The integrin family of extracellular matrix receptors plays an important role in angiogenesis. Integrins are readily accessible as drug targets and may provide an avenue to novel therapeutic approaches. The role of the a1B1 and a2B1 integrins, the 2 major endothelial cell collagen receptors, in angiogenesis also has been evaluated in vitro and in vivo. Senger and colleagues argued that collagen receptors, receptors for the predominant extracellular matrix molecules within the microenvironment of tumors, are critical for the development of new vessels. However, our recent findings in a2B1 integrin-deficierit mice suggest that the a2B1 integrin provides an anti-angiogenic rather than a pro-angiogenic stimulus. We show in Preliminary Data that a2-null mice exhibit more rapid tumor growth and increased angiogenesis when compared to their wildtype littermate controls. We furthermore show that the tumor vessels formed were of abnormal size and shape, suggesting that the integrin, although not required for angiogenesis per se, is required for normal vascular morphogenesis and maturation. Based on this exciting preliminary data, we hypothesize that the a2B1 integrin is required for maintainance and control of the angiostatic setpoint or switch. This hypothesis fuirthermore suggests that a2B1 integrin expression favors an anti-angiogenic phenotype by opposing pro-angiogenic signals from the a1B1 integrin to modulate and control tumor angiogenesis. To test this hypothesis we propose the following 4 Specific Aims:
SPECIFIC AIM #1 : To define the contributions of the a2B1 integrin in maintaining balance of the angiogenic setpoint or switch using a combination of in vitro biochemical, and cell biologic techniques coupled with in vivo mouse models. As part of this Aim, we will compare the molecular regulation of tumor angiogenesis in wild-type mice, mice lacking expression of the a2B1 integrin, and mice expressing a mutant a2 integrin subunit that exhibits """"""""the activated phenotype."""""""" SPECIFIC AIM #2: To define the role of the a2B1 integrin in vessel maturation in vivo and the role of the integrin in endothelial cell morphogenesis and tube formation in vitro.
SPECIFIC AIM #3 : To define the mechanisms underlying the dramatic differences between the contributions of the a2B1 integrin and the a1p1 integrin to tumor angiogenesis.
SPECIFIC AIM #4 : To define the role of a2B1 integrin expression by mast cells in regulating tumor growth and stimulating tumor angiogenesis.
