Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Fibroblast growth factor signalling: from development to cancer

Key Points

  • Fibroblast growth factors (FGFs) and their receptors (FGFRs) drive crucial developmental signalling pathways, which are responsible for many functions, including cell proliferation, survival and migration. As such, they are susceptible to hijack by cancer cells and have been shown to have oncogenic roles in many cancers.

  • Conversely, FGFR signalling can also have tumour suppressive roles, through driving differentiation, regulating other oncogenic pathways, protecting cells from damage or perhaps by mediating immune surveillance.

  • The specific cellular context in which FGF signalling occurs is clearly important for determining whether oncogenic or tumour protective outcomes are evoked, and understanding more about context-specific FGF signalling is a key area of research.

  • There are several types of genetic evidence that support an oncogenic function for FGFRs: identification of gene amplifications, activating mutations, chromosomal translocations, single nucleotide polymorphisms and aberrant splicing at the post-transcriptional level. Expression of FGFs can also be affected by gene amplification.

  • There is now evidence from multiple cancer types to implicate FGF signalling in several oncogenic behaviours, including proliferation, survival, migration, invasion and angiogenesis.

  • Therapeutic targeting of FGFs and their receptors is a major area of drug development research. Most agents are small-molecule tyrosine kinase inhibitors, but blocking antibodies and ligand-trap approaches are also being developed.

Abstract

Fibroblast growth factors (FGFs) and their receptors control a wide range of biological functions, regulating cellular proliferation, survival, migration and differentiation. Although targeting FGF signalling as a cancer therapeutic target has lagged behind that of other receptor tyrosine kinases, there is now substantial evidence for the importance of FGF signalling in the pathogenesis of diverse tumour types, and clinical reagents that specifically target the FGFs or FGF receptors are being developed. Although FGF signalling can drive tumorigenesis, in different contexts FGF signalling can mediate tumour protective functions; the identification of the mechanisms that underlie these differential effects will be important to understand how FGF signalling can be most appropriately therapeutically targeted.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: FGFR structure and control of ligand specificity.
Figure 2: FGFR signalling network.
Figure 3: Mechanisms of pathogenic cancer cell FGF signalling.

Similar content being viewed by others

References

  1. Kimelman, D. & Kirschner, M. Synergistic induction of mesoderm by FGF and TGF-β and the identification of an mRNA coding for FGF in the early Xenopus embryo. Cell 51, 869–877 (1987).

    Article  CAS  PubMed  Google Scholar 

  2. De Moerlooze, L. et al. An important role for the IIIb isoform of fibroblast growth factor receptor 2 (FGFR2) in mesenchymal-epithelial signalling during mouse organogenesis. Development 127, 483–492 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. Wiedemann, M. & Trueb, B. Characterization of a novel protein (FGFRL1) from human cartilage related to FGF receptors. Genomics 69, 275–279 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Ori, A., Wilkinson, M. C. & Fernig, D. G. The heparanome and regulation of cell function: structures, functions and challenges. Front. Biosci. 13, 4309–4338 (2008).

    Article  CAS  PubMed  Google Scholar 

  5. Harmer, N. J. et al. Towards a resolution of the stoichiometry of the fibroblast growth factor (FGF)-FGF receptor-heparin complex. J. Mol. Biol. 339, 821–834 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Mohammadi, M., Olsen, S. K. & Ibrahimi, O. A. Structural basis for fibroblast growth factor receptor activation. Cytokine Growth Factor Rev. 16, 107–137 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Zhang, X. et al. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J. Biol. Chem. 281, 15694–15700 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Ornitz, D. M. et al. Receptor specificity of the fibroblast growth-factor family. J. Biol. Chem. 271, 15292–15297 (1996).

    Article  CAS  PubMed  Google Scholar 

  9. Wu, D. Q., Kan, M. K., Sato, G. H., Okamoto, T. & Sato, J. D. Characterization and molecular cloning of a putative binding protein for heparin-binding growth factors. J. Biol. Chem. 266, 16778–16785 (1991).

    Article  CAS  PubMed  Google Scholar 

  10. Kurosu, H. et al. Regulation of fibroblast growth factor-23 signaling by klotho. J. Biol. Chem. 281, 6120–6123 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Eswarakumar, V. P., Lax, I. & Schlessinger, J. Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev. 16, 139–149 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Gotoh, N. Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins. Cancer Sci. 99, 1319–1325 (2008).

    Article  CAS  PubMed  Google Scholar 

  13. Altomare, D. A. & Testa, J. R. Perturbations of the AKT signaling pathway in human cancer. Oncogene 24, 7455–7464 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Peters, K. G. et al. Point mutation of an FGF receptor abolishes phosphatidylinositol turnover and Ca2+ flux but not mitogenesis. Nature 358, 678–681 (1992).

    Article  CAS  PubMed  Google Scholar 

  15. Klint, P. & Claesson-Welsh, L. Signal transduction by fibroblast growth factor receptors. Frontiers in Bioscience 4, 165–177 (1999).

    Article  Google Scholar 

  16. Hart, K. C. et al. Transformation and Stat activation by derivatives of FGFR1, FGFR3, and FGFR4. Oncogene 19, 3309–3320 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Kang, S. et al. Fibroblast growth factor receptor 3 associates with and tyrosine phosphorylates p90 RSK2, leading to RSK2 activation that mediates hematopoietic transformation. Mol. Cell. Biol. 29, 2105–2117 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Thien, C. B. & Langdon, W. Y. Cbl: many adaptations to regulate protein tyrosine kinases. Nature Rev. Mol. Cell Biol. 2, 294–307 (2001).

