Selective over‐expression of fibroblast growth factor receptors 1 and 4 in clinical prostate cancer

Abstract

Fibroblast growth factor receptors (FGFRs) mediate the tumourigenic effects of FGFs in prostate cancer. These receptors are therefore potential therapeutic targets in the development of inhibitors to this pathway. To identify the most relevant targets, we simultaneously investigated FGFR1-4 expression using a prostate cancer tissue microarray (TMA) and in laser capture microdissected (LCM) prostate epithelial cells. In malignant prostates (n = 138) we observed significant FGFR1 and FGFR4 protein over-expression in comparison with benign prostates (n = 58; p < 0.0001). FGFR1 was expressed at high levels in the majority of tumours (69% of grade 3 or less, 74% of grade 4 and 70% of grade 5), while FGFR4 was strongly expressed in 83% of grade 5 cancers but in only 25% of grade 1-3 cancers (p < 0.0001). At the transcript level we observed a similar pattern, with FGFR1 and FGFR4 mRNA over-expressed in malignant epithelial cells compared to benign cells (p < 0.0005 and p < 0.05, respectively). While total FGFR2 was increased in some cancers, there was no association between expression and tumour grade or stage. Transcript analysis, however, revealed a switch in the predominant isoform expressed from FGFR2IIIb to FGFR2IIIc among malignant epithelial cells. In contrast, protein and transcript expression of FGFR3 was very similar between benign and cancer biopsies. The functional effect of targeting FGFR4 in prostate cancer cells has not previously been investigated. In in vitro experiments, suppression of FGFR4 by RNA interference effectively blocked prostate cancer cell proliferation (p < 0.0001) and invasion (p < 0.001) in response to exogenous stimulation. This effect was evident regardless of whether the cells expressed the FGFR4 Arg388 or Gly388 allele. In parallel experiments, FGFR3 suppression had no discernible effect on cancer cell behaviour. These results suggest evidence of selective over-expression of FGFR1 and FGFR4 in clinical prostate cancer and support the notion of targeted inhibition of these receptors to disrupt FGF signalling.

FGFR4 Gly388Arg polymorphism may affect the clinical stage of patients with lung cancer by modulating the transcriptional profile of normal lung

“…4a and 4b), indicates a functional role for the FGFR4 polymorphism in vivo in human normal lung tissue, consistent with the established in vitro functional effects of this polymorphism. 17,18 Interestingly, the gene expression profile pointed to association of the Notch biochemical pathway with Arg388 allele status, revealing upregulation of NOTCH1 and downregulation of UNC5B (Figs. 3 and 4).…”

FGFR3 mutations in prostate cancer: association with low-grade tumors

“…3 In the prostate, the aberrant signaling of FGFs is a strong factor in the disruption of tissue homeostasis, which, in turn, may contribute to prostate tumor development and progression. [6][7][8] FGFs 6,8,and 17 are overexpressed in human prostate cancer. In addition, FGF6 expression has also been found to be increased in prostatic intraepithelial neoplasia.…”

“…However, neither FGFR1 nor FGFR2 expression was found to be statistically related to clinical parameters. [15][16][17] Although the overexpression of FGFR1 protein is a common event in both early and late prostate cancer, FGFR4 is increasingly expressed in high-grade tumors. Increased FGFR4 immunoreactivity appears to be significantly associated with decreased patient survival, but not with metastasis.…”

“…Increased FGFR4 immunoreactivity appears to be significantly associated with decreased patient survival, but not with metastasis. 17,18 Alterations in FGF signaling regulators also have an impact on prostate tumorigenesis. In this regard, downregulation of Sprouty 1 and Sprouty 2 has been recently reported.…”

“…FGFR3 protein expression studies show heterogeneous expression levels in benign and malignant prostate epithelium. 17,18 Gain-of-function mutations have been identified in different dominant autosomal human skeletal disorders such as hypochondroplasia, achondroplasia, and thanatophoric dysplasia. [22][23][24] FGFR3 mutations identical to those found in these disorders have been reported in multiple myelomas, cervix and bladder cancer, colon cancer, and benign skin tumors.…”