FIBROBLAST GROWTH FACTOR SIGNALING REGULATES TUMOR ANGIOGENESIS AND CANCER METABOLISM

Acquisition of ectopic expression of type 1 receptor for the fibroblast growth factor receptor type1 (FGFR1) in prostate cancer (PCa) is well documented. However, while it is known that FGFR confers a growth advantage and promotes cell survival, how this aberrantly expressed transmembrane receptor tyrosine kinase contributes to PCa progression is not fully understood. Therefore, we investigated the roles of FGF signaling in both cancer metabolism and tumor angiogenesis. In first part of our study, we used a TRAMP mouse model with tissue specific deletion of fibroblast growth factor receptor substrate 2α (Frs2α), a key adaptor protein of the FGF signaling, in the prostate epithelium to investigate whether epithelial FGF signaling affects blood vessel cell functionality. Results showed that deletion of Frs2α decreased the blood vessels in prostate tumors. Similarly, conditioned medium of Frs2α knockdown prostate cancer cells inhibited the tube formation of human umbilical vein endothelial cells (HUVEC). Frs2α knockdown also decreased the ability of tumor cells to recruit HUVECs. We also discovered that ablation of Frs2α decreased the production of vascular endothelial growth factor A (VEGFA) primarily through preventing the binding of transcription factors HIF1α and c-Jun to its promoter region in prostate cancer cells and in vivo. We also demonstrated that hyperactivity of Frs2α, as well as upregulation of c-Jun and HIF1α, were positively associated with vessel density and progression of human PCa. In the second part of this study, we reported that FGFR1 tyrosine kinase promoted aerobic glycolysis via regulating the expression pattern of lactate dehydrogenase (LDH): it tyrosine phosphorylated type A LDH (LDHA) and enhanced its stability, which favors the conversion of pyruvate to lactate, and therefore, decreases oxidative phosphorylation. Concurrently, FGFR1 downregulated the expression of type B LDH (LDHB) via increasing promoter methylation, which favors the conversion of lactate to pyruvate. Furthermore, consistent with the expression level of ectopic FGFR1, high levels of phosphorylated LDHA accompanied by diminished LDHB were associated with short overall survival and biochemical recurrence free survival time in PCa patients. This suggests that the dysregulated expression of LDH isozymes is of clinical value for PCa prognosis