    Article  CAS  Google Scholar 

  19. Zhao, Y. & Zhang, Z. Y. The mechanism of dephosphorylation of extracellular signal-regulated kinase 2 by mitogen-activated protein kinase phosphatase 3. J. Biol. Chem. 276, 32382–32391 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Casci, T., Vinos, J. & Freeman, M. Sprouty, an intracellular inhibitor of Ras signaling. Cell 96, 655–665 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Hacohen, N., Kramer, S., Sutherland, D., Hiromi, Y. & Krasnow, M. A. Sprouty encodes a novel antagonist of FGF signaling that patterns apical branching of the Drosophila airways. Cell 92, 253–263 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Furthauer, M., Lin, W., Ang, S. L., Thisse, B. & Thisse, C. Sef is a feedback-induced antagonist of Ras/MAPK-mediated FGF signalling. Nature Cell Biol. 4, 170–174 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Tsang, M., Friesel, R., Kudoh, T. & Dawid, I. B. Identification of Sef, a novel modulator of FGF signalling. Nature Cell Biol. 4, 165–169 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Thisse, B. & Thisse, C. Functions and regulations of fibroblast growth factor signaling during embryonic development. Dev. Biol. 287, 390–402 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Tsang, M. & Dawid, I. B. Promotion and attenuation of FGF signaling through the Ras-MAPK pathway. Sci. STKE 228, 7 (2004).

    Google Scholar 

  26. Yu, K. et al. Conditional inactivation of FGF receptor 2 reveals an essential role for FGF signaling in the regulation of osteoblast function and bone growth. Development 130, 3063–3074 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Colvin, J. S., Bohne, B. A., Harding, G. W., McEwen, D. G. & Ornitz, D. M. Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nature Genet. 12, 390–397 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Ornitz, D. M. & Marie, P. J. FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev. 16, 1446–1465 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Muenke, M. et al. A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome. Nature Genet. 8, 269–274 (1994).

    Article  CAS  PubMed  Google Scholar 

  30. Corson, L. B., Yamanaka, Y., Lai, K. M. & Rossant, J. Spatial and temporal patterns of ERK signaling during mouse embryogenesis. Development 130, 4527–4537 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Ho, A. & Dowdy, S. F. Regulation of G1 cell-cycle progression by oncogenes and tumor suppressor genes. Curr. Opin. Genet. Dev. 12, 47–52 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Dailey, L., Ambrosetti, D., Mansukhani, A. & Basilico, C. Mechanisms underlying differential responses to FGF signaling. Cytokine Growth Factor Rev. 16, 233–247 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Raucci, A., Laplantine, E., Mansukhani, A. & Basilico, C. Activation of the ERK1/2 and p38 mitogen-activated protein kinase pathways mediates fibroblast growth factor-induced growth arrest of chondrocytes. J. Biol. Chem. 279, 1747–1756 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Maher, P. p38 mitogen-activated protein kinase activation is required for fibroblast growth factor-2-stimulated cell proliferation but not differentiation. J. Biol. Chem. 274, 17491–17498 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Peters, G., Lee, A. E. & Dickson, C. Concerted activation of two potential proto-oncogenes in carcinomas induced by mouse mammary tumour virus. Nature 320, 628–631 (1986). For the first time, this study shows a co-operative oncogenic effect of FGF and WNT signalling in mammary tumorigenesis.

    Article  CAS  PubMed  Google Scholar 

  36. Marshall, C. J. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80, 179–185 (1995).

    Article  CAS  PubMed  Google Scholar 

  37. Vainikka, S. et al. Signal transduction by fibroblast growth factor receptor-4 (FGFR-4). Comparison with FGFR-1. J. Biol. Chem. 269, 18320–18326 (1994).

    Article  CAS  PubMed  Google Scholar 

  38. Xian, W., Schwertfeger, K. L. & Rosen, J. M. Distinct roles of fibroblast growth factor receptor 1 and 2 in regulating cell survival and epithelial-mesenchymal transition. Mol. Endocrinol. 21, 987–1000 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Freeman, K. W. et al. Conditional activation of fibroblast growth factor receptor (FGFR) 1, but not FGFR2, in prostate cancer cells leads to increased osteopontin induction, extracellular signal-regulated kinase activation, and in vivo proliferation. Cancer Res. 63, 6237–6243 (2003).

    CAS  PubMed  Google Scholar 

  40. Freeman, K. W. et al. Inducible prostate intraepithelial neoplasia with reversible hyperplasia in conditional FGFR1-expressing mice. Cancer Res. 63, 8256–8263 (2003).

    CAS  PubMed  Google Scholar 

  41. Greenman, C. et al. Patterns of somatic mutation in human cancer genomes. Nature 446, 153–158 (2007). This screen for somatic mutations in the human kinome identified components of FGF signalling pathways as the most frequently mutated coding regions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Cappellen, D. et al. Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nature Genet. 23, 18–20 (1999). This report describes the detection of somatic FGFR3 mutations in solid tumours that are identical to those underpinning FGFR3-dependent developmental defects.

    Article  CAS  PubMed  Google Scholar 

  43. van Rhijn, B. W. et al. Novel fibroblast growth factor receptor 3 (FGFR3) mutations in bladder cancer previously identified in non-lethal skeletal disorders. Eur. J. Hum. Genet. 10, 819–824 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Naski, M. C., Wang, Q., Xu, J. & Ornitz, D. M. Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia. Nature Genet. 13, 233–237 (1996).

    Article  CAS  PubMed  Google Scholar 

  45. di Martino, E., L'Hote, C., G., Kennedy, W., Tomlinson, D. C. & Knowles, M. A. Mutant fibroblast growth factor receptor 3 induces intracellular signaling and cellular transformation in a cell type- and mutation-specific manner. Oncogene 28, 4306–4316 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Munro, N. P. & Knowles, M. A. Fibroblast growth factors and their receptors in transitional cell carcinoma. J. Urol. 169, 675–682 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Rosty, C. et al. Clinical and biological characteristics of cervical neoplasias with FGFR3 mutation. Mol. Cancer 4, 15 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Hernandez, S. et al. FGFR3 mutations in prostate cancer: association with low-grade tumors. Mod. Pathol. 22, 848–856 (2009).

