FGF8 over-expression in prostate cancer is associated with decreased patient survival and persists in androgen independent disease

Abstract

Identification of prostate cancers at high risk of progression is difficult and a better understanding of how peptide growth factors influence cellular function might be useful. Fibroblast growth factors (FGFs) have been implicated in prostate cancer development. FGF8 was identified in the Shionogi mouse mammary carcinoma SC-3 cell line as an androgen-induced mitogen. We tested if FGF8 was over-expressed in human prostate cancer and if its expression correlated with clinical data and outcome. One hundred and six cases of prostate cancer and ten cases of BPH were examined. In situ hybridization was employed to detect FGF8 mRNA expression, which was identified within the malignant prostatic epithelium in 85/106 (80.2%) cases. Increased expression of FGF8 correlated significantly with higher Gleason scores (P=0.0004) and advanced tumour stage (P=0.0016). Using immunohistochemistry, we confirmed over-expression of the FGF8b isoform. Men with tumours which expressed high levels of FGF8 had worse survival (P=0.034), although FGF8 mRNA was not able to provide additional prognostic information in a multivariate analysis. Additionally, FGF8 expression was shown to persist in androgen independent prostate cancer. Using a range of normal adult tissues, FGF8 expression was restricted to neurones and the germinal epithelium in addition to the prostate. In vitro studies demonstrated that in the presence of neutralizing antibody to FGF8b there was significant inhibition of prostate cancer cell growth, confirming the biological significance of FGF8 in prostate carcinogenesis.

FGF8 isoform b expression in human prostate cancer

“…Previous expression studies, including work from our own centre, have assayed total FGF8 levels in clinical material (Leung et al, 1996;Dorkin et al, 1999;Valve et al, 2001). Data concerning FGF8 correlation with clinical parameters, however, have been conflicting and may reflect differences in splice form utilisation (Leung et al, 1996;Tanaka et al, 1998;Dorkin et al, 1999;Valve et al, 2001). Transcript studies of isoform expression are limited by reliance on semiquantitative RT -PCR on heterogeneous frozen materials.…”

“…These blocks included samples of placenta as well as testis, breast cancer and prostate cancer known to express FGF8 (Tanaka et al, 1998;Dorkin et al, 1999). A dilution of 1 : 500 gave the optimal signals.…”

“…The peptide was first implicated in prostate cancer when FGF8 mRNA was found to be expressed in prostate cancer cell lines (Ghosh et al, 1996;Schmitt et al, 1996). In clinical prostate cancer, overexpression of FGF8 mRNA was found to be associated with high-grade and late-stage disease (Leung et al, 1996;Dorkin et al, 1999). Subsequent work has shown that distinct isoforms of FGF8 possess different transforming potential.…”

FGF8b oncogene mediates proliferation and invasion of Epstein–Barr virus-associated nasopharyngeal carcinoma cells: implication for viral-mediated FGF8b upregulation

“…Clinical studies revealed that FGF8b overexpression was found in the majority of prostate cancer (40-80%) (Dorkin et al, 1999;Gnanapragasam et al, 2002Gnanapragasam et al, , 2003Tanaka et al, 2002;Zhong et al, 2006) and breast cancer (B70-100%) . Moreover, its overexpression was clinically associated with disease progression (mainly staging and grading), poor prognosis, poor survival (Dorkin et al, 1999;Valve et al, 2001), and potentially metastasis in prostate cancer (Gnanapragasam et al, 2003;Valta et al, 2008).…”

“…Clinical studies revealed that FGF8b overexpression was found in the majority of prostate cancer (40-80%) (Dorkin et al, 1999;Gnanapragasam et al, 2002Gnanapragasam et al, , 2003Tanaka et al, 2002;Zhong et al, 2006) and breast cancer (B70-100%) . Moreover, its overexpression was clinically associated with disease progression (mainly staging and grading), poor prognosis, poor survival (Dorkin et al, 1999;Valve et al, 2001), and potentially metastasis in prostate cancer (Gnanapragasam et al, 2003;Valta et al, 2008). Although the molecular mechanisms for FGF8b overexpression in prostate and breast cancers are not fully understood, the human sex hormone androgen (Tanaka et al, 1992) is known to play a key role, even in the case of breast cancer (Castellano et al, 2010Park et al, 2010 (in addition to prostate cancer (Gnanapragasam et al, 2002)).…”