Fibroblast Growth Factor Signaling in Prostate Stem Cells and Prostate Cancer

The prostate is an androgen-dependent male reproductive organ that is comprised of epithelial and stromal compartments. The epithelial compartment contains basal, luminal, and neuroendocrine cells. Two types of prostate epithelial stem cells (P-SCs), basal stem cells and luminal stem cells, have been identified in both human and mouse adult prostates based on tissue recombination models, cell lineage tracing, and in vitro prostasphere or organoid cultures. Using lineage-tracing with P63CreERT2 and prostasphere culture, we show here that the sphere-forming P-SCs are P63-expressing cells and reside in the basal compartment. Therefore we designate them as basal P-SCs (P-bSCs). P-bSCs are capable of differentiating into AR+ and CK18+ organoid cells, but not vice versa. We also report that prostaspheres contain quiescent stem cells, which possess more potent self-renewal capacity. Distinct from other tissue stem cells, P-bSCs do not contain Lgr5+ cells. The fibroblast growth factor signaling axis regulates embryonic stem cell development as well as tissue specific stem cell maintenance and differentiation. However, the role of FGF signaling in P-SC self-renewal and differentiation is still elusive. We show that the type 2 FGF receptor (FGFR2) signaling axis is crucial for preserving self-renewal and preventing the differentiation of P-bSCs. FGFR2 signaling mediated by FGFR substrate 2α (FRS2α) is indispensable for formation and maintenance of prostaspheres derived from P63+ P-bSCs. Ablation of Fgfr2 in vivo reduces P63-expressing basal cells, and promotes basal-to-luminal differentiation. In addition, ablation of Fgfr2 in P63+ cells disrupts postnatal development of the prostate. Accumulating evidence has also shown that prostate cancer (PCa) progression is frequently associated with dysregulation of FGF signaling. Herein, we report that forced expression of FGF9 in prostate epithelial cells leads to high grade prostatic intraepithelial neoplasia (PIN). Overexpression of FGF9 in TRAMP mice induces more malignant PCa and higher frequency of metastasis. Hyperproliferative stromal cells are shown in the F9TG and F9TRAMP mouse prostates. Reactive stroma which upregulates TGF-β1, was observed in F9TG and F9TRAMP prostates. We also show that transcription factor c-Jun is a mediator in the FGF9-TGFβ1 axis. Collectively, our study provides new insights into prostate stem cells and prostate cancer. Upset of the intricate balance of FGF signaling in the prostate disrupts stem cell homeostastasis and prostate development, and initiates prostate tumorigenesis