To Enhance or to Inhibit Integrin Function in Angiogenesis, that is the Question

The idea that tumors recruit blood vessels to survive, grow, and metastasize was proposed more than 40 years ago by Dr. Judah Folkman. Since then, studies have been conducted to identify factors able to stimulate endothelial cell functions and to inhibit their pro-angiogenic activity in pathological conditions, such as tumor-associated angiogenesis. The process of angiogenesis requires three major steps, namely endothelial cell proliferation, migration and tubulogenesis. Although release of growth factors, cytokines, and proteases is critical for the regulation of endothelial cell functions, interactions of endothelial cells with the surrounding extracellular matrix initiate intracellular signaling that result in proand/ or anti-angiogenic cues. Interactions of cells with the extracellular matrix are made possible by the transmembrane receptors integrins. Upon ligand activation, these receptors can activate various intracellular signaling, thus regulating processes such as adhesion, migration, proliferation and survival. The finding that these receptors are expressed on vascular endothelial cells and they can either promote or inhibit endothelial cell functions, has initiated studies to determine their role in physiological and pathological angiogenesis. In this review, we will focus on the role of integrins, with emphasis on the collagen binding and the alpha v containing integrins, in angiogenesis and highlight hope and tribulations of targeting these receptors for anti-angiogenic therapy. This review is dedicated to Dr. Judah Folkman who introduced us to the concept of ‘malignant’ angiogenesis.