Prostate cancer is the most commonly diagnosed malignancy in men (189,000 per year), and ranks second in mortality rate (30,200) in the USA. The social and economic impact is increasing as a consequence of increased lifespan, the changing definition and detection of the presence of """"""""cancer"""""""" and demand for immediate treatment. Understanding the steps in the slow progression from a premalignant hormone responsive relatively benign state to incurable malignancy is essential for prevention and treatment of the life-threatening aspects of the disease. The hypothesis underlying this continuation project is that malignant progression in the epithelial compartment is a gradual upset in the symbiotic homeostasis provided by precise communication between stroma and epithelium in which FGF family signaling plays a key role. The FGF tyrosine kinase receptor complex is tripartite comprised of a transmembrane tyrosine kinase, pericellular matrix heparan sulfate and an FGF activator, which create cell- and tissue-context specificity. FGF7, FGF10 and their specific FGFR isotype, FGFR2IIIb, are partitioned to mediate directionally specific net homeostasis-promoting signals from stroma to epithelium. The structural basis and potential role of heparan sulfate in specificity of FGF7 and FGF10 action will be determined. FGF9 signaling to FGFR3 (and possibly FGFR1) in the stroma will be characterized as a potential directionally-specific epitheliium to the stroma signaling system that determines stromal cell phenotypes, which control or permit progression of premalignant epithelium. The hypothesis that androgen impacts two-way compartment-specific paracrine signaling between stroma and epithelium by the FGF family, and FGF signaling impacts androgen responsiveness that underlies windows of both progression-promoting and progression-limiting action at the clonal level will be explored. Mechanism of loss of androgen response in clonal cell types of different malignant potential and FGFR phenotype will be examined.
These aims will be explored at the cellular level in the well-characterized Dunning in vitro/in vivo shuttle model of progression of two-compartment nonmalignant (premalignant) tumors to one compartment malignant tumors. Emergent mouse genetic models with alterations in the three subunits of the FGFR signaling complex will be designed and exploited to test lessons learned from the former model in physiological context.
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