The long term objective of these studies has been to use transgenic mice to test the hypothesis that keratinocyte growth factor (KGF; FGF-7) and members of the fibroblast growth factor receptor (FGFR) family regulate the growth and metastasis of prostatic cancer in vivo. The rational for these studies was based on the implication that KGF acts as an andromedin to influence prostate epithelial development, growth, and differentiation. Now, based on transgenic and cell line data obtained during the initial period of this project, it is clear that epithelial KGF expression disrupts epithelial-mesenchymal signaling and causes a hyperplastic prostatic epithelium and is probably an early event during the initiation and progression of prostate cancer. Furthermore, based on data from transgenic mice expressing the rat probasin (rPB)-directed dominant-negative form of FGFR2iiib receptor, it is clear that abrogation of KGF signaling in the prostate leads to poorly differentiated and disorganized epithelium and stroma. In fact, abrogated KGF signaling was associated with apoptotic epithelial cell death and impaired smooth muscle differentiation in the prostate. The proposed studies exploit the investigators' autochthonous TRAMP model, derivative TRAMP-C cell lines and the novel rPB-KGF(PKS) and rPB-dnmFGFR2iiib(KDNR) transgenic mice to determine 1) whether epithelial expression of KGF facilitates the progression of prostate cancer to a state that is ultimately metastatic and independent of stroma and androgens; 2) whether ablation of andromedin signals inhibit the initiation, progression and metastasis of prostate cancer; and 3) whether novel FGFR splice forms identified in the TRAMP model influence the proliferation and malignant transformation of prostate epithelial cells.
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