Neuropilin and Semaphorin Function in Development and Tumor Angiogenesis

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Our laboratory has had a long standing interest in identifying the molecules and understanding the mechanisms that regulate angiogenesis, tumor growth and progression. We have recently reported the presence of ADAMT2 (A Disintegrin and Metalloproteinase 12),in the urine of women with breast cancer and have further demonstrated that its presence predicts both clinical status and stage in these women. In this same study, we reported, for the first time, that ADAM12 can degrade extracellular matrix components including type IV collagen and fibronectin and that it has gelatinase activity as well. These data have led us to hypothesize that ADAM12 may play a role in tumor angiogenesis and progression by remodeling the extracellular matrix and/or through a variety of other mechanisms that have been attributed to this family of enzymes, including ectodomain shedding, regulation of growth factor availability and mediating cell-cell and cell-matrix interactions. We have also recently demonstrated that ADAM12 levels are significantly upregulated during one of the earliest checkpoints during tumor progression, the angiogenic switch and that its overexpression in human breast cancer cells results in a significant increase in the production of VEGF. ADAM12 overexpression also resulted in a significant increase in human breast cancer cell motility and invasivity, an upregulation of the classic mesenchymal markers vimentin and fibronectin and the acquisition of a scattering phenotype, all of which are consistent with the induction of EMI (Epithelial to Mesenchymal Transformation), a hallmark of cancer progression. ADAM12 also conferred estrogen-independent(ER) growth status to ER positive breast cancer cells. Finally, in a series of preliminary studies, we found that ADAM12 overexpression promoted prthotopic human breast cancer growth in vivo. Within the context of the Specific Aims of our proposal, we will determine the mechanism(s) by which ADAM12 may be regulating angiogenesis, tumor growth and metastasis. These mechanistic studies will be complimented by a series of in vivo ones in which we will determine the effects of ADAM12 on human breast tumor growth and progression using three complimentary in vivo models. These studies will also be informative as to the potential role of ADAM12 as a therapeutic target in the treatment of breast cancer and its progression. In the third Aim of this study, we will determine whether urinary ADAM12, alone or in combination with other cancer biomarkers, may be a diagnostic and/or prognostic biomarker for breast cancer and its progression. These studies are proposed within the context of the following Specific Aims: 1. To determine the mechanism(s) by which ADAM12 may regulate angiogenesis, tumor growth and metastasis 2. To determine whether ADAM12 promotes human breast cancer growth and progression in vivo 3. To determine whether the presence of ADAM12, alone or multiplexed with other urinary cancer biomarkers, predicts tumor presence, progression, and therapeutic efficacy in animal models of breast cancer and in human patients with oreast cancer. By systematically identifying novel molecules that may be playing a role in the development and progression of breast cancer, and by dissecting the mechanisms by which such molecules may be exerting their effects, we will have the opportunity to develop new and improved therapeutic, diagnostic and prognostic strategies that could result in significantly improved cancer patient survival.