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Advances in Cancer Research 2020Vascular mimicry is induced by a wide array of genes with functions related to cancer stemness, hypoxia, angiogenesis and autophagy. Vascular mimicry competent... (Review)
Review
Vascular mimicry is induced by a wide array of genes with functions related to cancer stemness, hypoxia, angiogenesis and autophagy. Vascular mimicry competent (VM-competent) cells that form de novo blood vessels are common in solid tumors facilitating tumor cell survival and metastasis. VM-competent cells display increased levels of vascular mimicry selecting for stem-like cells in an O-gradient-dependent manner in deeply hypoxic tumor regions, while also aiding in maintaining tumor cell metabolism and stemness. Three of the principal drivers of vascular mimicry are EphA2, Nodal and HIF-1α, however, directly or indirectly many of these molecules affect VE-Cadherin (VE-Cad), which forms gap-junctions to bind angiogenic blood vessels together. During vascular mimicry, the endothelial-like functions of VM-competent cancer stem cells co-opt VE-Cad to bind cancer cells together to create cancer cell-derived blood conducting vessels. This process potentially compensates for the lack of access to blood and nutrient in avascular tumors, simultaneously providing nutrients and enhancing cancer invasion and metastasis. Current evidence also supports that vascular mimicry promotes cancer malignancy and metastasis due to the cooperation of oncogenic signaling molecules driving cancer stemness and autophagy. While a number of currently used cancer therapeutics are effective inhibitors of vascular mimicry, developing a new class of vascular mimicry specific inhibitors could allow for the treatment of angiogenesis-resistant tumors, inhibit cancer metastasis and improve patient survival. In this review, we describe the principal vascular mimicry pathways in addition to emphasizing the roles of hypoxia, autophagy and select proangiogenic oncogenes in this process.
Topics: Animals; Autophagy; Cell Hypoxia; Disease Models, Animal; Humans; Neoplasm Proteins; Neoplasms; Neovascularization, Pathologic
PubMed: 32723566
DOI: 10.1016/bs.acr.2020.06.001 -
Journal of Pharmacy & Pharmaceutical... 2016Since early seventies of the twentieth century, through seminal work of Judah Folkman, angiogenesis, the process of new blood vessel sprouting from the existing... (Review)
Review
Since early seventies of the twentieth century, through seminal work of Judah Folkman, angiogenesis, the process of new blood vessel sprouting from the existing vasculature, was recognized as a necessary part of wound healing, development of placenta, tissue growth and regeneration as well as cancer progression. This process is induced by low tissue oxygenation and it is a crucial prerequisite for rapid tissue growth, providing proper oxygen supply and removal of toxic metabolites. Suppression of angiogenesis as a way of slowing down tumor progression continues to be one of the most important areas of cancer research. The angiogenic process is relatively complex and it is regulated by numerous pro- and anti-angiogenic factors. Intensive research in the last twenty years resulted in identification of more than 300 angiogenesis inhibitors, a trend that is expected to continue. Unfortunately, most of these treatments have demonstrated unacceptable toxicities or failed to show activity in clinical studies. Although not yet completely understood, the complex process of tumor angiogenesis involves highly regulated orchestration of multiple activating and inhibiting factors. Vascular endothelial growth factor (VEGF) and its cognate receptors appear to play a central role in angiogenesis activation. Thus, initial efforts to develop anti-angiogenic treatments focused largely on inhibiting VEGF action. Such approaches, however, often lead to transient responses due to multiple pathways able to compensate for a single pathway inhibited. Accordingly, more recent treatments have focused on simultaneous inhibition of multiple signaling pathways. This review concentrates on identifying those anti-angiogenic treatments that made to the clinic by receiving approval by USA Food and Drug Administration (FDA) as treatments for cancer. Regardless of observed problems, it is an imperative that research in angiogenesis regulation continues. Consequently, pharmacological manipulation of angiogenesis may yet to introduce truly new pharmacological therapies into the field of cancer therapy, the field that was rather dormant in the last several decades. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
Topics: Antineoplastic Agents; Humans; Neoplasms; Neovascularization, Pathologic
PubMed: 27518172
DOI: 10.18433/jpps.v19i2.27608 -
PLoS Computational Biology Jan 2020During angiogenesis, new blood vessels sprout and grow from existing ones. This process plays a crucial role in organ development and repair, in wound healing and in...
