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

Gowardhan B, Douglas DA, Mathers ME, McKie AB, McCracken SR, Robson CN, Leung HY - Br. J. Cancer (2005)

Bottom Line: Overall, FGFR4 expression was significantly upregulated in CaP when compared to BPH.FGFR4 overexpression was associated with an unfavourable outcome with decreased disease-specific survival (P<0.04, log rank test).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) or gamma-irradiation.

View Article: PubMed Central - PubMed

Affiliation: Urology Research Group, Northern Institute for Cancer Research, University of Newcastle, Newcastle upon Tyne, NE2 4HH, UK.

ABSTRACT
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=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 (P<0.0001, Fisher's exact test), Gleason score 4-6 tumours compared to BPH (P<0.0004), and Gleason 7-10 compared to Gleason 4-6 tumours (P<0.005). FGFR4 overexpression was associated with an unfavourable outcome with decreased disease-specific survival (P<0.04, 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) or gamma-irradiation. In summary, our data support the model of FGF system as valid target for therapy in CaP.

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Related in: MedlinePlus

(A) FGFR4 immunoreactivity in a Gleason 8 prostate cancer specimen, showing moderate to strong FGFR4 immunoreactivity. The staining is predominantly epithelial and within the epithelium, there is no nuclear expression of FGFR4. There appears to be increased staining at the cell membrane, in keeping with the transmembranous nature of the FGFR4. (B) Comparison of FGFR4 staining in a benign gland next to an area of prostate cancer (Gleason 9), on the same tissue section. This figure shows increased FGFR4 expression in the malignant epithelium, in contrast to the adjacent benign prostate epithelium with no detectable signals.
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fig2: (A) FGFR4 immunoreactivity in a Gleason 8 prostate cancer specimen, showing moderate to strong FGFR4 immunoreactivity. The staining is predominantly epithelial and within the epithelium, there is no nuclear expression of FGFR4. There appears to be increased staining at the cell membrane, in keeping with the transmembranous nature of the FGFR4. (B) Comparison of FGFR4 staining in a benign gland next to an area of prostate cancer (Gleason 9), on the same tissue section. This figure shows increased FGFR4 expression in the malignant epithelium, in contrast to the adjacent benign prostate epithelium with no detectable signals.

Mentions: FGFR4 immunoreactivity was seen in both benign and malignant prostate sections. Signals observed in the stroma were scanty and at low intensity. The malignant epithelium showed uniform moderate to strong immunoreactivity for FGFR4. FGFR4 staining was entirely cytoplasmic, with no nuclear signals. In some sections, there was also convincing membranous staining in keeping with a transmembranous localisation of FGFR4 (Figure 2).


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

Gowardhan B, Douglas DA, Mathers ME, McKie AB, McCracken SR, Robson CN, Leung HY - Br. J. Cancer (2005)

(A) FGFR4 immunoreactivity in a Gleason 8 prostate cancer specimen, showing moderate to strong FGFR4 immunoreactivity. The staining is predominantly epithelial and within the epithelium, there is no nuclear expression of FGFR4. There appears to be increased staining at the cell membrane, in keeping with the transmembranous nature of the FGFR4. (B) Comparison of FGFR4 staining in a benign gland next to an area of prostate cancer (Gleason 9), on the same tissue section. This figure shows increased FGFR4 expression in the malignant epithelium, in contrast to the adjacent benign prostate epithelium with no detectable signals.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2361833&req=5

fig2: (A) FGFR4 immunoreactivity in a Gleason 8 prostate cancer specimen, showing moderate to strong FGFR4 immunoreactivity. The staining is predominantly epithelial and within the epithelium, there is no nuclear expression of FGFR4. There appears to be increased staining at the cell membrane, in keeping with the transmembranous nature of the FGFR4. (B) Comparison of FGFR4 staining in a benign gland next to an area of prostate cancer (Gleason 9), on the same tissue section. This figure shows increased FGFR4 expression in the malignant epithelium, in contrast to the adjacent benign prostate epithelium with no detectable signals.
Mentions: FGFR4 immunoreactivity was seen in both benign and malignant prostate sections. Signals observed in the stroma were scanty and at low intensity. The malignant epithelium showed uniform moderate to strong immunoreactivity for FGFR4. FGFR4 staining was entirely cytoplasmic, with no nuclear signals. In some sections, there was also convincing membranous staining in keeping with a transmembranous localisation of FGFR4 (Figure 2).

Bottom Line: Overall, FGFR4 expression was significantly upregulated in CaP when compared to BPH.FGFR4 overexpression was associated with an unfavourable outcome with decreased disease-specific survival (P<0.04, log rank test).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) or gamma-irradiation.

View Article: PubMed Central - PubMed

Affiliation: Urology Research Group, Northern Institute for Cancer Research, University of Newcastle, Newcastle upon Tyne, NE2 4HH, UK.

ABSTRACT
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=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 (P<0.0001, Fisher's exact test), Gleason score 4-6 tumours compared to BPH (P<0.0004), and Gleason 7-10 compared to Gleason 4-6 tumours (P<0.005). FGFR4 overexpression was associated with an unfavourable outcome with decreased disease-specific survival (P<0.04, 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) or gamma-irradiation. In summary, our data support the model of FGF system as valid target for therapy in CaP.

Show MeSH
Related in: MedlinePlus