    Article  CAS  PubMed  Google Scholar 

  49. Goriely, A. et al. Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors. Nature Genet. 41, 1247–1252 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Zhang, Y. et al. Constitutive activating mutation of the FGFR3b in oral squamous cell carcinomas. Int. J. Cancer 117, 166–168 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Aubertin, J., Tourpin, S., Janot, F., Ahomadegbe, J. C. & Radvanyi, F. Analysis of fibroblast growth factor receptor 3 G697C mutation in oral squamous cell carcinomas. Int. J. Cancer 120, 2058–2059 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Hafner, C. et al. Mosaicism of activating FGFR3 mutations in human skin causes epidermal nevi. J. Clin. Invest. 116, 2201–2207 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Logie, A. et al. Activating mutations of the tyrosine kinase receptor FGFR3 are associated with benign skin tumors in mice and humans. Hum. Mol. Genet. 14, 1153–1160 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Mandinova, A. et al. A positive FGFR3/FOXN1 feedback loop underlies benign skin keratosis versus squamous cell carcinoma formation in humans. J. Clin. Invest. 119, 3127–3137 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Dutt, A. et al. Drug-sensitive FGFR2 mutations in endometrial carcinoma. Proc. Natl Acad. Sci. USA 105, 8713–8717 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Jebar, A. H. et al. FGFR3 and Ras gene mutations are mutually exclusive genetic events in urothelial cell carcinoma. Oncogene 24, 5218–5225 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Lopez-Knowles, E. et al. PIK3CA mutations are an early genetic alteration associated with FGFR3 mutations in superficial papillary bladder tumors. Cancer Res. 66, 7401–7404 (2006).

    Article  CAS  PubMed  Google Scholar 

  58. Platt, F. M. et al. Spectrum of phosphatidylinositol 3-kinase pathway gene alterations in bladder cancer. Clin. Cancer Res. 15, 6008–6017 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Byron, S. A. et al. Inhibition of activated fibroblast growth factor receptor 2 in endometrial cancer cells induces cell death despite PTEN abrogation. Cancer Res. 68, 6902–6907 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Nord, H. et al. Focal amplifications are associated with high-grade and recurrences in stage Ta bladder carcinoma. Int. J. Cancer 9 Oct 2009 (doi:10.1002/ijc.24954).

  61. Kunii, K. et al. FGFR2-amplified gastric cancer cell lines require FGFR2 and Erbb3 signaling for growth and survival. Cancer Res. 68, 2340–2348 (2008).

    Article  CAS  PubMed  Google Scholar 

  62. Takeda, M. et al. AZD2171 shows potent antitumor activity against gastric cancer over-expressing fibroblast growth factor receptor 2/keratinocyte growth factor receptor. Clin. Cancer Res. 13, 3051–3057 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Nakazawa, K., Yashiro, M. & Hirakawa, K. Keratinocyte growth factor produced by gastric fibroblasts specifically stimulates proliferation of cancer cells from scirrhous gastric carcinoma. Cancer Res. 63, 8848–8852 (2003).

    CAS  PubMed  Google Scholar 

  64. Ueda, T. et al. Deletion of the carboxyl-terminal exons of K-sam/FGFR2 by short homology-mediated recombination, generating preferential expression of specific messenger RNAs. Cancer Res. 59, 6080–6086 (1999). The amplification of FGFR2 in gastric cancer cell lines is accompanied by the expression of a C-terminal truncated FGFR2 variant that has subsequently been shown to be important for transformation.

    CAS  PubMed  Google Scholar 

  65. Cha, J. Y., Maddileti, S., Mitin, N., Harden, T. K. & Der, C. J. Aberrant receptor internalization and enhanced FRS2-dependent signaling contribute to the transforming activity of the fibroblast growth factor receptor 2 IIIb C3 isoform. J. Biol. Chem. 284, 6227–6240 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Courjal, F. et al. Mapping of DNA amplifications at 15 chromosomal localizations in 1875 breast tumors: definition of phenotypic groups. Cancer Res. 57, 4360–4367 (1997).

    CAS  PubMed  Google Scholar 

  67. Jacquemier, J. et al. Expression of the FGFR1 gene in human breast-carcinoma cells. Int. J. Cancer 59, 373–378 (1994).

    Article  CAS  PubMed  Google Scholar 

  68. Reis-Filho, J. S. et al. FGFR1 emerges as a potential therapeutic target for lobular breast carcinomas. Clin. Cancer Res. 12, 6652–6662 (2006).

    Article  CAS  PubMed  Google Scholar 

  69. Freier, K. et al. Recurrent FGFR1 amplification and high FGFR1 protein expression in oral squamous cell carcinoma (OSCC). Oral Oncol. 43, 60–66 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Gorringe, K. L. et al. High-resolution single nucleotide polymorphism array analysis of epithelial ovarian cancer reveals numerous microdeletions and amplifications. Clin. Cancer Res. 13, 4731–4739 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Simon, R. et al. High-throughput tissue microarray analysis of 3p25 (RAF1) and 8p12 (FGFR1) copy number alterations in urinary bladder cancer. Cancer Res. 61, 4514–4519 (2001).

    CAS  PubMed  Google Scholar 

  72. Missiaglia, E. et al. Genomic imbalances in rhabdomyosarcoma cell lines affect expression of genes frequently altered in primary tumors: an approach to identify candidate genes involved in tumor development. Genes Chromosom. Cancer 48, 455–467 (2009).

