Prostate cancer is a disease typified by a reactive stroma response, which is likely tumor promoting. The reactive stroma is composed of myofibroblasts and fibroblasts, activated to remodel extracellular matrix and induce angiogenesis. This response is similar to generic wound repair responses. In the previous project period, we have defined reactive stroma in human prostate cancer progression and have developed new models to address mechanisms of reactive stroma biology. These studies have shown the induction of reactive stroma during prostatic intraepithelial neoplasia (PIN) and evolution with cancer progression. Elevated expression of TGF-beta1 by PIN epithelium was correlated with induction of adjacent reactive stroma. To address reactive stroma mechanisms, we developed the differential reactive stroma (DRS) model. The DRS model permits transgene gene expression in both the stromal and epithelial compartments of a human xenograft tumor in host mice. Our recent studies show that tumor incidence, angiogenesis, and tumor growth are dependent on reactive stroma. Different human prostate stromal cell lines produced differential tumorigenesis. Differential expression of connective tissue growth factor (CTGF) in stromal cells was associated with tumorigenesis. CTGF is a downstream mediator of TGF-beta1 action in stroma and a stimulator of angiogenesis. Inhibition of TGF-beta1 action in DRS tumors inhibited angiogenesis and tumor growth. Furthermore, FGF-2 action regulates reactive stroma, particularly in a TGF-beta1 microenvironment. It is our hypothesis that TGF-beta31 induced reactive stroma is a critical regulator of angiogenesis in early prostate cancer, and that both CTGF and FGF-2 are key co-regulatory factors of TFG-beta1 paracrine actions in reactive stroma. We propose three Specific Aims to address this hypothesis in detail: 1.) To test the hypothesis that the paracrine action of epithelial expressed TGF-beta1 is a key inducer of prostate reactive stroma and that TGF-beta1 induced reactive stroma drives angiogenesis and tumor progression; 2.) To test the hypothesis that FGF-2 functions as a co-regulator with TGF-beta1 in reactive stroma induced angiogenesis and tumor progression; 3.) To test the hypothesis that CTGF functions as a key downstream mediator of TGF-beta1 and FGF-2 action in reactive stroma. These studies will dissect the paracrine and autocrine actions of these growth factors in reactive stroma regulation of prostate cancer using novel transgenic and DRS model approaches. The proposed studies will expand our understanding of the role of interdependent epithelial-stromal signaling in prostate cancer and may lead to new therapeutic approaches targeted to specific mechanisms in the reactive stroma compartment.
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