During angiogenesis, new blood vessels sprout and grow from existing ones. This process plays a crucial role in organ development and repair, in wound healing and in numerous pathological processes such as cancer progression or diabetes. Here, we present a mathematical model of early stage angiogenesis that permits exploration of the relative importance of mechanical, chemical and cellular cues. Endothelial cells proliferate and move over an extracellular matrix by following external gradients of Vessel Endothelial Growth Factor, adhesion and stiffness, which are incorporated to a Cellular Potts model with a finite element description of elasticity. The dynamics of Notch signaling involving Delta-4 and Jagged-1 ligands determines tip cell selection and vessel branching. Through their production rates, competing Jagged-Notch and Delta-Notch dynamics determine the influence of lateral inhibition and lateral induction on the selection of cellular phenotypes, branching of blood vessels, anastomosis (fusion of blood vessels) and angiogenesis velocity. Anastomosis may be favored or impeded depending on the mechanical configuration of strain vectors in the ECM near tip cells. Numerical simulations demonstrate that increasing Jagged production results in pathological vasculatures with thinner and more abundant vessels, which can be compensated by augmenting the production of Delta ligands.
Topics: Algorithms; Animals; Computational Biology; Computer Simulation; Models, Biological; Neovascularization, Pathologic; Neovascularization, Physiologic; Receptors, Notch; Signal Transduction; Taxis Response
PubMed: 31986145
DOI: 10.1371/journal.pcbi.1006919 -
American Journal of Physiology.... Aug 2013The renin angiotensin system (RAS) is a network of enzymes and peptides that coalesce primarily on the angiotensin II type 1 receptor (AT1R) to induce cell... (Review)
Review
The renin angiotensin system (RAS) is a network of enzymes and peptides that coalesce primarily on the angiotensin II type 1 receptor (AT1R) to induce cell proliferation, angiogenesis, fibrosis, and blood pressure control. Angiotensin-converting enzyme (ACE), the key peptidase of the RAS, is promiscuous in that it cleaves other substrates such as substance P and bradykinin. Accumulating evidence implicates ACE in the pathophysiology of carcinogenesis. While the role of ACE and its peptide network in modulating angiogenesis via the AT1R is well documented, its involvement in shaping other aspects of the tumor microenvironment remains largely unknown. Here, we review the role of ACE in modulating the immune compartment of the tumor microenvironment, which encompasses the immunosuppressive, cancer-promoting myeloid-derived suppressor cells, alternatively activated tumor-associated macrophages, and T regulatory cells. We also discuss the potential roles of peptides that accumulate in the setting of chronic ACE inhibitor use, such as bradykinin, substance P, and N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), and how they may undercut the gains of anti-angiogenesis from ACE inhibition. These emerging mechanisms may harmonize the often-conflicting results on the role of ACE inhibitors and ACE polymorphisms in various cancers and call for further investigations into the potential benefit of ACE inhibitors in some neoplasms.
Topics: Animals; Humans; Myeloid Cells; Neoplasms; Neovascularization, Pathologic; Neovascularization, Physiologic; Peptidyl-Dipeptidase A; Renin-Angiotensin System; T-Lymphocytes; Tumor Microenvironment
PubMed: 23739345
DOI: 10.1152/ajpregu.00544.2012 -
Advanced Science (Weinheim,... Feb 2024Chemotherapy is widely used to treat colorectal cancer (CRC). Despite its substantial benefits, the development of drug resistance and adverse effects remain...
