated concentration-dependent decrease in the proangiogenic factor vascular endothelial growth factor (VEGF) in the CM, with both BCP inhibitory effects (tube formation, VEGF secretion) being CB2 receptor-dependent. A reduction of the transcription factor hypoxia-inducible factor 1α (HIF-1α) was furthermore detected. The antiangiogenic and VEGF-lowering properties of BCP were confirmed when CM from another lung cancer cell line, H358, were tested. When directly exposed to HUVECs, BCP showed no significant effect on tube formation, but at 10 µM, impaired VEGF receptor 2 (VEGFR2) phosphorylation triggered by recombinant VEGF in a CB2 receptor-independent manner. In summary, BCP has a dual antiangiogenic effect on HUVECs, manifested in the inhibition of tube formation through modulation of the tumor cell secretome and additionally in the inhibition of VEGF-induced VEGFR2 activation. Because the CB2 agonist has no psychoactive properties, BCP should continue to be evaluated preclinically for further antitumor effects.
Organ-specific metastasis is the primary cause of cancer patient death. The distant metastasis of tumor cells to specific organs depends on both the intrinsic characteristics of the tumor cells and extrinsic factors in their microenvironment. During an intermediate stage of metastasis, circulating tumor cells (CTCs) are released into the bloodstream from primary and metastatic tumors. CTCs harboring aggressive or metastatic features can extravasate to remote sites for continuous colonizing growth, leading to further lesions. In the past decade, numerous studies demonstrated that CTCs exhibited huge clinical value including predicting distant metastasis, assessing prognosis and monitoring treatment response et al. Furthermore, increasingly numerous experiments are dedicated to identifying the key molecules on or inside CTCs and exploring how they mediate CTC-related organ-specific metastasis. Based on the above molecules, more and more inhibitors are being developed to target CTCs and being utilized to completely clean CTCs, which should provide promising prospects to administer advanced tumor. Recently, the application of various nanomaterials and microfluidic technologies in CTCs enrichment technology has assisted to improve our deep insights into the phenotypic characteristics and biological functions of CTCs as a potential therapy target, which may pave the way for us to make practical clinical strategies. In the present review, we mainly focus on the role of CTCs being involved in targeted organ metastasis, especially the latest molecular mechanism research and clinical intervention strategies related to CTCs.
Simple Summary
Peritoneum is the most common metastasis site of gastric cancer, and angiogenesis plays a key role in peritoneal metastasis which the specific mechanism of is unknown. We focused on the peritoneal metastasis-associated secretory protein ESM1 based on the previous RNA-seq. The expression of ESM1 is up-regulated in gastric cancer tissues, and even higher in primary gastric cancer with peritoneal metastasis. Moreover, the high expression of ESM1 is significantly associated with poor prognosis. Through clinicopathological data analysis, it was found that ESM1 was positively correlated with vascular invasion. The conditioned medium of gastric cancer cells overexpressing ESM1 promoted tube formation in vitro and gastric cancer cells overexpressing ESM1 induced angiogenesis in vitro. Mechanically, ESM1 binds to c-Met receptor on the surface of endothelial cells, activates the downstream MAPK/ERK signaling pathway, and promotes the transcription and translation of pro-angiogenic molecules (such as HIF1α, VEGFA and MMP9) in endothelial cell, thereby promoting peritoneal metastasis of gastric cancer. Our study may provide a new direction for the diagnosis and treatment of peritoneal metastasis of gastric cancer.
Abstract
The peritoneum is the most common metastatic site of advanced gastric cancer and is associated with extremely poor prognosis. Endothelial-specific molecule 1 (ESM1) was found to be significantly associated with gastric cancer peritoneal metastasis (GCPM); however, the biological functions and molecular mechanisms of ESM1 in regulating GCPM remain unclear. Herein, we demonstrated that ESM1 expression was significantly upregulated in gastric cancer tissues and positively correlated with platelet endothelial cell adhesion molecule-1 (CD31) levels. Moreover, clinical validation, in in vitro and in vivo experiments, confirmed that ESM1 promoted gastric cancer angiogenesis, eventually promoting gastric cancer peritoneal metastasis. Mechanistically, ESM1 promoted tumor angiogenesis by binding to c-Met on the vascular endothelial cell membrane. In addition, our results confirmed that ESM1 upregulated VEGFA, HIF1α, and MMP9 expression and induced angiogenesis by activating the MAPK/ERK pathway. In conclusion, our findings identified the role of ESM1 in gastric cancer angiogenesis and GCPM, thus providing insights into the diagnosis and treatment of advanced gastric cancer.
A possible link between diet and cancer has long been considered, with growing interest in phytochemicals. Soy isoflavones have been associated with a reduced risk of prostate cancer in Asian populations. Of the soy isoflavones, genistein and daidzein, in particular, have been studied, but recently, equol as a derivative has gained interest because it is more biologically potent. Different mechanisms of action have already been studied for the different isoflavones in multiple conditions, such as breast, gastrointestinal, and urogenital cancers. Many of these mechanisms of action could also be demonstrated in the prostate, both in vitro and in vivo. This review focuses on the known mechanisms of action at the cellular level and compares them between genistein, daidzein, and equol. These include androgen- and estrogen-mediated pathways, regulation of the cell cycle and cell proliferation, apoptosis, angiogenesis, and metastasis. In addition, antioxidant and anti-inflammatory effects and epigenetics are addressed.
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