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Horm Metab Res 2005; 37(6): 355-360
DOI: 10.1055/s-2005-870151
Review
© Georg Thieme Verlag KG Stuttgart · New York

FGF Receptor Signaling at the Crossroads of Endocrine Homeostasis and Tumorigenesis

S.  Ezzat1 , S.  L.  Asa2
  • 1Departments of Medicine, University of Toronto, Endocrine Oncology Site Group, Mount Sinai & Princess Margaret Hospitals, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada
  • 2Pathology and Laboratory Medicine, University of Toronto, Endocrine Oncology Site Group, Mount Sinai & Princess Margaret Hospitals, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada
Further Information

Publication History

Received 5 August 2004

Accepted after revision 20 September 2004

Publication Date:
07 July 2005 (online)

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Abstract

Multiple endocrine neoplasia (MEN) syndromes represent familial disorders characterized by endocrine cell growth and hormone production dysregulation. For several decades, the fibroblast growth factor (FGF) system has been suspected of playing a unique function in MEN-type I (MEN I). However, specific elucidation of these actions has been hampered by the overwhelming redundancy of this complex system. The human FGF family is composed of 22 members organized into 6 groups based on phylogenetic relationships. Signaling is mediated through membrane-spanning tyrosine kinase receptors encoded by four independent genes, some of which generate multiple products via alternative splicing or transcription initiation. High-affinity interaction between an FGF and its cognate receptor induces receptor dimerization and activation. Many FGFs display high-affinity interactions with multiple FGFRs, while some activate unique receptors or receptor isoforms. Most FGFs have demonstrated mitogenic activity in a variety of systems; however, a growing number display predominantly metabolic actions. This review will examine the evidence that FGF/FGFRs play a role in sporadic endocrine neoplasia and the pathways in which these molecules may be selectively targeted for therapeutic purposes.

Key words

FGF - FGF receptors - Pituitary tumors - Pancreatic neuroendocrine tumors

References

  • 1 Asa S L, Ezzat S. The cytogenesis and pathogenesis of pituitary adenomas.  Endocr Rev. 1998;  19 798-827
    CrossrefPubMedSearch in Google Scholar
  • 2 Alexander J M. Tumor suppressor loss in pituitary tumors.  Brain Pathol. 2001;  11 342-355
    PubMedSearch in Google Scholar
  • 3 Asa S L, Ezzat S. The pathogenesis of pituitary tumours.  Nat Rev Cancer. 2002;  2 836-849
    PubMedSearch in Google Scholar
  • 4 Shimada T, Kakitani M, Yamazaki Y. et al . Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism.  J Clin Invest. 2004;  113 561-568
    CrossrefPubMedSearch in Google Scholar
  • 5 Givol D, Yayon A. Complexity of FGF receptors: genetic basis for structural diversity and functional specificity.  FASEB J. 1992;  6 3362-3369
    PubMedSearch in Google Scholar
  • 6 Yan G, Wang F, Fukabori Y, Sussman D, Hou J, McKeehan W L. Expression and transformation of a variant of the heparin-binding fibroblast growth factor receptor (flg) gene resulting from splicing of the exon at alternate 3'-acceptor site.  Biochem Biophys Res Commun. 1992;  183 423-430
    CrossrefPubMedSearch in Google Scholar
  • 7 Peters K G, Werner S, Chen G, Williams L T. Two FGF receptor genes are differentially expressed in epithelial and mesenchymal tissues during limb formation and organogenesis in the mouse.  Develop. 1992;  114 233-243
    PubMedSearch in Google Scholar
  • 8 Crumley G, Bellot F, Kaplow J M, Schlessinger J, Jaye M, Dionne C A. High-affinity binding and activation of a truncated FGF receptor by both aFGF and bFGF.  Oncogene. 1991;  6 2255-2262
    PubMedSearch in Google Scholar
  • 9 Hanneken A, Ying W, Ling N, Baird A. Identification of soluble forms of the fibroblast growth factor receptor in blood.  Proc Natl Acad Sci USA. 1994;  91 9170-9174
    PubMedSearch in Google Scholar
  • 10 Kostrzewa M, Muller U. Genomic structure and complete sequence of the human FGFR4 gene.  Mamm Genome. 1998;  9 131-135
    CrossrefPubMedSearch in Google Scholar
  • 11 Partanen J, Mäkelä T P, Eerola E. et al . FGFR-4, a novel acidic fibroblast growth factor receptor with a distinct expression pattern.  EMBO J. 1991;  10 1347-1354
    PubMedSearch in Google Scholar
  • 12 Hughes S E. Differential expression of the fibroblast growth factor receptor (FGFR) multigene family in normal human adult tissues.  J Histochem Cytochem. 1997;  45 1005-1019
    PubMedSearch in Google Scholar
  • 13 Yayon A, Aviezer D, Safran M. et al . Isolation of peptides that inhibit binding of basic fibroblast growth factor to its receptor from a random phage-epitope library.  Biochemistry. 1993;  90 10 643-10 647
    PubMedSearch in Google Scholar
  • 14 Dode C, Levilliers J, Dupont J M, De Paepe A, Le Du N, Soussi-Yanicostas N, Coimbra R S, Delmaghani S, Compain-Nouaille S, Baverel F, Pecheux C, Le Tessier D, Cruaud C, Delpech M, Speleman F, Vermeulen S, Amalfitano A, Bachelot Y, Bouchard P, Cabrol S, Carel J C, Delemarre-van de Waal H, Goulet-Salmon B, Kottler M L, Richard O, Sanchez-Franco F, Saura R, Young J, Petit C, Hardelin J P. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome.  Nat Genet. 2003;  33 440-442
    PubMedSearch in Google Scholar
  • 15 Weinstein M, Xu X, Ohyama K, Deng C X. FGFR-3 and FGFR-4 function cooperatively to direct alveogenesis in the murine lung.  Develop. 1998;  125 3615-3623
    PubMedSearch in Google Scholar
  • 16 Treier M, Gleiberman A S, O’Connell S M. et al . Multistep signaling requirements for pituitary organogenesis in vivo.  Genes Dev. 1998;  12 1691-1704
    PubMedSearch in Google Scholar
  • 17 Paez-Pereda M, Giacomini D, Refojo D. et al . Involvement of bone morphogenetic protein 4 (BMP-4) in pituitary prolactinoma pathogenesis through a Smad/estrogen receptor crosstalk.  Proc Natl Acad Sci USA. 2003;  100 1034-1039
    CrossrefPubMedSearch in Google Scholar
  • 18 De Moerlooze L, Spencer-Dene B, Revest J, Hajihosseini M, Rosewell I, Dickson C. An important role for the IIIb isoform of fibroblast growth factor receptor 2 (FGFR2) in mesenchymal-epithelial signalling during mouse organogenesis.  Develop. 2000;  127 483-492
    PubMedSearch in Google Scholar
  • 19 Celli G, LaRochelle W J, Mackem S, Sharp R, Merlino G. Soluble dominant-negative receptor uncovers essential roles for fibroblast growth factors in multi-organ induction and patterning.  EMBO J. 1998;  17 1642-1655