Chemotherapy is widely used to treat colorectal cancer (CRC). Despite its substantial benefits, the development of drug resistance and adverse effects remain challenging. This study aimed to elucidate a novel role of glucagon in anti-cancer therapy. In a series of in vitro experiments, glucagon inhibited cell migration and tube formation in both endothelial and tumor cells. In vivo studies demonstrated decreased tumor blood vessels and fewer pseudo-vessels in mice treated with glucagon. The combination of glucagon and chemotherapy exhibited enhanced tumor inhibition. Mechanistic studies demonstrated that glucagon increased the permeability of blood vessels, leading to a pronounced disruption of vessel morphology. Signaling pathway analysis identified a VEGF/VEGFR-dependent mechanism whereby glucagon attenuated angiogenesis through its receptor. Clinical data analysis revealed a positive correlation between elevated glucagon expression and chemotherapy response. This is the first study to reveal a role for glucagon in inhibiting angiogenesis and vascular mimicry. Additionally, the delivery of glucagon-encapsulated PEGylated liposomes to tumor-bearing mice amplified the inhibition of angiogenesis and vascular mimicry, consequently reinforcing chemotherapy efficacy. Collectively, the findings demonstrate the role of glucagon in inhibiting tumor vessel network and suggest the potential utility of glucagon as a promising predictive marker for patients with CRC receiving chemotherapy.
Topics: Humans; Animals; Mice; Glucagon; Neovascularization, Pathologic; Colorectal Neoplasms; Signal Transduction; Cell Line, Tumor
PubMed: 38072640
DOI: 10.1002/advs.202307271 -
Seminars in Cancer Biology Dec 2015Deregulation of angiogenesis--the growth of new blood vessels from an existing vasculature--is a main driving force in many severe human diseases including cancer. As... (Review)
Review
Deregulation of angiogenesis--the growth of new blood vessels from an existing vasculature--is a main driving force in many severe human diseases including cancer. As such, tumor angiogenesis is important for delivering oxygen and nutrients to growing tumors, and therefore considered an essential pathologic feature of cancer, while also playing a key role in enabling other aspects of tumor pathology such as metabolic deregulation and tumor dissemination/metastasis. Recently, inhibition of tumor angiogenesis has become a clinical anti-cancer strategy in line with chemotherapy, radiotherapy and surgery, which underscore the critical importance of the angiogenic switch during early tumor development. Unfortunately the clinically approved anti-angiogenic drugs in use today are only effective in a subset of the patients, and many who initially respond develop resistance over time. Also, some of the anti-angiogenic drugs are toxic and it would be of great importance to identify alternative compounds, which could overcome these drawbacks and limitations of the currently available therapy. Finding "the most important target" may, however, prove a very challenging approach as the tumor environment is highly diverse, consisting of many different cell types, all of which may contribute to tumor angiogenesis. Furthermore, the tumor cells themselves are genetically unstable, leading to a progressive increase in the number of different angiogenic factors produced as the cancer progresses to advanced stages. As an alternative approach to targeted therapy, options to broadly interfere with angiogenic signals by a mixture of non-toxic natural compound with pleiotropic actions were viewed by this team as an opportunity to develop a complementary anti-angiogenesis treatment option. As a part of the "Halifax Project" within the "Getting to know cancer" framework, we have here, based on a thorough review of the literature, identified 10 important aspects of tumor angiogenesis and the pathological tumor vasculature which would be well suited as targets for anti-angiogenic therapy: (1) endothelial cell migration/tip cell formation, (2) structural abnormalities of tumor vessels, (3) hypoxia, (4) lymphangiogenesis, (5) elevated interstitial fluid pressure, (6) poor perfusion, (7) disrupted circadian rhythms, (8) tumor promoting inflammation, (9) tumor promoting fibroblasts and (10) tumor cell metabolism/acidosis. Following this analysis, we scrutinized the available literature on broadly acting anti-angiogenic natural products, with a focus on