Angiogenesis is a hallmark of breast cancer. In fact, the prognosis of a given breast tumor biopsy is directly related to the number of blood vessels per area of tissue. Angiogenesis not only facilitates the growth of primary breast tumors but likely hastens the metastatic spread of individual tumor cells by providing direct access to the circulation. Thus, by controlling angiogenesis it may be feasible to impact the growth and metastasis of breast carcinoma. We propose that blood vessels undergoing angiogenesis in response to breast carcinoma and other tumors have certain distinct biological and biochemical properties compared to mature preexisting blood vessels in normal tissues. To this end, we identified the integrin alpha-v-beta-3 associated with blood vessels undergoing angiogenesis in human tissues and in the well established check chorioallantoic membrane (CAM) model. More importantly, we observed that antagonists of integrin alpha-v-beta-3 target these vessels and block the angiogenesis induced by specific cytokines or fragments of human breast carcinoma. In this proposal we will examine the mechanism by which antagonists of vascular integrin alpha-v-beta-3 block angiogenesis induced by breast tumors. Specifically, we will characterize the expression of this receptor and its putative ligand(s) on human biopsy material from normal breast, pre-malignant lesions and various stage breast carcinoma. We will also examine angiogenesis in human breast carcinoma tumors using two experimental models. These include an examination of the growth and metastatic properties of breast carcinoma cells inoculated on the chick CAM. A second model involves the growth of human breast carcinoma cells in human skin grafted onto the SCID mouse allowing an examination of human blood vessels responding to human breast tumors growing in a human tissue. Furthermore, we have developed a method to specifically isolate the angiogenic vascular cells from these breast tumor models. This will facilitate the additional goals of this proposal which are to examine the role of integrin alpha-v-beta-3 in the signaling events leading to the proliferation, differentiation and apoptosis of vascular cells invading breast carcinoma. Ultimately these studies may facilitate the design of a novel biological therapy for the treatment of breast carcinoma.
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