Prostate cancer is the most commonly diagnosed malignancy in men, and ranks second in mortality rate after lung cancer in the USA. Cancer and benign prostatic hyperplasia (BPH) is an increasing socio-economic burden on the medical care system with increase in life span of males. Prostate cancer is progressive to malignancy, but occurs primarily in two stages. Type I cancers are largely responsive to anti-androgen treatment, but over long periods progress to the type II malignant and untreatable state. Understanding of the progressive transition from type I to type II states is urgently needed to guide diagnosis, prevention and treatment. The hypothesis underlying this continuation project is that the progression from the non-malignant to malignant states is a stepwise disruption of homeostasis mediated by communication between epithelium and stroma of the prostate. The heparin-binding fibroblast growth factor (FGF) family of polypeptides and its receptor (FGF-R) has been firmly implicated in mediation of growth and differentiation within the prostate. The FGF family is an extremely heterogenous three component system-FGF polypeptides, FGF receptor kinase and FGF heparan sulfate proteoglycan. This project will determine the molecular and cellular mechanisms underlying mediation of homeostasis (growth, growth inhibition/death and differentiation) by specific members of the FGF family in prostate and the changes that occur during progression to malignancy. Specifically, the project will determine (1) the specific roles of stromal derived FGF-7 and FGF-10 in instruction of epithelial phenotypes; (2) the time course and sequence of changes in the FGF signaling system during progression of pre-malignant tumor epithelial cells to malignancy; (3) relative roles of the ecto- and intracellular domains of FGFR1 and FGFR2 in the process; (4) role of androgen and its receptor in squamous versus glandular differentiation; (5) structural motifs in FGFR1 and FGFR2 underlying effects on non-malignant and malignant cell phenotypes; (6) impact of changes in specific peri- cellular heparan sulfates; (7) conditions that regulate alternate splicing of the FGFR2 gene. Lastly, the project will employ mouse genetics to test the physiological consequence of FGFR1 and FGFR2 on prostate tumor progression. These results will open up new avenues for early diagnosis of prostate tumor potential for progression, for prevention of progression and for treatment of malignancies targeted to the FGFR signaling system.
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