    Article  CAS  PubMed  Google Scholar 

  73. Garcia, M. J. et al. A 1 Mb minimal amplicon at 8p11–12 in breast cancer identifies new candidate oncogenes. Oncogene 24, 5235–5245 (2005).

    Article  CAS  PubMed  Google Scholar 

  74. Bernard-Pierrot, I. et al. Characterization of the recurrent 8p11–12 amplicon identifies PPAPDC1B, a phosphatase protein, as a new therapeutic target in breast cancer. Cancer Res. 68, 7165–7175 (2008).

    Article  CAS  PubMed  Google Scholar 

  75. Koziczak, M., Holbro, T. & Hynes, N. E. Blocking of FGFR signaling inhibits breast cancer cell proliferation through downregulation of D-type cyclins. Oncogene 23, 3501–3508 (2004).

    Article  CAS  PubMed  Google Scholar 

  76. Xiao, S. et al. FGFR1 is fused with a novel zinc-finger gene, ZNF198, in the t(8;13) leukaemia/lymphoma syndrome. Nature Genet. 18, 84–87 (1998).

    Article  CAS  PubMed  Google Scholar 

  77. Roumiantsev, S. et al. Distinct stem cell myeloproliferative/T lymphoma syndromes induced by ZNF198FGFR1 and BCRFGFR1 fusion genes from 8p11 translocations. Cancer Cell 5, 287–298 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Yagasaki, F. et al. Fusion of ETV6 to fibroblast growth factor receptor 3 in peripheral T-cell lymphoma with a t(4;12)(p16;p13) chromosomal translocation. Cancer Res. 61, 8371–8374 (2001).

    CAS  PubMed  Google Scholar 

  79. Avet-Loiseau, H. et al. High incidence of translocations t(11;14)(q13;q32) and t(4;14)(p16;q32) in patients with plasma cell malignancies. Cancer Res. 58, 5640–5645 (1998).

    CAS  PubMed  Google Scholar 

  80. Chesi, M. et al. Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3. Nature Genet. 16, 260–264 (1997). The identification of t(4:14) translocations in multiple myeloma, which bring FGFR3 under the control of the IgH promoter.

    Article  CAS  PubMed  Google Scholar 

  81. Lauring, J. et al. The multiple myeloma associated MMSET gene contributes to cellular adhesion, clonogenic growth, and tumorigenicity. Blood 111, 856–864 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Li, Z. et al. The myeloma-associated oncogene fibroblast growth factor receptor 3 is transforming in hematopoietic cells. Blood 97, 2413–2419 (2001).

    Article  CAS  PubMed  Google Scholar 

  83. Qing, J. et al. Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice. J. Clin. Invest. 119, 1216–1229 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Trudel, S. et al. The inhibitory anti-FGFR3 antibody, PRO-001, is cytotoxic to t(4;14) multiple myeloma cells. Blood 107, 4039–4046 (2006).

    Article  CAS  PubMed  Google Scholar 

  85. Avet-Loiseau, H. et al. 14q32 translocations and monosomy 13 observed in monoclonal gammopathy of undetermined significance delineate a multistep process for the oncogenesis of multiple myeloma. Intergroupe Francophone du Myelome. Cancer Res. 59, 4546–4550 (1999).

    CAS  PubMed  Google Scholar 

  86. Otsuki, T. et al. Expression of fibroblast growth factor and FGF-receptor family genes in human myeloma cells, including lines possessing t(4;14)(q16.3;q32. 3) and FGFR3 translocation. Int. J. Oncol. 15, 1205–1212 (1999).

    CAS  PubMed  Google Scholar 

  87. Onwuazor, O. N. et al. Mutation, SNP, and isoform analysis of fibroblast growth factor receptor 3 (FGFR3) in 150 newly diagnosed multiple myeloma patients. Blood 102, 772–773 (2003).

    Article  CAS  PubMed  Google Scholar 

  88. Chesi, M. et al. Activated fibroblast growth factor receptor 3 is an oncogene that contributes to tumor progression in multiple myeloma. Blood 97, 729–736 (2001).

    Article  CAS  PubMed  Google Scholar 

  89. Wang, Y. & Becker, D. Antisense targeting of basic fibroblast growth factor and fibroblast growth factor receptor-1 in human melanomas blocks intratumoral angiogenesis and tumor growth. Nature Med. 3, 887–893 (1997). The demonstration that human tumour cell lines can induce angiogenesis by releasing FGF2.

    Article  CAS  PubMed  Google Scholar 

  90. Birrer, M. J. et al. Whole genome oligonucleotide-based array comparative genomic hybridization analysis identified fibroblast growth factor 1 as a prognostic marker for advanced-stage serous ovarian adenocarcinomas. J. Clin. Oncol. 25, 2281–2287 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Marek, L. et al. Fibroblast growth factor (FGF) and FGF receptor-mediated autocrine signaling in non-small-cell lung cancer cells. Mol. Pharmacol. 75, 196–207 (2009).

    Article  CAS  PubMed  Google Scholar 

  92. Poon, R. T., Fan, S. T. & Wong, J. Clinical implications of circulating angiogenic factors in cancer patients. J. Clin. Oncol. 19, 1207–1225 (2001).

    Article  CAS  PubMed  Google Scholar 

  93. Presta, M. et al. Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev. 16, 159–178 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Giri, D., Ropiquet, F. & Ittmann, M. Alterations in expression of basic fibroblast growth factor (FGF) 2 and its receptor FGFR-1 in human prostate cancer. Clin. Cancer Res. 5, 1063–1071 (1999).

    CAS  PubMed  Google Scholar 

  95. Ropiquet, F., Giri, D., Kwabi-Addo, B., Mansukhani, A. & Ittmann, M. Increased expression of fibroblast growth factor 6 in human prostatic intraepithelial neoplasia and prostate cancer. Cancer Res. 60, 4245–4250 (2000).

