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

Gowardhan, Bharat; Douglas, David; Mathers, Marie E.; McKie, Arthur B.; McCracken, Stuart; Robson, Craig; Leung, Hing Y.

doi:10.1038/sj.bjc.6602274

Cited by 91 publications

(73 citation statements)

References 39 publications

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“…High expression of FGFR4 has been described already for breast cancer (Lehtola et al, 1992;Jaakkola et al, 1993), pancreatic cancer (Leung et al, 1994) and renal cell carcinoma (Takahashi et al, 1999). The cytoplasmic staining of the FGFR4 in melanoma cells is in agreement with other publications investigating the expression for FGFR4 in other types of cancer (Gowardhan et al, 2005;Mawrin et al, 2005). In contrast to FGFR1, no nuclear staining could be observed for FGFR4 (Maher, 1996;Stachowiak et al, 1997).…”

Section: Discussionsupporting

confidence: 90%

FGFR4 Arg388 allele correlates with tumour thickness and FGFR4 protein expression with survival of melanoma patients

et al. 2006

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A single nucleotide polymorphism in the gene for FGFR4 (ÀArg388) has been associated with progression in various types of human cancer. Although fibroblast growth factors (FGFs) belong to the most important growth factors in melanoma, expression of FGF receptor subtype 4 has not been investigated yet. In this study, the protein expression of this receptor was analysed in 137 melanoma tissues of different progression stages by immunohistochemistry. FGFR4 protein was expressed in 45% of the specimens and correlated with pTNM tumour stages (UICC, P ¼ 0.023 and AJCC, P ¼ 0.046), presence of microulceration (P ¼ 0.009), tumour vascularity (P ¼ 0.001), metastases (P ¼ 0.025), number of primary tumours (P ¼ 0.022), overall survival (P ¼ 0.047) and disease-free survival (P ¼ 0.024). Furthermore, FGFR4 Arg388 polymorphism was analysed in 185 melanoma patients by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The Arg388 allele was detected in 45% of the melanoma patients and was significantly associated with tumour thickness (by Clark's level of invasion (P ¼ 0.004) and by Breslow in mm (P ¼ 0.02)) and the tumour subtype nodular melanoma (P ¼ 0.002). However, there was no correlation of the FGFR4 Arg388 allele with overall and disease-free survival. In conclusion, the Arg388 genotype and the protein expression of FGFR4 may be potential markers for progression of melanoma.

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Section: Discussionsupporting

confidence: 90%

FGFR4 Arg388 allele correlates with tumour thickness and FGFR4 protein expression with survival of melanoma patients

et al. 2006

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“…Also, FGF8b has been implicated in the inappropriate activation of growth factor signaling cascade that overcome steroid hormone sensitivity of these tumors, resulting in the progression toward a refractory neoplasm insensitive to hormone deprivation therapy (4,34,35). On this basis, the FGF/FGFR system has been hypothesized as a target for the treatment of steroid hormone-regulated tumors (2,(35)(36)(37)(38), also in a possible synergistic combination with g-irradiation or antineoplastic drug therapies (39). Here, we show that PTX3 represents a novel FGF8b antagonist endowed with antiangiogenic and antineoplastic activity.…”

Section: Discussionmentioning

confidence: 99%

Long Pentraxin-3 Inhibits FGF8b-Dependent Angiogenesis and Growth of Steroid Hormone–Regulated Tumors

Leali

Alessi

Coltrini

et al. 2011

Molecular Cancer Therapeutics

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Fibroblast growth factor-8b (FGF8b) exerts nonredundant autocrine/paracrine functions in steroid hormone-regulated tumors. Previous observations had shown that the soluble pattern recognition receptor long pentraxin-3 (PTX3) is a natural selective antagonist for a restricted number of FGF family members, inhibiting FGF2 but not FGF1 and FGF4 activity. Here, we assessed the capacity of PTX3 to antagonize FGF8b and to inhibit the vascularization and growth of steroid hormone-regulated tumors. Surface plasmon resonance analysis shows that PTX3 binds FGF8b with high affinity (K d ¼ 30-90 nmol/L). As a consequence, PTX3 prevents the binding of FGF8b to its receptors, inhibits FGF8b-driven ERK1/2 activation, cell proliferation, and chemotaxis in endothelial cells, and suppresses FGF8b-induced neovascularization in vivo. Also, PTX3 inhibits dihydrotestosterone (DHT)-and FGF8b-driven proliferation of androgen-regulated Shionogi 115 (S115) mouse breast tumor cells. Furthermore, DHT-treated, PTX3 overexpressing hPTX3_S115 cell transfectants show a reduced proliferation rate in vitro and a limited angiogenic activity in the chick embryo chorioallantoic membrane and murine s.c. Matrigel plug assays. Accordingly, hPTX3_S115 cells show a dramatic decrease of their tumorigenic activity when grafted in immunodeficient male mice. These results identify PTX3 as a novel FGF8b antagonist endowed with antiangiogenic and antineoplastic activity with possible implications for the therapy of hormonal tumors. Mol Cancer Ther; 10(9); 1600-10. Ó2011 AACR.

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“…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.…”

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confidence: 99%

“…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.…”

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confidence: 99%

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

et al. 2009

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Prostate cancer is the second cause of cancer-related death in men of the Western World. The role of FGFR3 and its abnormalities in prostate cancer are not known. FGFR3 mutations have been reported in some human tumors. Few studies have analyzed the mutations of FGFR3 in prostate tumors, and no mutations have been previously reported. Prevalence of FGFR3 somatic mutations was investigated in a series of prostate tumors. The presence of other tumors in these patients, including urothelial, skin, colon, and lung neoplasms, was recorded. Mutational analysis of exons 7, 10, and 15 of FGFR3 revealed 9 mutations in the 112 prostate tumors studied (8%). Most of them consisted of the missense change S249C. The prevalence of mutations in tumors with combined Gleason score ¼ 6 is 18% (8/45) compared to 3% (1/36) for tumors with grade ¼ 7, and 0% (0/31) for those with grade Z8 and metastases (P ¼ 0.007). The frequency of FGFR3 mutations in autopsy and biopsy samples was 6 and 9%, respectively. The prevalence of FGFR3 mutations in prostate tumors from patients with only prostate cancer was 2% compared to 23% in prostate tumors from patients with other associated neoplasms (P ¼ 0.001). This is the first report of molecular changes of FGFR3 in prostate cancer. This gene does not seem to be central to the pathogenesis of prostate cancer, but it is significantly associated with a subgroup of low-grade prostate tumors, and with the finding of other tumors, mainly arising in bladder and skin.

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

Cited by 91 publications

References 39 publications

FGFR4 Arg388 allele correlates with tumour thickness and FGFR4 protein expression with survival of melanoma patients

FGFR4 Arg388 allele correlates with tumour thickness and FGFR4 protein expression with survival of melanoma patients

Long Pentraxin-3 Inhibits FGF8b-Dependent Angiogenesis and Growth of Steroid Hormone–Regulated Tumors

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

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