    CrossrefPubMedSearch in Google Scholar
  • 20 Hardikar A A, Marcus-Samuels B, Geras-Raaka E, Raaka B M, Gershengorn M C. Human pancreatic precursor cells secrete FGF2 to stimulate clustering into hormone-expressing islet-like cell aggregates.  Proc Natl Acad Sci USA. 2003;  100 7117-7122
    CrossrefPubMedSearch in Google Scholar
  • 21 Hart A W, Baeza N, Apelqvist A, Edlund H. Attenuation of FGF signalling in mouse beta-cells leads to diabetes.  Nature. 2000;  408 864-868
    CrossrefPubMedSearch in Google Scholar
  • 22 Yu C, Wang F, Kan M. et al . Elevated cholesterol metabolism and bile acid synthesis in mice lacking membrane tyrosine kinase receptor FGFR4.  J Biol Chem. 2000;  275 15 482-15 489
    PubMedSearch in Google Scholar
  • 23 Tomlinson E, Fu L, John L. et al . Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity.  Endocrinology. 2002;  143 1741-1747
    CrossrefPubMedSearch in Google Scholar
  • 24 Gospodarowicz D, Abraham J A, Schilling J. Isolation and characterization of a vascular endothelial cell mitogen produced by pituitary-derived folliculo stellate cells.  Proc Natl Acad Sci USA. 1989;  86 7311-7315
    PubMedSearch in Google Scholar
  • 25 Ezzat S, Smyth H S, Ramyar L, Asa S L. Heterogeneous in vivo and in vitro expression of basic fibroblast growth factor by human pituitary adenomas.  J Clin Endocrinol Metab. 1995;  80 878-884
    CrossrefPubMedSearch in Google Scholar
  • 26 Heaney A P, Horwitz G A, Wang Z, Singson R, Melmed S. Early involvement of estrogen-induced pituitary tumor transforming gene and fibroblast growth factor expression in prolactinoma pathogenesis.  Nature Medicine. 1999;  5 1317-1321
    PubMedSearch in Google Scholar
  • 27 Zimering M B, Katsumata N, Sato Y. et al . Increased basic fibroblast growth factor in plasma from multiple endocrine neoplasia type 1: Relation to pituitary tumor.  J Clin Endocrinol Metab. 1993;  76 1182-1187
    CrossrefPubMedSearch in Google Scholar
  • 28 Asa S L, Ramyar L, Murphy P R, Li A W, Ezzat S. The endogenous fibroblast growth factor-2 antisense gene product regulates pituitary cell growth and hormone production.  Mol Endocrinol. 2001;  15 589-599
    CrossrefPubMedSearch in Google Scholar
  • 29 Yu S, Zheng L, Asa S L, Ezzat S. Fibroblast growth factor receptor 4 (FGFR4) mediates signaling to the prolactin but not the FGFR4 promoter.  Am J Physiol Endocrinol Metab. 2002;  283 E490-E495
    PubMedSearch in Google Scholar
  • 30 Yu S, Asa S L, Ezzat S. Fibroblast growth factor receptor 4 is a target for the zinc-finger transcription factor Ikaros in the pituitary.  Mol Endocrinol. 2002;  16 1069-1078
    CrossrefPubMedSearch in Google Scholar
  • 31 Abbass S AA, Asa S L, Ezzat S. Altered expression of fibroblast growth factor receptors in human pituitary adenomas.  J Clin Endocrinol Metab. 1997;  82 1160-1166
    CrossrefPubMedSearch in Google Scholar
  • 33 Ezzat S, Zheng L, Zhu X F, Wu G E, Asa S L. Targeted expression of a human pituitary tumor-derived isoform of FGF receptor-4 recapitulates pituitary tumorigenesis.  J Clin Invest. 2002;  109 69-78
    CrossrefPubMedSearch in Google Scholar
  • 32 Ezzat S, Yu S, Asa S L. Ikaros isoforms in human pituitary tumors: distinct localization, histone acetylation, and activation of the 5' fibroblast growth factor receptor-4 promoter.  Am J Pathol. 2003;  163 1177-1184
    PubMedSearch in Google Scholar
  • 34 Yu S J, Asa S L, Weigel R J, Ezzat S. Pituitary Tumor AP-2 Recognizes A Cryptic Promoter in Intron 4 of Fibroblast Growth Factor Receptor 4.  J Biol Chem. 2003;  278 19 597-19 602
    PubMedSearch in Google Scholar
  • 35 Hirohashi S, Kanai Y. Cell adhesion system and human cancer morphogenesis.  Cancer Sci. 2003;  94 575-581
    PubMedSearch in Google Scholar
  • 36 Christofori G. Changing neighbours, changing behaviour: cell adhesion molecule-mediated signalling during tumour progression.  EMBO J. 2003;  22 2318-2323
    CrossrefPubMedSearch in Google Scholar
  • 37 Ezzat S, Zheng L, Asa S L. Tumor-Derived FGFR4 Isoform Disrupts NCAM/N-cadherin Signaling to Diminish Cell Adhesiveness: A Mechanism Underlying Pituitary Neoplasia.  Molecular Endocrinology. 2004;  18 2543-2552
    CrossrefPubMedSearch in Google Scholar
  • 38 Cavallaro U, Schaffhauser B, Christofori G. Cadherins and the tumour progression: is it all in a switch?.  Cancer Lett. 2002;  176 123-128
    CrossrefPubMedSearch in Google Scholar
  • 39 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
    PubMedSearch in Google Scholar
  • 40 Ezzat S, Zheng L, Yu S, Asa S L. A soluble dominant negative fibroblast growth factor receptor 4 isoform in human mcf-7 breast cancer cells.  Biochem Biophys Res Commun. 2001;  287 60-65
    CrossrefPubMedSearch in Google Scholar
  • 41 Cavallaro U, Niedermeyer J, Fuxa M, Christofori G. N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling.  Nat Cell Biol. 2001;  3 650-657
    CrossrefPubMedSearch in Google Scholar
  • 42 Daniel L, Trouillas J, Renaud W. et al . Polysialylated-neural cell adhesion molecule expression in rat pituitary transplantable tumors (spontaneous mammotropic transplantable tumor in Wistar-Furth rats) is related to growth rate and malignancy.  Cancer Res. 2000;  60 80-85
    PubMedSearch in Google Scholar
  • 43 Fujimoto I, Bruses J L, Rutishauser U. Regulation of cell adhesion by polysialic acid. Effects on cadherin, immunoglobulin cell adhesion molecule, and integrin function and independence from neural cell adhesion molecule binding or signaling activity.  J Biol Chem. 2001;  276 31 745-31 751
    PubMedSearch in Google Scholar
  • 44 Conacci-Sorrell M, Zhurinsky J, Ben Ze’ev A. The cadherin-catenin adhesion system in signaling and cancer.  J Clin Invest. 2002;  109 987-991
    CrossrefPubMedSearch in Google Scholar
  • 45 Heinrich C A, Lail-Trecker M R, Peluso J J, White B A. Negative regulation of N-cadherin-mediated cell-cell adhesion by the estrogen receptor signaling pathway in rat pituitary GH3 cells.  Endocrine. 1999;  10 67-76
    CrossrefPubMedSearch in Google Scholar
  • 46 Yap A S, Kovacs E M. Direct cadherin-activated cell signaling: a view from the plasma membrane.  J Cell Biol. 2003;  160 11-16
    CrossrefPubMedSearch in Google Scholar
  • 47 Xu G, Arregui C, Lilien J, Balsamo J. PTP1B modulates the association of beta-catenin with N-cadherin through binding to an adjacent and partially overlapping target site.  J Biol Chem. 2002;  277 49 989-49 997
    PubMedSearch in Google Scholar
  • 48 Lilien J, Arregui C, Li H, Balsamo J. The juxtamembrane domain of cadherin regulates integrin-mediated adhesion and neurite outgrowth.  J Neurosci Res. 1999;  58 727-734
    CrossrefPubMedSearch in Google Scholar
  • 49 Kinch M S, Clark G J, Der C J, Burridge K. Tyrosine phosphorylation regulates the adhesions of ras-transformed breast epithelia.  J Cell Biol. 1995;  130 461-471
    CrossrefPubMedSearch in Google Scholar
  • 50 Hoschuetzky H, Aberle H, Kemler R. Beta-catenin mediates the interaction of the cadherin-catenin complex with epidermal growth factor receptor.  J Cell Biol. 1994;  127 1375-1380
    CrossrefPubMedSearch in Google Scholar
  • 51 Shibamoto S, Hayakawa M, Takeuchi K. et al . Tyrosine phosphorylation of beta-catenin and plakoglobin enhanced by hepatocyte growth factor and epidermal growth factor in human carcinoma cells.  Cell Adhes Commun. 1994;  1 295-305
    PubMedSearch in Google Scholar
  • 52 Bonvini P, An W G, Rosolen A. et al . Geldanamycin abrogates ErbB2 association with proteasome-resistant beta-catenin in melanoma cells, increases beta-catenin-E-cadherin association, and decreases beta-catenin-sensitive transcription.  Cancer Res. 2001;  61 1671-1677
    PubMedSearch in Google Scholar
  • 53 Shibata T, Ochiai A, Kanai Y. et al . Dominant negative inhibition of the association between beta-catenin and c-erbB-2 by N-terminally deleted beta-catenin suppresses the invasion and metastasis of cancer cells.  Oncogene. 1996;  13 883-889
    PubMedSearch in Google Scholar
  • 54 Qian Z R, Li C C, Yamasaki H. et al . Role of E-cadherin, alpha-, beta-, and gamma-catenins, and p120 (cell adhesion molecules) in prolactinoma behavior.  Mod Pathol. 2002;  15 1357-1365
    CrossrefPubMedSearch in Google Scholar
  • 55 Hood J D, Cheresh D A. Role of integrins in cell invasion and migration. Nat. Rev.  Cancer. 2002;  2 91-100
    PubMedSearch in Google Scholar
  • 56 Horacek M J, Kawaguchi T, Terracio L. Adult adenohypophysial cells express beta 1 integrins and prefer laminin during cell-substratum adhesion.  In Vitro Cell Dev Biol Anim. 1994;  30A 35-40
    PubMedSearch in Google Scholar

Dr. S. Ezzat

Princess Margaret Hospital · Pathology - 4-302

610 University Avenue · Toronto · Ontario · Canada · M5G-2M9

Phone: +1 (416) 946-2088

Fax: +1 (416) 586-8834

Email: sezzat@mtsinai.on.ca