    CAS  PubMed  Google Scholar 

  96. Yamaguchi, F., Saya, H., Bruner, J. M. & Morrison, R. S. Differential expression of 2 fibroblast growth factor-receptor genes is associated with malignant progression in human astrocytomas. Proc. Natl. Acad. Sci. USA 91, 484–488 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Savagner, P., Valles, A. M., Jouanneau, J., Yamada, K. M. & Thiery, J. P. Alternative splicing in fibroblast growth factor receptor 2 is associated with induced epithelial-mesenchymal transition in rat bladder carcinoma cells. Mol. Biol. Cell 5, 851–862 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Fritzsche, S. et al. Concomitant down-regulation of SPRY1 and SPRY2 in prostate carcinoma. Endocr. Relat Cancer 13, 839–849 (2006).

    Article  CAS  PubMed  Google Scholar 

  99. Darby, S. et al. Loss of Sef (similar expression to FGF) expression is associated with high grade and metastatic prostate cancer. Oncogene 25, 4122–4127 (2006).

    Article  CAS  PubMed  Google Scholar 

  100. Kwabi-Addo, B., Ozen, M. & Ittmann, M. The role of fibroblast growth factors and their receptors in prostate cancer. Endocr. Relat. Cancer 11, 709–724 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Finak, G. et al. Stromal gene expression predicts clinical outcome in breast cancer. Nature Med. 14, 518–527 (2008).

    Article  CAS  PubMed  Google Scholar 

  102. Relf, M. et al. Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor β-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res. 57, 963–969 (1997).

    CAS  PubMed  Google Scholar 

  103. Nicholes, K. et al. A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Am. J. Pathol. 160, 2295–2307 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Desnoyers, L. R. et al. Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models. Oncogene 27, 85–97 (2008).

    Article  CAS  PubMed  Google Scholar 

  105. Pai, R. et al. Inhibition of fibroblast growth factor 19 reduces tumor growth by modulating beta-catenin signaling. Cancer Res. 68, 5086–5095 (2008).

    Article  CAS  PubMed  Google Scholar 

  106. Easton, D. F. et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447, 1087–1093 (2007). These genome-wide association studies identified an SNP in the second intron of FGFR2 that was associated with an increased incidence of breast cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Hunter, D. J. et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nature Genet. 39, 870–874 (2007).

    Article  CAS  PubMed  Google Scholar 

  108. Garcia-Closas, M. et al. Heterogeneity of breast cancer associations with five susceptibility Loci by clinical and pathological characteristics. PLoS Genet. 4, e1000054 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Meyer, K. B. et al. Allele-specific up-regulation of FGFR2 increases susceptibility to breast cancer. PLoS Biol. 6, 108 (2008).

    Article  CAS  Google Scholar 

  110. Carroll, J. S. et al. Genome-wide analysis of estrogen receptor binding sites. Nature Genet. 38, 1289–1297 (2006).

    Article  CAS  PubMed  Google Scholar 

  111. Bange, J. et al. Cancer progression and tumor cell motility are associated with the FGFR4 Arg(388) allele. Cancer Res. 62, 840–847 (2002).

    CAS  PubMed  Google Scholar 

  112. Spinola, M. et al. FGFR4 Gly388Arg polymorphism and prognosis of breast and colorectal cancer. Oncol. Rep. 14, 415–419 (2005).

    CAS  PubMed  Google Scholar 

  113. Thussbas, C. et al. FGFR4 Arg388 allele is associated with resistance to adjuvant therapy in primary breast cancer. J. Clin. Oncol. 24, 3747–3755 (2006).

    Article  CAS  PubMed  Google Scholar 

  114. Maeda, T., Yagasaki, F., Ishikawa, M., Takahashi, N. & Bessho, M. Transforming property of TEL-FGFR3 mediated through PI3-K in a T-cell lymphoma that subsequently progressed to AML. Blood 105, 2115–2123 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. Abate-Shen, C. & Shen, M. M. FGF signaling in prostate tumorigenesis--new insights into epithelial-stromal interactions. Cancer Cell 12, 495–497 (2007).

    Article  CAS  PubMed  Google Scholar 

  116. Memarzadeh, S. et al. Enhanced paracrine FGF10 expression promotes formation of multifocal prostate adenocarcinoma and an increase in epithelial androgen receptor. Cancer Cell 12, 572–585 (2007). Although previous studies had shown that autocrine release of FGFs from epithelial cells could initiate tumorigenesis, this study provided evidence that paracrine release of FGF10 from stroma could also act on the epithelium to induce prostate adenocarcinoma.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Zhong, C., Saribekyan, G., Liao, C. P., Cohen, M. B. & Roy-Burman, P. Cooperation between FGF8b overexpression and PTEN deficiency in prostate tumorigenesis. Cancer Res. 66, 2188–2194 (2006).

    Article  CAS  PubMed  Google Scholar 

  118. Zhang, Y. et al. Role of epithelial cell fibroblast growth factor receptor substrate 2α in prostate development, regeneration and tumorigenesis. Development 135, 775–784 (2008).

    Article  CAS  PubMed  Google Scholar 

  119. Ruotsalainen, T., Joensuu, H., Mattson, K. & Salven, P. High pretreatment serum concentration of basic fibroblast growth factor is a predictor of poor prognosis in small cell lung cancer. Cancer Epidemiol. Biomarkers Prev. 11, 1492–1495 (2002).

    CAS  PubMed  Google Scholar 

  120. Pardo, O. E. et al. Fibroblast growth factor-2 induces translational regulation of Bcl-XL and Bcl-2 via a MEK-dependent pathway: correlation with resistance to etoposide-induced apoptosis. J. Biol. Chem. 277, 12040–12046 (2002).

    Article  CAS  PubMed  Google Scholar 

  121. Pardo, O. E. et al. Fibroblast growth factor 2-mediated translational control of IAPs blocks mitochondrial release of Smac/DIABLO and apoptosis in small cell lung cancer cells. Mol. Cell. Biol. 23, 7600–7610 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Pardo, O. E. et al. FGF-2 protects small cell lung cancer cells from apoptosis through a complex involving PKCepsilon, B-Raf and S6K2. EMBO J. 25, 3078–3088 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Xian, W. et al. Fibroblast growth factor receptor 1-transformed mammary epithelial cells are dependent on RSK activity for growth and survival. Cancer Res. 69, 2244–2251 (2009).

    Article  CAS  PubMed  Google Scholar 

  124. Tomlinson, D. C., Lamont, F. R., Shnyder, S. D. & Knowles, M. A. Fibroblast growth factor receptor 1 promotes proliferation and survival via activation of the mitogen-activated protein kinase pathway in bladder cancer. Cancer Res. 69, 4613–4620 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Nomura, S. et al. FGF10/FGFR2 signal induces cell migration and invasion in pancreatic cancer. Br. J. Cancer 99, 305–313 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Welm, B. E. et al. Inducible dimerization of FGFR1: development of a mouse model to analyze progressive transformation of the mammary gland. J. Cell Biol. 157, 703–714 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Xian, W., Schwertfeger, K. L., Vargo-Gogola, T. & Rosen, J. M. Pleiotropic effects of FGFR1 on cell proliferation, survival, and migration in a 3D mammary epithelial cell model. J. Cell Biol. 171, 663–673 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Acevedo, V. D. et al. Inducible FGFR-1 activation leads to irreversible prostate adenocarcinoma and an epithelial-to-mesenchymal transition. Cancer Cell 12, 559–571 (2007). This study demonstrates that prolonged FGFR signalling is sufficient for the development of prostate cancer.

    Article  CAS  PubMed  Google Scholar 

  129. Winter, S. F. et al. Conditional activation of FGFR1 in the prostate epithelium induces angiogenesis with concomitant differential regulation of Ang-1 and Ang-2. Oncogene 26, 4897–4907 (2007).

    Article  CAS  PubMed  Google Scholar 

  130. Kang, Y. & Massague, J. Epithelial-mesenchymal transitions: twist in development and metastasis. Cell 118, 277–279 (2004).

    Article  CAS  PubMed  Google Scholar 

  131. Schaeffer, E. M. et al. Androgen-induced programs for prostate epithelial growth and invasion arise in embryogenesis and are reactivated in cancer. Oncogene 27, 7180–7191 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Aman, A. & Piotrowski, T. Wnt/beta-catenin and Fgf signaling control collective cell migration by restricting chemokine receptor expression. Dev. Cell 15, 749–761 (2008).

    Article  CAS  PubMed  Google Scholar 

  133. Werner, S. et al. The function of KGF in morphogenesis of epithelium and reepithelialization of wounds. Science 266, 819–822 (1994).

    Article  CAS  PubMed  Google Scholar 

  134. Werner, S. & Grose, R. Regulation of wound healing by growth factors and cytokines. Physiol. Rev. 83, 835–870 (2003).

    Article  CAS  PubMed  Google Scholar 

  135. Hanahan, D. & Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353–364 (1996).

    Article  CAS  PubMed  Google Scholar 

  136. Kandel, J. et al. Neovascularization is associated with a switch to the export of bFGF in the multistep development of fibrosarcoma. Cell 66, 1095–1104 (1991).

    Article  CAS  PubMed  Google Scholar 

  137. Presta, M., Tiberio, L., Rusnati, M., Dell'Era, P. & Ragnotti, G. Basic fibroblast growth factor requires a long-lasting activation of protein kinase C to induce cell proliferation in transformed fetal bovine aortic endothelial cells. Cell Regul. 2, 719–726 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Daviet, I., Herbert, J. M. & Maffrand, J. P. Involvement of protein kinase C in the mitogenic and chemotaxis effects of basic fibroblast growth factor on bovine cerebral cortex capillary endothelial cells. FEBS Lett. 259, 315–317 (1990).

    Article  CAS  PubMed  Google Scholar 

  139. Landgren, E., Klint, P., Yokote, K. & Claesson-Welsh, L. Fibroblast growth factor receptor-1 mediates chemotaxis independently of direct SH2-domain protein binding. Oncogene 17, 283–291 (1998).

    Article  CAS  PubMed  Google Scholar 

  140. Czubayko, F. et al. A secreted FGF-binding protein can serve as the angiogenic switch in human cancer. Nature Med. 3, 1137–1140 (1997).

    Article  CAS  PubMed  Google Scholar 

  141. Schweigerer, L. et al. Capillary endothelial cells express basic fibroblast growth factor, a mitogen that promotes their own growth. Nature 325, 257–259 (1987).

    Article  CAS  PubMed  Google Scholar 

  142. Ensoli, B. et al. Synergy between basic fibroblast growth factor and HIV-1 Tat protein in induction of Kaposi's sarcoma. Nature 371, 674–680 (1994).

    Article  CAS  PubMed  Google Scholar 

  143. Casanovas, O., Hicklin, D. J., Bergers, G. & Hanahan, D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8, 299–309 (2005). This study showed that FGFs mediate resistance to VEFGR2 targeting by reactivating tumour angiogenesis, and that dual inhibition of FGF and VEGF impaired tumour progression.

    Article  CAS  PubMed  Google Scholar 

  144. Kerbel, R. S. Therapeutic implications of intrinsic or induced angiogenic growth factor redundancy in tumors revealed. Cancer Cell 8, 269–271 (2005).

