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FGF19 and Cancer

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Endocrine FGFs and Klothos

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 728))

Abstract

Fibroblast growth factors (FGFs) and their cognate receptors, FGF receptors (FGFRs), play critical roles in a variety of normal developmental and physiological processes. Numerous reports support a role for deregulation of FGF-FGFR signaling, whether it is at the ligand and/or receptor level, in tumor development and progression. The FGF19-FGFR4 signaling axis has been implicated in the pathogenesis of several cancers, including hepatocellular carcinomas in mice and potentially in humans. This chapter focuses on recent progress in the understanding of the molecular mechanisms of FGF19 action and its potential involvement in cancer.

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References

  1. Ornitz DM, Itoh N. Fibroblast growth factors. Genome Biol 2001; 2:REVIEWS3005.

    Google Scholar 

  2. Eswarakumar VP, Lax I, Schlessinger J. Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev 2005; 16:139–149.

    Article  PubMed  CAS  Google Scholar 

  3. Sleeman M, Fraser J, McDonald M et al. Identification of a new fibroblast growth factor receptor, FGFR5. Gene 2001; 271:171–182.

    Article  PubMed  CAS  Google Scholar 

  4. Powers CJ, McLeskey SW, Wellstein A. Fibroblast growth factors, their receptors and signaling. Endocr Relat Cancer 2000; 7:165–197.

    Article  PubMed  CAS  Google Scholar 

  5. Desnoyers LR, Pai R, Ferrando RE et al. Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models. Oncogene 2008; 27:85–97.

    Article  PubMed  CAS  Google Scholar 

  6. Nicholes K, Guillet S, Tomlinson E et al. A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Am J Pathol 2002; 160:2295–2307.

    Article  PubMed  CAS  Google Scholar 

  7. Pai R, Dunlap D, Qing J et al. Inhibition of fibroblast growth factor 19 reduces tumor growth by modulating beta-catenin signaling. Cancer Res 2008; 68:5086–5095.

    Article  PubMed  CAS  Google Scholar 

  8. Kurosu H, Choi M, Ogawa Y et al. Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem 2007; 282:26687–26695.

    Article  PubMed  CAS  Google Scholar 

  9. Lin BC, Wang M, Blackmore C et al. Liver-specific activities of FGF19 require Klotho beta. J Biol Chem 2007; 282:27277–27284.

    Article  PubMed  CAS  Google Scholar 

  10. Nishimura T, Utsunomiya Y, Hoshikawa M et al. Structure and expression of a novel human FGF, FGF-19, expressed in the fetal brain. Biochim Biophys Acta 1999; 1444:148–151.

    PubMed  CAS  Google Scholar 

  11. Xie MH, Holcomb I, Deuel B et al. FGF-19, a novel fibroblast growth factor with unique specificity for FGFR4. Cytokine 1999; 11:729–735.

    Article  PubMed  CAS  Google Scholar 

  12. Inagaki T, Choi M, Moschetta A et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2005; 2:217–225.

    Article  PubMed  CAS  Google Scholar 

  13. Choi M, Moschetta A, Bookout AL et al. Identification of a hormonal basis for gallbladder filling. Nat Med 2006; 12:1253–1255.

    Article  PubMed  CAS  Google Scholar 

  14. Asada M, Shinomiya M, Suzuki M et al. Glycosaminoglycan affinity of the complete fibroblast growth factor family. Biochim Biophys Acta 2009; 1790:40–48.

    Article  PubMed  CAS  Google Scholar 

  15. Goetz R, Beenken A, Ibrahimi OA et al. Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Mol Cell Biol 2007; 27:3417–3428.

    Article  PubMed  CAS  Google Scholar 

  16. Harmer NJ, Pellegrini L, Chirgadze D et al. The crystal structure of fibroblast growth factor (FGF) 19 reveals novel features of the FGF family and offers a structural basis for its unusual receptor affinity. Biochemistry 2004; 43:629–640.

    Article  PubMed  CAS  Google Scholar 

  17. Zhang X, Ibrahimi OA, Olsen SK et al. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem 2006; 281:15694–15700.

    Article  PubMed  CAS  Google Scholar 

  18. Kuro-o M. Endocrine FGFs and Klothos: emerging concepts. Trends Endocrinol Metab 2008; 19:239–245.

    Article  PubMed  CAS  Google Scholar 

  19. Kurosu H, Ogawa Y, Miyoshi M et al. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 2006; 281:6120–6123.

    Article  PubMed  CAS  Google Scholar 

  20. Wu X, Ge H, Lemon B et al. Selective activation of FGFR4 by an FGF19 variant does not improve glucose metabolism in ob/ob mice. Proc Natl Acad Sci USA 2009; 106:14379–14384.

    Article  PubMed  CAS  Google Scholar 

  21. Tomiyama K, Maeda R, Urakawa I et al. Relevant use of Klotho in FGF19 subfamily signaling system in vivo. Proc Natl Acad Sci USA 2010; 107:1666–1671.

    Article  PubMed  CAS  Google Scholar 

  22. Grose R, Dickson C. Fibroblast growth factor signaling in tumorigenesis. Cytokine Growth Factor Rev 2005; 16:179–186.

    Article  PubMed  CAS  Google Scholar 

  23. Korc M, Friesel RE. The role of fibroblast growth factors in tumor growth. Curr Cancer Drug Targets 2009; 9:639–651.

    Article  PubMed  CAS  Google Scholar 

  24. Fausto N. Mouse liver tumorigenesis: models, mechanisms and relevance to human disease. Semin Liver Dis 1999; 19:243–252.

    Article  PubMed  CAS  Google Scholar 

  25. Spangenberg HC, Thimme R, Blum HE. Serum markers of hepatocellular carcinoma. Semin Liver Dis 2006; 26:385–390.

    Article  PubMed  CAS  Google Scholar 

  26. Lilien J, Balsamo J. The regulation of cadherin-mediated adhesion by tyrosine phosphorylation/ dephosphorylation of beta-catenin. Curr Opin Cell Biol 2005; 17:459–465.

    Article  PubMed  CAS  Google Scholar 

  27. Nelson WJ, Nusse R. Convergence of Wnt, beta-catenin, and cadherin pathways. Science 2004; 303:1483–1487.

    Article  PubMed  CAS  Google Scholar 

  28. Clevers H. Wnt/beta-catenin signaling in development and disease. Cell 2006; 127:469–480.

    Article  PubMed  CAS  Google Scholar 

  29. Peifer M, Polakis P. Wnt signaling in oncogenesis and embryogenesis—a look outside the nucleus. Science 2000; 287:1606–1609.

    Article  PubMed  CAS  Google Scholar 

  30. Polakis P. Wnt signaling and cancer. Genes Dev 2000; 14:1837–1851.

    PubMed  CAS  Google Scholar 

  31. Morin PJ. beta-catenin signaling and cancer. Bioessays 1999; 21:1021–1030.

    Article  PubMed  CAS  Google Scholar 

  32. Wu X, Ge H, Lemon B et al. FGF19-induced hepatocyte proliferation is mediated through FGFR4 activation. J Biol Chem 2010; 285:5165–5170.

    Article  PubMed  CAS  Google Scholar 

  33. Ho HK, Pok S, Streit S et al. Fibroblast growth factor receptor 4 regulates proliferation, anti-apoptosis and alpha-fetoprotein secretion during hepatocellular carcinoma progression and represents a potential target for therapeutic intervention. J Hepatol 2009; 50:118–127.

    Article  PubMed  CAS  Google Scholar 

  34. Yu C, Wang F, Jin C et al. Increased carbon tetrachloride-induced liver injury and fibrosis in FGFR4-deficient mice. Am J Pathol 2002; 161:2003–2010.

    Article  PubMed  CAS  Google Scholar 

  35. Huang X, Yang C, Jin C et al. Resident hepatocyte fibroblast growth factor receptor 4 limits hepatocarcinogenesis. Mol Carcinog 2009; 48:553–562.

    Article  PubMed  CAS  Google Scholar 

  36. Jaakkola S, Salmikangas P, Nylund S et al. Amplification of fgfr4 gene in human breast and gynecological cancers. Int J Cancer 1993; 54:378–382.

    Article  PubMed  CAS  Google Scholar 

  37. Roidl A, Berger HJ, Kumar S et al. Resistance to chemotherapy is associated with fibroblast growth factor receptor 4 up-regulation. Clin Cancer Res 2009; 15:2058–2066.

    Article  PubMed  CAS  Google Scholar 

  38. Bange J, Prechtl D, Cheburkin Y et al. Cancer progression and tumor cell motility are associated with the FGFR4 Arg(388) allele. Cancer Res 2002; 62:840–847.

    PubMed  CAS  Google Scholar 

  39. Roidl A, Foo P, Wong W et al. The FGFR4 Y367C mutant is a dominant oncogene in MDA-MB453 breast cancer cells. Oncogene 2010; 29:1543–1552.

    Article  PubMed  CAS  Google Scholar 

  40. Spinola M, Leoni V, Pignatiello C et al. Functional FGFR4 Gly388Arg polymorphism predicts prognosis in lung adenocarcinoma patients. J Clin Oncol 2005; 23:7307–7311.

    Article  PubMed  CAS  Google Scholar 

  41. Ma Z, Tsuchiya N, Yuasa T et al. Polymorphisms of fibroblast growth factor receptor 4 have association with the development of prostate cancer and benign prostatic hyperplasia and the progression of prostate cancer in a Japanese population. Int J Cancer 2008; 123:2574–2579.

    Article  PubMed  CAS  Google Scholar 

  42. Wang J, Stockton DW, Ittmann M. The fibroblast growth factor receptor-4 Arg388 allele is associated with prostate cancer initiation and progression. Clin Cancer Res 2004; 10:6169–6178.

