The role of fibroblast growth factors and their receptors in prostate cancer

Abstract

Prostate cancer is the most common malignancy in men in the USA and the second leading cause of cancer deaths. Fibroblast growth factors (FGFs), including FGF1 (acidic FGF), FGF2 (basic FGF), FGF6 and FGF8 are all expressed at increased levels in prostate cancer as paracrine and/or autocrine growth factors for the prostate cancer cells. In addition, increased mobilization of FGFs from the extracellular matrix in cancer tissues can increase the availability of FGFs to cancer cells. Prostate cancer epithelial cells express all four types of FGF receptors (FGFR-1 to -4) at variable frequencies. Expression of FGFR-1 and FGFR-4 is most closely linked to prostate cancer progression, while the role of FGFR-2 remains controversial. Activation of FGF receptors can activate multiple signal transduction pathways including the phospholipase Cg, phosphatidyl inositol 3-kinase, mitogenactivated protein kinase and signal transducers and activators of transcription (STAT) pathways, all of which play a role in prostate cancer progression. Sprouty proteins can negatively regulate FGF signal transduction, potentially limiting the impact of FGF signaling in prostate cancer, but in a significant fraction of prostate cancers there is decreased expression of Sprouty1 mRNA and protein. The effects of increased FGF receptor signaling are wide ranging and involve both the cancer cells and surrounding stroma, including the vasculature. The net result of increased FGF signaling includes enhanced proliferation, resistance to cell death, increased motility and invasiveness, increased angiogenesis, enhanced metastasis, resistance to chemotherapy and radiation and androgen independence, all of which can enhance tumor progression and clinical aggressiveness. For this reason, the FGF signaling system it is an attractive therapeutic target, particularly since therapies targeting FGF receptors and/or FGF signaling can affect both the tumor cells directly and tumor angiogenesis. A number of approaches that could target FGF receptors and/or FGF receptor signaling in prostate cancer are currently being developed.

Conditional activation of FGFR1 in the prostate epithelium induces angiogenesis with concomitant differential regulation of Ang-1 and Ang-2

“…Indeed, we were able to detect stabilization of HIF-1a and a concomitant upregulation of VEGF, VEGFR1 and VEGFR2. This was consistent with previous studies demonstrating that HIF-1a can be upregulated under normoxic conditions by PI3K and ERK signaling (Dery et al, 2005), both of which are known to be activated by FGFR1 (Kwabi-Addo et al, 2004). Clearly the upregulation of the VEGF signaling axis plays a significant role in the angiogenic phenotype as a consequence of iFGFR1 activation.…”

“…It is a generally held view that such reciprocal stromal-epithelial signaling pathways act to maintain the microenvironment and homeostasis of a terminally differentiated quiescent epithelium. So it is notable that several changes in the FGF signaling axis have been described in prostate cancer (CaP) that can disrupt normal stromal-epithelial interactions (Kwabi-Addo et al, 2004). One such event is alternative mRNA splicing that generates the FGFR2IIIc isoform, which preferentially recognizes epithelial-derived FGF1, FGF2, FGF6 as well as FGF8, which is preferentially expressed in malignant prostate epithelium (Gnanapragasam et al, 2003).…”

Androgen receptor signalling in prostate: Effects of stromal factors on normal and cancer stem cells

“…Growth factors secreted in response to PDGF stimulation include insulin like growth factor (IGF-1), hepatocyte growth factor (HGF), FGF2, and endothelin-3. While there is no evidence for PDGF binding to AR, PDGF can stimulate both TGF1 and FGF2, which have been shown to bind AR (Gerdes et al, 2004, Kwabi-Addo et al, 2004. Small molecule inhibitors against TGF and PDGF are now in clinical trials and may represent a stromal targeted therapy (De Wever et al, 2003).…”

“…FGF2, 8, 9, 10 and keratinocyte growth factor (KGF/FGF7) are the main stromal Page 7 of 24 A c c e p t e d M a n u s c r i p t 7 expressed proteins (Kwabi-Addo et al, 2004). FGF9 is a more potent mitogen for BPH epithelium and stroma than FGF2 or FGF7 (Giri et al, 1999 …”

Transcriptional and post-transcriptional regulation of Sprouty1, a receptor tyrosine kinase inhibitor in prostate cancer

“…Antibodies used for western blotting, electrophoretic mobility shift assays (EMSAs) and chromatin immunoprecipitation (ChIP) were the following: rabbit anti-Spry1, mouse anti-actin, rabbit anti-Egr-1, goat anti-Egr-2, goat anti-rabbit GATA-2, rabbit anti-GATA-4, rabbit anti-p-ERK 1 2 (Thr 202/Tyr 204), anti-PBX1 rabbit polyclonal immunoglobin G, anti-SP1 mouse monoclonal immunoglobin G and anti-HNF4a goat polyclonal immunoglobin G. Anti-acetyl-Histone H4 rabbit antiserum was purchased from Upstate Biotech (Lake Placid, NY, USA). All antibodies were purchased from Santa Cruz Biotech (Santa Cruz, CA, USA) unless otherwise stated.…”