    Article  CAS  PubMed  Google Scholar 

  145. Grose, R. et al. The role of fibroblast growth factor receptor 2b in skin homeostasis and cancer development. EMBO J. 26, 1268–1278 (2007). A mouse model with a FGFR2-IIIb deletion demonstrates a tumour-protective role for FGFR2-IIIb in the skin.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Fogarty, M. P., Emmenegger, B. A., Grasfeder, L. L., Oliver, T. G. & Wechsler-Reya, R. J. Fibroblast growth factor blocks Sonic hedgehog signaling in neuronal precursors and tumor cells. Proc. Natl Acad. Sci. USA 104, 2973–2978 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Yan, G., Fukabori, Y., McBride, G., Nikolaropolous, S. & McKeehan, W. L. Exon switching and activation of stromal and embryonic fibroblast growth factor (FGF)-FGF receptor genes in prostate epithelial cells accompany stromal independence and malignancy. Mol. Cell. Biol. 13, 4513–4522 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Ricol, D. et al. Tumour suppressive properties of fibroblast growth factor receptor 2-IIIb in human bladder cancer. Oncogene 18, 7234–7243 (1999).

    Article  CAS  PubMed  Google Scholar 

  149. Zhang, Y. et al. Growth inhibition by keratinocyte growth factor receptor of human salivary adenocarcinoma cells through induction of differentiation and apoptosis. Proc. Natl Acad. Sci. USA 98, 11336–11340 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Gartside, M. G. et al. Loss-of-function fibroblast growth factor receptor-2 mutations in melanoma. Mol. Cancer Res. 7, 41–54 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. auf dem Keller, U. et al. Nrf transcription factors in keratinocytes are essential for skin tumor prevention but not for wound healing. Mol. Cell. Biol. 26, 3773–3784 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Boismenu, R. & Havran, W. L. Modulation of epithelial cell growth by intraepithelial gamma delta T cells. Science 266, 1253–1255 (1994).

    Article  CAS  PubMed  Google Scholar 

  153. Shimada, T. et al. FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa. Biochem. Biophys. Res. Commun. 314, 409–414 (2004).

    Article  CAS  PubMed  Google Scholar 

  154. Martinez-Torrecuadrada, J. et al. Targeting the extracellular domain of fibroblast growth factor receptor 3 with human single-chain Fv antibodies inhibits bladder carcinoma cell line proliferation. Clin. Cancer Res. 11, 6280–6290 (2005).

    Article  CAS  PubMed  Google Scholar 

  155. Qing, J. et al. Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice. J. Clin. Invest. 119, 1216–1229 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Sun, H. D. et al. Monoclonal antibody antagonists of hypothalamic FGFR1 cause potent but reversible hypophagia and weight loss in rodents and monkeys. Am. J. Physiol. Endocrinol. Metab. 292, 964–976 (2007).

    Article  CAS  Google Scholar 

  157. Zhang, H. et al. FP-1039 (FGFR1:Fc), a soluble FGFR1 receptor antagonist, inhibits tumor growth and angiogenesis (AACR–NCI–EORTC International Conference, San Francisco, 2007).

  158. Beenken, A. & Mohammadi, M. The FGF family: biology, pathophysiology and therapy. Nature Rev. Drug Discov. 8, 235–253 (2009).

    Article  CAS  Google Scholar 

  159. Bryant, D. M. & Stow, J. L. Nuclear translocation of cell-surface receptors: lessons from fibroblast growth factor. Traffic 6, 947–954 (2005).

    Article  CAS  PubMed  Google Scholar 

  160. Tekin, M. et al. Homozygous mutations in fibroblast growth factor 3 are associated with a new form of syndromic deafness characterized by inner ear agenesis, microtia, and microdontia. Am. J. Hum. Genet. 80, 338–344 (2007).

    Article  CAS  PubMed  Google Scholar 

  161. Falardeau, J. et al. Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice. J. Clin. Invest. 118, 2822–2831 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Milunsky, J. M., Zhao, G., Maher, T. A., Colby, R. & Everman, D. B. LADD syndrome is caused by FGF10 mutations. Clin. Genet. 69, 349–354 (2006).

    Article  CAS  PubMed  Google Scholar 

  163. Consortium, A. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nature Genet. 26, 345–348 (2000).

    Article  CAS  Google Scholar 

  164. Arman, E., Haffnerkrausz, R., Chen, Y., Heath, J. K. & Lonai, P. Targeted disruption of fibroblast growth-factor (FGF) receptor-2 suggests a role for FGF signaling in pregastrulation mammalian development. Proc. Natl. Acad. Sci. USA 95, 5082–5087 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Meyers, E. N., Lewandoski, M. & Martin, G. R. An Fgf8 mutant allelic series generated by Cre- and Flp-mediated recombination. Nature Genet. 18, 136–141 (1998).

    Article  CAS  PubMed  Google Scholar 

  166. Colvin, J. S., Green, R. P., Schmahl, J., Capel, B. & Ornitz, D. M. Male-to-female sex reversal in mice lacking fibroblast growth factor 9. Cell 104, 875–889 (2001).

    Article  CAS  PubMed  Google Scholar 

  167. Sekine, K. et al. Fgf10 is essential for limb and lung formation. Nature Genet. 21, 138–141 (1999).

    Article  CAS  PubMed  Google Scholar 

  168. Min., H. et al. Fgf-10 is required for both limb and lung development and exhibits striking functional similarity to Drosophila branchless. Genes Dev. 12, 3156–3161 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Dillon, C., Spencer-Dene, B. & Dickson, C. A crucial role for fibroblast growth factor signaling in embryonic mammary gland development. J. Mammary Gland Biol. Neoplasia 9, 207–215 (2004).

    Article  PubMed  Google Scholar 

  170. Jackson, D. et al. Fibroblast growth-factor receptor signaling has a role in lobuloalveolar development of the mammary-gland. J. Cell. Sci. 110, 1261–1268 (1997).

    Article  CAS  PubMed  Google Scholar 

  171. Kuslak, S. L. & Marker, P. C. Fibroblast growth factor receptor signaling through MEK–ERK is required for prostate bud induction. Differentiation 75, 638–651 (2007).

    Article  CAS  PubMed  Google Scholar 

  172. Thomson, A. A. & Cunha, G. R. Prostatic growth and development are regulated by FGF10. Development 126, 3693–3701 (1999).

    Article  CAS  PubMed  Google Scholar 

  173. Ornitz, D. M. & Itoh, N. Fibroblast growth factors. Genome Biol. 2, 3005–3005.12 (2001).

    Article  Google Scholar 

  174. Callahan, R. & Smith, G. H. MMTV-induced mammary tumorigenesis: gene discovery, progression to malignancy and cellular pathways. Oncogene 19, 992–1001 (2000).

    Article  CAS  PubMed  Google Scholar 

  175. Daphna-Iken, D. et al. MMTV-Fgf8 transgenic mice develop mammary and salivary gland neoplasia and ovarian stromal hyperplasia. Oncogene 17, 2711–2717 (1998).

    Article  CAS  PubMed  Google Scholar 

  176. Clark, J. C. et al. FGF-10 disrupts lung morphogenesis and causes pulmonary adenomas in vivo. Am. J. Physiol. Lung Cell. Mol. Physiol. 280, L705–715 (2001).

    Article  CAS  PubMed  Google Scholar 

  177. Wagner, E. J. et al. Characterization of the intronic splicing silencers flanking FGFR2 exon IIIb. J. Biol. Chem. 280, 14017–14027 (2005).

    Article  CAS  PubMed  Google Scholar 

  178. Seth, P., Miller, H. B., Lasda, E. L., Pearson, J. L. & Garcia-Blanco, M. A. Identification of an intronic splicing enhancer essential for the inclusion of FGFR2 exon IIIc. J. Biol. Chem. 283, 10058–10067 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Baraniak, A. P., Chen, J. R. & Garcia-Blanco, M. A. Fox-2 mediates epithelial cell-specific fibroblast growth factor receptor 2 exon choice. Mol. Cell Biol. 26, 1209–1222 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Lin, W. M. et al. Modeling genomic diversity and tumor dependency in malignant melanoma. Cancer Res. 68, 664–673 (2008).

    Article  CAS  PubMed  Google Scholar 

  181. Jang, J. H., Shin, K. H. & Park, J. G. Mutations in fibroblast growth factor receptor 2 and fibroblast growth factor receptor 3 genes associated with human gastric and colorectal cancers. Cancer Res. 61, 3541–3543 (2001).

    CAS  PubMed  Google Scholar 

  182. Vekony, H. et al. DNA copy number gains at loci of growth factors and their receptors in salivary gland adenoid cystic carcinoma. Clin. Cancer Res. 13, 3133–3139 (2007).

    Article  CAS  PubMed  Google Scholar 

  183. Cross, N. C. & Reiter, A. Tyrosine kinase fusion genes in chronic myeloproliferative diseases. Leukemia 16, 1207–1212 (2002).

    Article  CAS  PubMed  Google Scholar 

  184. Mohammadi, M. et al. Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain. EMBO J. 17, 5896–5904 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Sarker, D. et al. A phase I pharmacokinetic and pharmacodynamic study of TKI258, an oral, multitargeted receptor tyrosine kinase inhibitor in patients with advanced solid tumors. Clin. Cancer Res. 14, 2075–2081 (2008).

    Article  CAS  PubMed  Google Scholar 

  186. Hilberg, F. et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 68, 4774–4782 (2008).

    Article  CAS  PubMed  Google Scholar 

  187. Chen, J. et al. FGFR3 as a therapeutic target of the small molecule inhibitor PKC412 in hematopoietic malignancies. Oncogene 24, 8259–8267 (2005).

    Article  CAS  PubMed  Google Scholar 

  188. Matsui, J. et al. E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition. Int. J. Cancer 122, 664–671 (2008).

    Article  CAS  PubMed  Google Scholar 

  189. Machida, S. et al. Inhibition of peritoneal dissemination of ovarian cancer by tyrosine kinase receptor inhibitor SU6668 (TSU-68). Int. J. Cancer 114, 224–229 (2005).

    Article  CAS  PubMed  Google Scholar 

  190. Spielberger, R. et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N. Engl. J. Med. 351, 2590–2598 (2004).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

R.G. would like to acknowledge financial support from The Wellcome Trust, Medical Research Council and Barts and The London Charitable Foundation. N.T. would like to acknowledge financial support from Cancer Research UK and Breakthrough Breast Cancer Research, UK. We thank S. Werner and A. Reynolds for critical reading of the manuscript.

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

National Cancer Institute Drug Dictionary

gefitinib

OMIM

CML

Kaposi's sarcoma

multiple myeloma

Pfeiffer syndrome

FURTHER INFORMATION

Richard Grose's homepage

Glossary

Craniosynostosis syndromes

Characterized by premature fusion of the skull sutures, which often results in cranial deformities and associated pathologies.

Chondrodysplasia syndromes

Characterized by abnormal shortening of long bones owing to premature growth arrest of chondrocytes in the epiphyseal plates.

Seborrhoeic keratosis

A benign wart-like growth of skin keratinocytes.

Monoclonal gammopathy of uncertain significance

A clonal proliferation of plasma cells that manifests as excess monoclonal immunoglobulin in the blood. A common condition of old age that progresses to multiple myeloma at a rate of 2% per year.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Turner, N., Grose, R. Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 10, 116–129 (2010). https://doi.org/10.1038/nrc2780

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2780

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer