Endothelial cell integrins and COX-2: mediators and therapeutic targets of tumor angiogenesis.
Vascular integrins are essential regulators and mediators of physiological and pathological angiogenesis, including tumor angiogenesis. Integrins provide the physical interaction with the extracellular matrix (ECM) necessary for cell adhesion, migration and positioning, and induce signaling events essential for cell survival, proliferation and differentiation. Integrins preferentially expressed on neovascular endothelial cells, such as alphaVbeta3 and alpha5beta1, are considered as relevant targets for anti-angiogenic therapies. Anti-integrin antibodies and small molecular integrin inhibitors suppress angiogenesis and tumor progression in many animal models, and are currently tested in clinical trials as anti-angiogenic agents. Cyclooxygense-2 (COX-2), a key enzyme in the synthesis of prostaglandins and thromboxans, is highly up-regulated in tumor cells, stromal cells and angiogenic endothelial cells during tumor progression. Recent experiments have demonstrated that COX-2 promotes tumor angiogenesis. Chronic intake of nonsteroidal anti-inflammatory drugs and COX-2 inhibitors significantly reduces the risk of cancer development, and this effect may be due, at least in part, to the inhibition of tumor angiogenesis. Endothelial cell COX-2 promotes integrin alphaVbeta3-mediated endothelial cell adhesion, spreading, migration and angiogenesis through the prostaglandin-cAMP-PKA-dependent activation of the small GTPase Rac. In this article, we review the role of integrins and COX-2 in angiogenesis, their cross talk, and discuss implications relevant to their targeting to suppress tumor angiogenesis.
Rüegg
Curzio
C
Centre Pluridisciplinaire d'Oncologie, University of Lausanne Medical School, CH-1011 Lausanne, Switzerland. curzio.ruegg@isrec.unil.ch
Dormond
Olivier
O
Mariotti
Agnese
A
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D002470:Cell Survival; D051546:Cyclooxygenase 2; D016503:Drug Delivery Systems; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D016023:Integrins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D008565:Membrane Proteins; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction
D020533:Angiogenesis Inhibitors; D039302:Integrin alphaVbeta3; D016023:Integrins; D007527:Isoenzymes; D008024:Ligands; D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases