- Angiogenesis is a stepwise process involving vascular hyperpermeability, degradation of extracellular matrix, endothelial cell migration and proliferation, and formation and maturation of new capillary tubes. Whereas primary angiogenesis is a prominent feature of mammalian embryonic development, normal adult skin exhibits little or no vascular proliferation. However, skin retains the capacity to initiate a brisk neovascular response in many disorders including tissue repair, inflammation, and neoplasia. The normal quiescence of adult cutaneous vasculature suggests that vascular homeostasis in the skin is maintained by a balance between secreted factors that enhance or inhibit endothelial cell growth. While several epidermis-derived angiogenic factors have been identified, little is known about inhibitors of skin angiogenesis. Thromposbondin-1 (TSP-1) is a member of a small group of recently identified endogenous inhibitors of angiogenesis. TSP-1 expression is downregulated in squamous cell carcinomas of the skin, lesions that are characterized by richly angiogenic stroma as compared to non-neoplastic epidermis. TSP-1 inhibited several biological effects induced by the potent skin angiogenesis factor, vascular endothelial growth factor (VEGF), including dermal microvascular endothelial cell proliferation, spreading, and matrix metalloproteinase expression in vitro and sprouting of blood microvessels in vivo. Overexpression of TSP-1 inhibited tumor growth and angiogenesis of human squamous cell carcinoma xenotransplants in vivo. In addition, preliminary studies by the principal investigator recently established transgenic mouse models for skin skin-specific TSP-1 overexpression and deficiency; and in contrast to his prior studies of skin-specific VEGF transgenic mice, these new studies suggest that TSP-1 is an important regulator of skin angiogenesis.
Three aims are proposed: 1) Determine the importance of TSP-1 in normal skin vascularization and in experimental skin inflammation, making use of skin specific TSP-1 and TSP-1 null mice and of crosses with VEGF transgenic mice; 2) determine the role of TSP-1 in the multistep process of skin carcinogenesis, and 3) determine the function of transfected wild type and distinct mutated TSP-1 gene constructs in modulating angiogenesis and malignant growth of human squamous cell carcinoma xenotransplants.
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