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

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 γ-irradiation. In summary, our data support the model of FGF system as valid target for therapy in CaP.

[1]  D. Rifkin,et al.  Heparin increases the affinity of basic fibroblast growth factor for its receptor but is not required for binding. , 1994, The Journal of biological chemistry.

[2]  J. Thrasher,et al.  Protein and messenger ribonucleic acid (mRNA) for the type 1 insulin-like growth factor (IGF) receptor is decreased and IGF-II mRNA is increased in human prostate carcinoma compared to benign prostate epithelium. , 1996, The Journal of clinical endocrinology and metabolism.

[3]  M. Jaye,et al.  Fibroblast growth factor receptor tyrosine kinases: molecular analysis and signal transduction. , 1992, Biochimica et biophysica acta.

[4]  R. Crystal,et al.  Variation in adenovirus receptor expression and adenovirus vector-mediated transgene expression at defined stages of the cell cycle. , 2001, Molecular therapy : the journal of the American Society of Gene Therapy.

[5]  P. Maher.  Nuclear Translocation of fibroblast growth factor (FGF) receptors in response to FGF-2 , 1996, The Journal of cell biology.

[6]  S. Kitano,et al.  Anti-tumor angiogenesis therapy using soluble receptors: enhanced inhibition of tumor growth when soluble fibroblast growth factor receptor-1 is used with soluble vascular endothelial growth factor receptor , 2002, Cancer Gene Therapy.

[7]  S. Coons,et al.  Nuclear accumulation of fibroblast growth factor receptors in human glial cells-association with cell proliferation , 1997, Oncogene.

[8]  P. Maher,et al.  Nuclear accumulation of fibroblast growth factor receptors is regulated by multiple signals in adrenal medullary cells. , 1996, Molecular biology of the cell.

[9]  C. Becker,et al.  Gene Therapy of Prostate Cancer with the Soluble Vascular Endothelial Growth Factor Receptor Fk1 , 2002, Cancer biology & therapy.

[10]  D. Neal,et al.  aFGF immunoreactivity in prostate cancer and its co‐localization with bFGF and FGF8 , 1999, The Journal of pathology.

[11]  D. Hill,et al.  Perinuclear localization of an intracellular binding protein related to the fibroblast growth factor (FGF) receptor 1 is temporally associated with the nuclear trafficking of FGF-2 in proliferating epiphyseal growth plate chondrocytes. , 1996, Endocrinology.

[12]  D. Neal,et al.  Peptide growth factors in the prostate as mediators of stromal epithelial interaction. , 1996, British journal of urology.

[13]  D. Neal,et al.  Keratinocyte growth factor expression in hormone insensitive prostate cancer , 1997, Oncogene.

[14]  M. Southey,et al.  Overexpression of the steroid receptor coactivator AIB1 in breast cancer correlates with the absence of estrogen and progesterone receptors and positivity for p53 and HER2/neu. , 2001, Cancer research.

[15]  G. Giles,et al.  Distinct molecular pathogeneses of early-onset breast cancers in BRCA1 and BRCA2 mutation carriers: a population-based study. , 1999, Cancer research.

[16]  J. Xu,et al.  Fibroblast growth factor receptor (FGFR) 3. Alternative splicing in immunoglobulin-like domain III creates a receptor highly specific for acidic FGF/FGF-1. , 1994, The Journal of biological chemistry.

[17]  C. Robson,et al.  Adenovirus‐mediated expression of a soluble fibroblast growth factor receptor inhibits in vitro growth of prostate DU145 cells , 2004, The Prostate.

[18]  J. Xu,et al.  Intact and functional fibroblast growth factor (FGF) receptor-1 trafficks near the nucleus in response to FGF-1. , 1994, The Journal of biological chemistry.

[19]  M. Ittman,et al.  Expression of fibroblast growth factors (FGFs) and FGF receptors in human prostate. , 1997, The Journal of urology.

[20]  C. Powers,et al.  Fibroblast growth factors, their receptors and signaling. , 2000, Endocrine-related cancer.

[21]  F. Marshall,et al.  The future of gene therapy in the treatment of urologic malignancies. , 1998, The Urologic clinics of North America.

[22]  E. Frenkel,et al.  Enhanced transgene expression in androgen independent prostate cancer gene therapy by taxane chemotherapeutic agents. , 2002, The Journal of urology.

[23]  N. Itoh,et al.  Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain. , 2000, Biochemical and biophysical research communications.

[24]  D. Neal,et al.  Over-expression of fibroblast growth factor-8 in human prostate cancer. , 1996, Oncogene.

[25]  D. Nettelbeck,et al.  Adenovirus-mediated soluble FLT-1 gene therapy for ovarian carcinoma. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[26]  J. Xu,et al.  Nuclear localization of a complex of fibroblast growth factor(FGF)-1 and an NH2-terminal fragment of FGF receptor isoforms R4 and R1alpha in human liver cells. , 1996, Biochimica et biophysica acta.

[27]  P. Boyle,et al.  Incidence of prostate cancer will double by the year 2030: the argument for. , 1996, European urology.

[28]  M. Ittmann,et al.  Increased expression of fibroblast growth factor 6 in human prostatic intraepithelial neoplasia and prostate cancer. , 2000, Cancer research.

[29]  S. Shousha,et al.  Altered intracellular localization of fibroblast growth factor receptor 3 in human breast cancer , 2001, The Journal of pathology.

[30]  M. Ittmann,et al.  Role of fibroblast growth factor receptor signaling in prostate cancer cell survival. , 2001, Journal of the National Cancer Institute.

[31]  S. Mackem,et al.  Soluble dominant‐negative receptor uncovers essential roles for fibroblast growth factors in multi‐organ induction and patterning , 1998, The EMBO journal.

[32]  D. Neal,et al.  FGF8 over-expression in prostate cancer is associated with decreased patient survival and persists in androgen independent disease , 1999, Oncogene.

[33]  S. Woolf.  Screening for prostate cancer with prostate-specific antigen. An examination of the evidence. , 1995, The New England journal of medicine.

[34]  M. Ittmann,et al.  Alterations in expression of basic fibroblast growth factor (FGF) 2 and its receptor FGFR-1 in human prostate cancer. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[35]  C. Stevens,et al.  High-efficiency stable gene transfer of adenovirus into mammalian cells using ionizing radiation. , 1997, Human gene therapy.

[36]  C. MacArthur,et al.  Receptor Specificity of the Fibroblast Growth Factor Family* , 1996, The Journal of Biological Chemistry.

[37]  S. J. Higgins,et al.  The endocrinology and developmental biology of the prostate. , 1987, Endocrine reviews.

[38]  H. Hanafusa,et al.  Characterization of the murine BEK fibroblast growth factor (FGF) receptor: activation by three members of the FGF family and requirement for heparin. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[39]  S. Werner,et al.  Immunoglobulin Domain. Receptor Forms That Differ in Their Third Underlies the Mechanisms for Generating Genes: a Common Structural Arrangement the Human Fibroblast Growth Factor Receptor , 1990 .

[40]  Nobuyuki Itoh,et al.  Fibroblast growth factors , 2001, Genome Biology.

[41]  V. Mehta,et al.  Fibroblast Variants Nonresponsive to Fibroblast Growth Factor 1 Are Defective in Its Nuclear Translocation* , 1998, The Journal of Biological Chemistry.

[42]  E. B. Butler,et al.  Combining radiotherapy with gene therapy (from the bench to the bedside): a novel treatment strategy for prostate cancer. , 2002, The oncologist.

[43]  D. Birnbaum,et al.  Fibroblast growth factor receptor‐4 shows novel features in genomic structure, ligand binding and signal transduction. , 1992, The EMBO journal.