Evidence for distinct alterations in the FGF axis in prostate cancer progression to an aggressive clinical phenotype

Abstract

Multiple fibroblast growth factor (FGF) axis alterations are known to occur in prostate cancer. Here we simultaneously profiled key components of this axis to determine their relevance in disease progression. An optimized immunohistochemistry protocol was used in expression analysis of FGF2, FGF8, FGFR1, FGFR4, and Sef (similar expression to FGF) in a single TMA of prostate cancer. FGF ligands and receptors were overexpressed in cancers compared to benign samples (p < 0.0001), while Sef expression was reduced (p < 0.0001). There was a positive association between higher grades and increased FGFR4 (p = 0.02), FGF2, and FGF8 (p = 0.002 and p < 0.0001). Sef expression was progressively lower with increasing grade (p = 0.005). Clinical stage was positively associated with FGF2, FGF8, and FGFR4 expression (p = 0.005, 0.03, and 0.012) but not with FGFR1 or Sef expression. Only reduced Sef was associated with bone metastasis (p = 0.02) and was also predictive of subsequent metastasis in initially localized tumours (p = 0.004). Down-regulation of Sef and increased FGFR4 were also the only independent variables associated with disease-specific survival (HR 1.73, p = 0.04 and HR 0.56, p = 0.01). In in vitro studies, silencing Sef enhanced the cell response to FGFs (p < 0.001) and substantially mitigated the effectiveness of an FGFR1 inhibitor. Conversely, increased Sef blocked the response to FGFs and had a comparable suppressive effect to the inhibitor. This study demonstrates that increased FGFR4 and reduced Sef may be critical FGF alterations associated with prostate cancer progression. Sef may also have a role in the tumour response to FGFR inhibition and warrants further investigation in this context.

Roles of Fibroblast Growth Factor Receptors in Carcinogenesis

“…Recent studies showed that Sef attenuates FGF-mediated mitogenic stimulation in prostate cancer cells and that loss of Sef is associated with high-grade and metastatic prostate cancer (142,143). Furthermore, loss of Sef correlated with increased FGF2, FGF8, and FGFR4 expression in metastatic prostate tumors (144). Thus, loss of regulatory factors that control the activity of FGFRs can play a role in carcinogenesis and the development of a malignant phenotype.…”

“…Increased levels of FGFs have been found in several human cancers, and studies done in mouse models or cancer cell lines have revealed their oncogenic potentials. For example, elevated levels of FGF8 have been reported in human breast and prostate cancer (33,(118)(119)(120). FGF8 as well as FGF3 and FGF4 have been identified as mammary proto-oncogenes in MMTV (mouse mammary tumor virus)-infected mice (121)(122)(123), and transgenic mice overexpressing FGF8 in prostate epithelial cells developed PINs (124).…”

FGF-2 Disrupts Mitotic Stability in Prostate Cancer through the Intracellular Trafficking Protein CEP57

“…Numerous in vitro and in vivo results underscore a crucial role of FGFs and their receptors in carcinogenesis and malignant progression (6)(7)(8). The human FGF gene family consists of more than 20 members that encode secreted polypeptides.…”

Application of a Novel Score Test for Genetic Association Incorporating Gene-Gene Interaction Suggests Functionality for Prostate Cancer Susceptibility Regions

“…Abnormalities in this family of sugars and particularly in HSPG2 (Perlecan) contribute to the disease progression of both type 2 diabetes [56] and PRCA [57,58] . Heparin sulfate proteoglycans influence the FGF axis and WNT signaling, both of which are disrupted in PRCA [59][60][61] . A positive regula-tor of SULF2 is insulin [62] , the hormone at the center of diabetes.…”