Suppression of tumor angiogenesis through the inhibition of integrin function and signaling in endothelial cells: which side to target?
Tumor angiogenesis is an essential step in tumor progression and metastasis formation. Suppression of tumor angiogenesis results in the inhibition of tumor growth. Recent evidence indicates that vascular integrins, in particular alpha V beta 3, are important regulators of angiogenesis, including tumor angiogenesis. Integrin alpha V beta 3 antagonists, such as blocking antibodies or peptides, suppress tumor angiogenesis and tumor progression in many preclinical tumor models. The potential therapeutic efficacy of extracellular integrin antagonists in human cancer is currently being tested in clinical trials. Selective disruption of the tumor vasculature by high doses of tumor necrosis factor (TNF) and interferon gamma (IFN-gamma), and the antiangiogenic activity of nonsteroidal anti-inflammatory drugs are associated with the suppression of integrin alpha V beta 3 function and signaling in endothelial cells. Furthermore, expression of isolated integrin cytoplasmic domains disrupts integrin-dependent adhesion, resulting in endothelial cell detachment and apoptosis. These results confirm the critical role of vascular integrins in promoting endothelial cell survival and angiogenesis and suggest that intracellular targeting of integrin function and signaling may be an alternative strategy to extracellular integrin antagonists for the therapeutic inhibition of tumor angiogenesis.
Rüegg
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Centre Pluridisciplinaire d'Oncologie, University of Lausanne Medical School, Switzerland. curzio.ruegg@isrec.unil.ch
Dormond
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O
Foletti
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A
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015815:Cell Adhesion Molecules / Q000502:physiology; D051546:Cyclooxygenase 2; D016503:Drug Delivery Systems; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors; D016023:Integrins / Q000037:antagonists & inhibitors*; D007371:Interferon-gamma / Q000494:pharmacology; D007527:Isoenzymes / Q000494:pharmacology; D008565:Membrane Proteins; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism; D009389:Neovascularization, Pathologic; D011451:Prostaglandin-Endoperoxide Synthases / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D015815:Cell Adhesion Molecules; D039302:Integrin alphaVbeta3; D016023:Integrins; D007527:Isoenzymes; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020741:rho GTP-Binding Proteins