Prostate cancers is the most highly diagnosed non-skin cancer in the US and second to lung cancer in mortatty. However, litte is known about the molecular changes that precede malignant transformation. While growth factor signaling is essential for development and homeostasis of the prostate, accumulating genetic damage (or epigenetic changes) in aging men may ultimately transform these homeostatic factors into deleterious agents. Upregulation of growth factors and their cognate receptors within secretory epithelial ceils may contribute to stromal independence and cancer progression through autocrine signaling. Members of the fibroblast growth factor receptor (FGFR) family and their ligands appear to be prominent in this disease process. Normal and benign prostate epithelial cells express the FGF-7 (and 10)-responsive """"""""epitheial"""""""" isoform of FGFR2 (R2), named FGFR-IIIb; however, more malignant cells express distinct isoforms, which responds instead to bFGF/FGF-2 (and other FGFs) that is concomitantly upregulated 1;5;13;18;24. In stll more malignant, androgen-independent cells, the entire FGFR2 locus is repressed and replaced by normally stroma-localized FGFR123. This stdking corre}ation of FGFR1 (R1) up-regulation with :umor progression is consistent with differential roles for R1 and R2. Understanding the progression of the disease san lead to new therapies at early stages, therefore increasing the chances for surviival. Thus, we will:(1) Test the hypothesis that FGFRt signaling promotes tumor progression while R2 promotes differentiation. (2) Determine if one or a small number of FGFR subregions can be mapped and can differentiate RI and R2 signaling, leading to osteopontin (OPN) expression and enhanced progression. (3) Detrmine if iFGFRs can be used along with proteomic and genomic approaches to identify downstream signaling molecules that differentiate R1 and R2 signaling.
| Acevedo, Victor D; Ittmann, Michael; Spencer, David M (2009) Paths of FGFR-driven tumorigenesis. Cell Cycle 8:580-8 |
| Acevedo, Victor D; Gangula, Rama D; Freeman, Kevin W et al. (2007) Inducible FGFR-1 activation leads to irreversible prostate adenocarcinoma and an epithelial-to-mesenchymal transition. Cancer Cell 12:559-71 |