    Article  PubMed  CAS  Google Scholar 

  43. Wang J, Yu W, Cai Y et al. Altered fibroblast growth factor receptor 4 stability promotes prostate cancer progression. Neoplasia 2008; 10:847–856.

    PubMed  CAS  Google Scholar 

  44. Falvella FS, Frullanti E, Galvan A et al. FGFR4 Gly388Arg polymorphism may affect the clinical stage of patients with lung cancer by modulating the transcriptional profile of normal lung. Int J Cancer 2009; 124:2880–2885.

    Article  PubMed  CAS  Google Scholar 

  45. Sasaki H, Okuda K, Kawano O et al. Fibroblast growth factor receptor 4 mutation and polymorphism in Japanese lung cancer. Oncol Rep 2008; 20:1125–1130.

    PubMed  CAS  Google Scholar 

  46. Ansell A, Farnebo L, Grenman R et al. Polymorphism of FGFR4 in cancer development and sensitivity to cisplatin and radiation in head and neck cancer. Oral Oncol 2009; 45:23–29.

    Article  PubMed  CAS  Google Scholar 

  47. da Costa Andrade VC, Parise O, Jr., Hors CP et al. The fibroblast growth factor receptor 4 (FGFR4) Arg388 allele correlates with survival in head and neck squamous cell carcinoma. Exp Mol Pathol 2007; 82:53–57.

    Article  PubMed  Google Scholar 

  48. Streit S, Bange J, Fichtner A et al. Involvement of the FGFR4 Arg388 allele in head and neck squamous cell carcinoma. Int J Cancer 2004; 111:213–217.

    Article  PubMed  CAS  Google Scholar 

  49. Streit S, Mestel DS, Schmidt M et al. FGFR4 Arg388 allele correlates with tumour thickness and FGFR4 protein expression with survival of melanoma patients. Br J Cancer 2006; 94:1879–1886.

    Article  PubMed  CAS  Google Scholar 

  50. Morimoto Y, Ozaki T, Ouchida M et al. Single nucleotide polymorphism in fibroblast growth factor receptor 4 at codon 388 is associated with prognosis in high-grade soft tissue sarcoma. Cancer 2003; 98:2245–2250.

    Article  PubMed  CAS  Google Scholar 

  51. Jezequel P, Campion L, Joalland MP et al. G388R mutation of the FGFR4 gene is not relevant to breast cancer prognosis. Br J Cancer 2004; 90:189–193.

    Article  PubMed  CAS  Google Scholar 

  52. Mawrin C, Kirches E, Diete S et al. Analysis of a single nucleotide polymorphism in codon 388 of the FGFR4 gene in malignant gliomas. Cancer Lett 2006; 239:239–245.

    Article  PubMed  CAS  Google Scholar 

  53. Yang YC, Lu ML, Rao JY et al. Joint association of polymorphism of the FGFR4 gene and mutation TP53 gene with bladder cancer prognosis. Br J Cancer 2006; 95:1455–1458.

    Article  PubMed  CAS  Google Scholar 

  54. Matakidou A, El Galta R, Rudd MF et al. Further observations on the relationship between the FGFR4 Gly388Arg polymorphism and lung cancer prognosis. Br J Cancer 2007; 96:1904–1907.

    Article  PubMed  CAS  Google Scholar 

  55. Nan H, Qureshi AA, Hunter DJ et al. Genetic variants in FGFR2 and FGFR4 genes and skin cancer risk in the Nurses’ Health Study. BMC Cancer 2009; 9:172.

    Article  PubMed  Google Scholar 

  56. Liu H, Fergusson MM, Castilho RM et al. Augmented Wnt signaling in a mammalian model of accelerated aging. Science 2007; 317:803–806.

    Article  PubMed  CAS  Google Scholar 

  57. Engstrom W, Granerus M. Effects of fibroblast growth factors 19 and 20 on cell multiplication and locomotion in a human embryonal carcinoma cell line (Tera-2) in vitro. Anticancer Res 2006; 26:3307–3310.

    PubMed  Google Scholar 

  58. Miyake A, Nakayama Y, Konishi M et al. Fgf19 regulated by Hh signaling is required for zebrafish forebrain development. Dev Biol 2005; 288:259–275.

    Article  PubMed  CAS  Google Scholar 

  59. Siffroi-Fernandez S, Felder-Schmittbuhl MP, Khanna H et al. FGF19 exhibits neuroprotective effects on adult mammalian photoreceptors in vitro. Invest Ophthalmol Vis Sci 2008; 49:1696–1704.

    Article  PubMed  Google Scholar 

  60. Thussbas C, Nahrig J, Streit S et al. FGFR4 Arg388 allele is associated with resistance to adjuvant therapy in primary breast cancer. J Clin Oncol 2006; 24:3747–3755.

    Article  PubMed  CAS  Google Scholar 

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Lin, B.C., Desnoyers, L.R. (2012). FGF19 and Cancer. In: Kuro-o, M. (eds) Endocrine FGFs and Klothos. Advances in Experimental Medicine and Biology, vol 728. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-0887-1_12

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