aFGF immunoreactivity in prostate cancer and its co-localization with bFGF and FGF8

Dorkin, Trevor J.; Robinson, Mary C.; Marsh, Colin; Neal, David E.; Leung, Hing Y.

doi:10.1002/(sici)1096-9896(199912)189:4<564::aid-path480>3.0.co;2-1

Cited by 56 publications

(35 citation statements)

References 26 publications

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“…Overexpression of multiple FGFs (namely aFGF/FGFl, bFGF/FGF2, FGF6 and FGF8) has been identified in prostate cancer Ittmann and Mansukhani, 1997;Dorkin et al, 1999b;Ropiquet et al, 2000). FGF8 appeared to be particularly important as paracrine and autocrine factors in prostate cancer (Leung et al, , 1997.…”

Section: Discussionmentioning

confidence: 99%

“…These mitogens enhance tumour proliferation and invasion while inhibiting apoptosis. Several peptide growth factors have been implicated in prostate cancer development and progression, including insulin-like growth factors, epidermal growth factor and members of the fibroblast growth factors (Byrne et al, 1996;Tennant et al, 1996;Dorkin et al, 1999a).The family of fibroblast growth factors (FGFs) and their receptors (FGFRs) are important in the prostate organogenesis as well as the pathogenesis of prostate cancer (Cunha et al, 1987;Leung et al, 1996;Ittmann and Mansukhani, 1997;Dorkin et al, 1999b). Fibroblast growth factors make up a large family of 23 related polypeptides with highly conserved amino-acid sequences, sharing 13 -71% sequence homology, ranging from 17 to 34 kDa in molecular weight (Ornitz and Itoh, 2001;Yamashita et al, 2000).…”

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confidence: 99%

“…The family of fibroblast growth factors (FGFs) and their receptors (FGFRs) are important in the prostate organogenesis as well as the pathogenesis of prostate cancer (Cunha et al, 1987;Leung et al, 1996;Ittmann and Mansukhani, 1997;Dorkin et al, 1999b). Fibroblast growth factors make up a large family of 23 related polypeptides with highly conserved amino-acid sequences, sharing 13 -71% sequence homology, ranging from 17 to 34 kDa in molecular weight (Ornitz and Itoh, 2001;Yamashita et al, 2000).…”

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Evaluation of the fibroblast growth factor system as a potential target for therapy in human prostate cancer

et al. 2005

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Overexpression of fibroblast growth factors (FGFs) has been implicated in prostate carcinogenesis. FGFs function via their high-affinity interactions with receptor tyrosine kinases, FGFR1 -4. Expression of FGFR1 and FGFR2 in prostate cancer (CaP) was not found to be associated with clinical parameters. In this report, we further investigated for abnormal FGFR expression in prostate cancer and explore their significance as a potential target for therapy. The expression levels of FGFR3 and FGFR4 in CaP were examined and corroborated to clinical parameters. FGFR3 immunoreactivity in benign prostatic hyperplasia (BPH) and CaP (n ¼ 26 and 57, respectively) had similar intensity and pattern. Overall, FGFR4 expression was significantly upregulated in CaP when compared to BPH. A significant positive correlation between FGFR4 expression and Gleason score was noted: Gleason score 7 -10 tumours compared to BPH (Po0.0001, Fisher's exact test), Gleason score 4 -6 tumours compared to BPH (Po0.0004), and Gleason 7 -10 compared to Gleason 4 -6 tumours (Po0.005). FGFR4 overexpression was associated with an unfavourable outcome with decreased disease-specific survival (Po0.04, log rank test). FGF-induced signalling is targeted using soluble FGF receptor (sFGFR), potent inhibitor of FGFR function. We have previously shown that sFGFR expression via a replication-deficient adenoviral vector (AdlllcRl) suppresses in vitro FGF-induced signalling and function in human CaP DU145 cells. We tested the significance of inhibiting FGF function along with conventional therapeutic modalities in CaP, and confirmed synergistic effects on in vitro cell growth (proliferation and colony formation) by combining sFGFR expression and treatment with either Paclitaxel (Taxol s ) or g-irradiation. In summary, our data support the model of FGF system as valid target for therapy in CaP. Prostate cancer is the commonest cancer in men and the second commonest cause of cancer-related death in men, and its incidence is increasing (Woolf, 1995;Boyle et al, 1996). Prostate cancer is an enigmatic disease. It is histologically present in 80% of men over the age of 80 years, but will only clinically manifest itself in about 10%. Increasing use of serum measurement of prostate-specific antigen is facilitating early diagnosis of prostate cancer. There are currently limited prognostic markers that may allow patients found to have early prostate cancer to be stratified into different management plans. Hence, new methods of predicting disease progression are urgently needed.Abnormal expression of peptide growth factors and their highaffinity receptor tyrosine kinases are important in the development and progression of prostate cancer. These mitogens enhance tumour proliferation and invasion while inhibiting apoptosis. Several peptide growth factors have been implicated in prostate cancer development and progression, including insulin-like growth factors, epidermal growth factor and members of the fibroblast growth factors (Byrne et al, 1996;Tennant et al, 1996;Dorkin et...

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Section: Discussionmentioning

confidence: 99%

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Evaluation of the fibroblast growth factor system as a potential target for therapy in human prostate cancer

et al. 2005

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“…Alternate splicing of FGFRs and differential expression of FGF ligands can impart stromal independence on the epithelium by establishing autocrine growth factorsignaling loops. Clinically, increased expression of FGF1 has been observed in regions of prostatic intraepithelial neoplasia (PIN) and CaP (Dorkin et al, 1999). Moreover, expression of FGF2 in stromal cells has been shown to be approximately 2.5-fold higher in clinically localized CaP compared to normal prostate (Giri et al, 1999), and epithelial expression of FGF2 has been detected in advanced CaP (Dorkin et al, 1999).…”

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“…Clinically, increased expression of FGF1 has been observed in regions of prostatic intraepithelial neoplasia (PIN) and CaP (Dorkin et al, 1999). Moreover, expression of FGF2 in stromal cells has been shown to be approximately 2.5-fold higher in clinically localized CaP compared to normal prostate (Giri et al, 1999), and epithelial expression of FGF2 has been detected in advanced CaP (Dorkin et al, 1999). This upregulation of FGF2 during CaP progression has been clinically correlated with angiogenesis (Doll et al, 2001).…”

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

Murphy

Darby

Mathers

et al. 2009

The Journal of Pathology

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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.

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aFGF immunoreactivity in prostate cancer and its co-localization with bFGF and FGF8

Cited by 56 publications

References 26 publications

Evaluation of the fibroblast growth factor system as a potential target for therapy in human prostate cancer

Evaluation of the fibroblast growth factor system as a potential target for therapy in human prostate cancer

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

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

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