finding qualitative information on phytochemicals which could inhibit these targets and came up with 10 prototypical phytochemical compounds: (1) oleanolic acid, (2) tripterine, (3) silibinin, (4) curcumin, (5) epigallocatechin-gallate, (6) kaempferol, (7) melatonin, (8) enterolactone, (9) withaferin A and (10) resveratrol. We suggest that these plant-derived compounds could be combined to constitute a broader acting and more effective inhibitory cocktail at doses that would not be likely to cause excessive toxicity. All the targets and phytochemical approaches were further cross-validated against their effects on other essential tumorigenic pathways (based on the "hallmarks" of cancer) in order to discover possible synergies or potentially harmful interactions, and were found to generally also have positive involvement in/effects on these other aspects of tumor biology. The aim is that this discussion could lead to the selection of combinations of such anti-angiogenic compounds which could be used in potent anti-tumor cocktails, for enhanced therapeutic efficacy, reduced toxicity and circumvention of single-agent anti-angiogenic resistance, as well as for possible use in primary or secondary cancer prevention strategies.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Phytogenic; Blood Vessels; Cell Proliferation; Humans; Immunotherapy; Neoplasms; Neovascularization, Pathologic
PubMed: 25600295
DOI: 10.1016/j.semcancer.2015.01.001 -
Science Advances Aug 2020Mechanical cues influence tissue regeneration, and although vasculature is known to be mechanically sensitive, little is known about the effects of bulk extracellular...
Mechanical cues influence tissue regeneration, and although vasculature is known to be mechanically sensitive, little is known about the effects of bulk extracellular matrix deformation on the nascent vessel networks found in healing tissues. Previously, we found that dynamic matrix compression in vivo potently regulated revascularization during bone tissue regeneration; however, whether matrix deformations directly regulate angiogenesis remained unknown. Here, we demonstrated that load initiation time, magnitude, and mode all regulate microvascular growth, as well as upstream angiogenic and mechanotransduction signaling pathways. Immediate load initiation inhibited angiogenesis and expression of early sprout tip cell selection genes, while delayed loading enhanced microvascular network formation and upstream signaling pathways. This research provides foundational understanding of how extracellular matrix mechanics regulate angiogenesis and has critical implications for clinical translation of new regenerative medicine therapies and physical rehabilitation strategies designed to enhance revascularization during tissue regeneration.
Topics: Bone Regeneration; Extracellular Matrix; Humans; Mechanotransduction, Cellular; Neovascularization, Pathologic; Neovascularization, Physiologic
PubMed: 32937368
DOI: 10.1126/sciadv.abb6351 -
Pharmacology & Therapeutics Aug 2016Interaction of numerous signaling pathways in endothelial and mesangial cells results in exquisite control of the process of physiological angiogenesis, with a central... (Review)
Review
Interaction of numerous signaling pathways in endothelial and mesangial cells results in exquisite control of the process of physiological angiogenesis, with a central role played by vascular endothelial growth factor receptor 2 (VEGFR-2) and its cognate ligands. However, deregulated angiogenesis participates in numerous pathological processes. Excessive activation of VEGFR-2 has been found to mediate tissue-damaging vascular changes as well as the induction of blood vessel expansion to support the growth of solid tumors. Consequently, therapeutic intervention aimed at inhibiting the VEGFR-2 pathway has become a mainstay of treatment in cancer and retinal diseases. In this review, we introduce the concepts of physiological and pathological angiogenesis, the crucial role played by the VEGFR-2 pathway in these processes, and the various inhibitors of its activity that have entered the clinical practice. We primarily focus on the development of ramucirumab, the antagonist monoclonal antibody (mAb) that inhibits VEGFR-2 and has recently been approved for use in patients with gastric, colorectal, and lung cancers. We examine in-depth the pre-clinical studies using DC101, the mAb to mouse VEGFR-2, which provided a conceptual foundation for the role of VEGFR-2 in physiological and pathological angiogenesis. Finally, we discuss further clinical development of ramucirumab and the future of targeting the VEGF pathway for the treatment of cancer.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Drug Resistance, Neoplasm; Drug Therapy, Combination; Humans; Neoplasms; Neovascularization, Pathologic; Vascular Endothelial Growth Factor Receptor-2; Ramucirumab
