Anti-integrins as a potential therapeutic target in angiogenesis

Several physiological processes including cell activation, migration, proliferation and differentiation require direct contact between cells or extracellular matrix (ECM) proteins. Cell-cell and cell-matrix interactions are mediated through several different families of cell adhesion molecules (CAMs), including the selectins, the integrins, the cadherins and the immunoglobulins. Newly discovered CAMs, along with the discovery of new roles of integrins, selectins and immunoglobulins in certain disease states, provide a great opportunity to develop therapeutic, and perhaps diagnostic, modalities. CAMs play a very significant and critical role in both normal and pathophysiological disease states. For this key reason, the selection of specific and relevant CAMs to target certain disease conditions, without interfering with other normal cellular functions is a very important prerequisite for the ultimate success in developing truly active and safe therapeutic strategies. Recent breakthroughs with animal models, the latest advances in the understanding of the signalling pathways, transcriptional regulation and the structure/function aspects of CAMs, the role of CAMs and ECM proteins in cellular migration, spreading, proliferation and survival illustrate the potential impact of using CAMs as a novel strategy. Exciting advances in our understanding of several CAMs, most notably the alpha v beta 3, alpha v beta 5, alpha 4 beta 1, alpha 5 beta 1 and alpha IIb/beta 3 integrin receptors, and their direct relationships to different disease states represent a tremendous therapeutic and diagnostic opportunity. The role of CAMs and ECM proteins in various pathological processes (including angiogenesis, thrombosis, apoptosis, cell migration and proliferation) leading to both acute and chronic disease states, (such as ocular diseases, metastasis, unstable angina, myocardial infarction, stroke, osteoporosis, a wide range of inflammatory diseases, vascular remodelling and neurodegenerative disorders) have been recently documented. One key success in this field is evidenced by the potential role of the platelet GPIIb/IIIa integrin in the prevention, treatment and diagnosis of various thromboembolic disorders. The discovery of various therapeutic candidates based on the key role of alpha v (alpha v beta 3 and alpha v beta 5) and alpha 5 beta 1 integrins in angiogenesis will be the focus of this review.