Project #3 has been designed to test the hypothesis that mesenchyme- prostate tumor cell interactions determine growth and invasive potentials of human prostate tumors in part through altered expression of matrix metalloproteinases. We have demonstrated that the matrix-metalloproteinase (MMP), matrilysin, can play a functional role in human prostate tumor cell growth and invasion. We also showed that prostate derived mesenchymal fibroblasts secrete a paracrine factor(s) that induces the expression of matrilysin in the human carcinoma cell line, LNCaP. We and other researchers have demonstrated that LNCaP tumor cells grow considerably better at an ectopic, subcutaneous site in athymic nude mice when the cells are co-injected with prostate derived fibroblasts suggesting critical mesenchymal-prostate tumor cell interactions. We are testing the hypothesis that this interaction would involve, in part, altered expression of the MMP, matrilysin, allowing for enhanced local growth and invasion.
The specific aims to test the hypothesis are: 1) to determine the identity of a prostate fibroblast elicited paracrine factor(s) that induces matrilysin gene expression in LNCaP cells 2) to determine in LNCaP cells the mechanism of transcriptional activation of the matrilysin gene by the prostate fibroblast derived paracrine factor(s) 3) to determine the in vivo expression pattern of matrilysin when LNCaP tumor cells are either co-injected subcutaneously into the athymic nude mouse with prostate derived fibroblasts or are injected orthotopically into the dorsal lateral prostate of the nude mouse 4) to determine whether the paracrine induction of matrilysin expression when LNCaP cells are co-injected with fibroblasts subcutaneously or when the LNCaP cells are injected orthotopically plays a functional role in prostate tumor cell growth and invasion by blocking either the expression of matrilysin in LNCaP cells or the expression of the paracrine factor(s) elicited by the fibroblasts. The proposed work in this project will compliment the human tissue studies to be carried out in Project #2 and the proposed work on the alpha6beta1 integrin receptor in Project #2. Project #3 will utilize all of the Core Services.
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