PubMed: 27288725
DOI: 10.1016/j.pharmthera.2016.06.001 -
Endokrynologia Polska 2011Angiogenesis is an important component of many physiological processes, such as the female sexual cycle, placenta formation, the processes of growth and differentiation... (Review)
Review
Angiogenesis is an important component of many physiological processes, such as the female sexual cycle, placenta formation, the processes of growth and differentiation of tissues, and reparative processes including wound healing, fracture repair, and liver regeneration. The formation of new blood vessels during angiogenesis and vasculogenesis allows the growth and functioning of multicellular organisms. Pathological angiogenesis most commonly occurs in ischaemic, inflammatory and neoplastic diseases. Conditions in the pathogenesis of which angiogenesis plays an important role are sometimes labelled angiogenic diseases. To date, a number of pro-and anti-angiogenic factors have been defined. VEGF is the only specific mitogen for endothelial cells. It stimulates their growth and inhibits apoptosis, increases vascular permeability in many tissues, promotes vasculogenesis and angiogenesis. VEGF signalling activity in relation to the cell is dependent on having its specific membrane receptors (Flt-1, KDR, Flt-4). Angiogenesis plays a protective role in ischaemic heart disease and myocardial infarction. Angiogenesis extends life for patients after a stroke. Most of the facts about physiological angiogenesis are derived from studies into liver regeneration as a result of an acute injury or partial hepatectomy. Pathological hepatic angiogenesis occurs in the course of inflammation, fibrosis, hypoxia, and during tumourogenesis. There is interesting data relating to liver steatosis and obesity.
Topics: Humans; Liver Neoplasms; Neovascularization, Pathologic; Neovascularization, Physiologic; Vascular Endothelial Growth Factor A
PubMed: 22069106
DOI: No ID Found -
Annals of Medicine 2008The adventitia and the outer layers of media of an atherosclerosis-prone arterial wall are vascularized by vasa vasorum. Upon growth of an atherosclerotic lesion in the... (Review)
Review
The adventitia and the outer layers of media of an atherosclerosis-prone arterial wall are vascularized by vasa vasorum. Upon growth of an atherosclerotic lesion in the intima, neovascular sprouts originating from the adventitial vasa vasorum enter the lesion, the local proangiogenic micromilieu in the lesion being created by intramural hypoxia, by increased intramural oxidant stress, and by inflammatory cell infiltration (macrophages, T cells and mast cells). The angiogenic factors present in the lesions include various growth factors, chemokines, cytokines, proteinases, and several other factors possessing direct or indirect angiogenic activities, while the current list of antiangiogenic factors is smaller. An imbalance between endogenous inducers and inhibitors of angiogenesis, with a predominance of the former ones, is essential for the development of neovessels during the progression of the lesion. By providing oxygen and nutrients to the cells of atherosclerotic lesions, neovascularization initially tends to prevent cellular death and so contributes to plaque growth and stabilization. However, the inflammatory cells may induce rupture of the fragile neovessels, and so cause intraplaque hemorrhage and ensuing plaque destabilization. Pharmacological inhibition of angiogenesis in atherosclerotic plaques with ensuing inhibition of lesion progression has been achieved in animal models, but clinical studies aiming at regulation of angiogenesis in the atherosclerotic arterial wall can be designed only after we have reached a firm conclusion about the role of angiogenesis at various stages of lesion development--good or bad.
Topics: Animals; Atherosclerosis; Cell Death; Clinical Trials as Topic; Disease Models, Animal; Disease Progression; Humans; Inflammation; Neovascularization, Pathologic; Vasa Vasorum
PubMed: 18608127
DOI: 10.1080/07853890802186913