FGF8 isoform b expression in human prostate cancer

Gnanapragasam, Vincent; Robinson, Max; Marsh, Colin; Robson, Craig; Hamdy, Freddie C.; Leung, Hing Y.

doi:10.1038/sj.bjc.6600875

Cited by 69 publications

(69 citation statements)

References 25 publications

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“…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). Alternate splicing of FGFRs and differential expression of FGF ligands can impart stromal independence on the epithelium by establishing autocrine growth factorsignaling loops.…”

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confidence: 99%

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

et al. 2007

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The expression of fibroblast growth factor receptor (FGFR)-1 correlates with angiogenesis and is associated with prostate cancer (CaP) progression. To more precisely define the molecular mechanisms whereby FGFR1 causes angiogenesis in the prostate we exploited a transgenic mouse model, JOCK-1, in which activation of a conditional FGFR1 allele in the prostate epithelium caused rapid angiogenesis and progressive hyperplasia. By labeling the vasculature in vivo and applying a novel method to measure the vasculature in three dimensions, we were able to observe a significant increase in vascular volume 1 week after FGFR1 activation. Although vessel volume and branching both continued to increase throughout a 6-week period of FGFR1 activation, importantly, we discovered that continued activation of FGFR1 was not required to maintain the new vasculature. Exploring the molecular mediators of the angiogenic phenotype, we observed consistent upregulation of HIF-1a, vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang-2), whereas expression of Ang-1 was lost. Further analysis revealed that loss of Ang-1 expression occurred in the basal epithelium, whereas the increase in Ang-2 expression occurred in the luminal epithelium. Reporter assays confirmed that the Ang-2 promoter was regulated by FGFR1 signaling and a small molecule inhibitor of FGFR activity, PD173074, could abrogate this response. These findings establish a method to follow spontaneous angiogenesis in a conditional autochthonous system, implicate the angiopoietins as downstream effectors of FGFR1 activation in vivo, and suggest that therapies targeting FGFR1 could be used to inhibit neovascularization during initiation and progression of CaP.

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confidence: 99%

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

et al. 2007

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“…Consistent with these findings, it has been demonstrated that FGF8b overexpression in both prostate and breast cancer cells can promote tumor cell growth and formation in nude mice (Song et al, 2000;Ruohola et al, 2001), whereas specific downregulation of FGF8b by antisense RNA inhibited the in vivo tumorigenicity of prostate cancer cells (Rudra-Ganguly et al, 1998). These cumulative evidences establish the role of FGF8b in carcinogenesis of hormone-related cancers (Tanaka et al, 1998;Marsh et al, 1999;Gnanapragasam et al, 2003).…”

Section: Introductionmentioning

confidence: 66%

“…Further genomic and functional characterization of the FGF8 family demonstrated that the FGF8b isoform (one of the four human FGF8 isoforms: FGF8a, b, e and f (Gemel et al, 1996)) possesses the greatest mitogenic and, more importantly, the greatest transforming activity than the other isoforms, both in vitro and in vivo (MacArthur et al, 1995a(MacArthur et al, , 1995bBlunt et al, 1997;Song et al, 2000;Olsen et al, 2006). It is believed that FGF8b is one of the most important FGF8 isoforms in human carcinogenesis Gnanapragasam et al, 2003), although the exact physiological function of each isoform is yet-to-be fully revealed.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…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)).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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The fibroblast growth factor 8b (FGF8b) oncogene is known to be primarily involved in the tumorigenesis and progression of hormone-related cancers. Its role in other epithelial cancers has not been investigated, except for esophageal cancer, in which FGF8b overexpression was mainly found in tumor biopsies of male patients. These observations were consistent with previous findings in these cancer types that the male sex-hormone androgen is responsible for FGF8b expression. Nasopharyngeal carcinoma (NPC) is a highly metastatic cancer of head and neck commonly found in Asia. It is etiologically associated with Epstein-Barr Virus (EBV) infection, inflammatory tumor microenvironment and relatively higher male predominance. Here, we reported for the first time that FGF8b is overexpressed in this EBV-associated non-hormone-related cancer of the head and neck, NPC. More importantly, overexpression of FGF8b mRNA and protein was detected in a large majority of NPC tumors from both male and female genders, in addition to multiple NPC cell lines. We hypothesized that FGF8b overexpression may contribute to NPC tumorigenesis. Using EBV-associated NPC cell lines, we demonstrated that specific knockdown of FGF8b by small interfering RNA inhibited cell proliferation, migration and invasion, whereas exogenous FGF8b stimulated these multiple phenotypes. Further mechanistic investigation revealed that in addition to NF-jB signaling (a major inflammatory signaling pathway known to be activated in NPC), an important EBV oncoprotein, the latent membrane protein 1 (LMP1), was found to be a direct inducer of FGF8b overexpression in NPC cells, whereas androgen (testosterone) has minimal effect on FGF8b expression in EBVassociated NPC cells. In summary, our study has identified LMP1 as the first viral oncogene capable of directly inducing FGF8b (an important cellular oncogene) expression in human cancer cells. This novel mechanism of viral-mediated FGF8 upregulation may implicate a new role of oncoviruses in human carcinogenesis.

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FGF‐8 is involved in bone metastasis of prostate cancer

Valta

Tuomela

Bjartell

et al. 2008

Intl Journal of Cancer

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Prostate cancer is the most common malignancy of men in Western countries. Patients with advanced prostate cancer suffer from incurable bone metastases. Recent data indicate that interactions between prostate cancer cells, osteoblasts, osteoclasts and the bone matrix are essential in the formation of bone metastases. FGF-8 is widely overexpressed in prostate cancer. Recently, FGF-8 has been found to affect both osteoblast and osteoclast differentiation. The aim of this study was to examine the role of FGF-8 in bone metastasis of prostate cancer. Immunohistochemistry was used to analyse FGF-8 expression in clinical samples of prostate cancer bone metastases. The functional significance of FGF-8 in growth of bone metastasis and formation of bone lesions was verified by using intratibial inoculations of FGF-8 or mock transfected PC-3 prostate cancer cells in nude mice. Intratibial tumors and bone lesions were analysed with X-ray, micro-CT and detailed histomorphometry using image analysis software and with immunostaining for osteocalcin and cathepsin K. Immunohistochemical analysis of tissue microarray of bone metastases of human prostate cancer showed that 76% of human bone metastasis samples (n 5 25 from 11 patients) were positive for FGF-8. FGF-8 increased the growth of intratibial tumors and local formation of lytic and sclerotic lesions of bone. These results demonstrate that FGF-8 is expressed at a high frequency in bone metastases of human prostate cancer and that expression of FGF-8 in PC-3 prostate cancer cells increases their growth as intratibial tumors and modulates formation of bone lesions in an in vivo model of prostate cancer bone metastasis. '

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FGF8 isoform b expression in human prostate cancer

Cited by 69 publications

References 25 publications

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

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

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

FGF‐8 is involved in bone metastasis of prostate cancer

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