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Epithelial Cell Plasticity in Development and Tumor Progression

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Abstract

Various mechanisms of epithelial cell plasticity in morphogenesis have been studied at the genetic and molecular levels. Several control genes have been identified including genes encoding transcription factors and growth factor receptors. These mechanisms may be reactivated during the progression of carcinomas. One of the mechanisms underlying epithelial plasticity is the epithelial–mesenchymal transition. This process has been extensively studied using the NBT-II bladder carcinoma cell line. Cells of this line undergo a reversible transition following exposure to several growth factors including FGF1, EGF, TGFα and SF/HGF, which activate tyrosine kinase surface receptors. Two separate transduction pathways have been identified. The transient activation of c-Src is involved in cytoskeleton remodeling whereas the Ras pathway controls the transcription of genes such as the transcription factor Slug which is involved in the internalization of desmosomes. These two pathways cooperate to induce the morphological transition, scattering and locomotion of fibroblast-like cells. Growth/scatter factor-producing NBT-II cells are more invasive than cells that do not contain this factor, in orthotopic confrontation assay. In vivo, these cells are very tumorigenic and may confer a more malignant phenotype on parental cells via a community effect. The role of several growth factors and their receptors has been investigated in human bladder carcinomas. A subset of these tumors with poor outcomes produce low levels of FGFR2-IIIb. The synthesis of this receptor de novo in bladder cell lines reduces proliferation in vitro and tumor growth in nude mice. FGFR2-IIIb functions as a tumor suppressor, consistent with the differentiation-inducing capacities of FGF receptors in the suprabasal cells of the skin. FGFR2-IIIb signaling may be involved in the maintenance of E-cadherin, the prototype epithelial adhesion molecule, which is only downregulated in a fraction of tumors with low FGFR2-IIIb synthesis. Human bladder tumors may also activate autocrine loops such as that for EGFR and their ligands, as already demonstrated for murine bladder tumors. Therefore, our results suggest that multifunctional growth factors and their receptors are involved in cell proliferation and epithelial cell plasticity, acting either as positive or negative regulators of tumor progression. The effect on the morphological transition is also clearly relevant to the mechanism governing dissemination and the formation of micrometastatic tumor cells. The extrapolation of these discoveries to human carcinomas should provide markers facilitating the more accurate prediction of the biological behavior of a given tumor and identify clinically and pathologically significant parameters. The identification of critical changes in the growth factor pathways involved in tumor progression will not only provide insight into the genetic and molecular basis of this process, but should also identify targets for new therapies.

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References

  1. Lengauer C, Kinzler KW, Vogelstein B: Genetic instabilities in human cancers. Nature 396: 643–649, 1998

    Google Scholar 

  2. Shackney SE, Shankey TV: Common patterns of genetic evolution in human solid tumors. Cytometry 29: 1–27, 1997

    Google Scholar 

  3. Fagnou C, Michon J, Peter M, Oberlin O, Zucker JM, Magdelenat H, Delattre O: Presence of tumor cells in bone marrow but not in blood is associated with adverse prognosis in patients with Ewing's tumor. J Clin Invest 16: 1707–1711, 1998

    Google Scholar 

  4. Thibodeau SN, Bren G, Shaid D: Micro satellite instability in cancer of the proximal colon. Science 260: 816–819, 1993

    Google Scholar 

  5. Lothe A, Peltomäki P, Meling GI, Aaltonen LA, Nyström-Lahti M et al.: Genomic instability in colorectal cancer: relationship to clinicopathological variables and family history. Cancer Res 53: 5849–5852, 1993

    Google Scholar 

  6. Kochhar R, Hailing KC, McDonnell S, Shaid DJ, French AM, O'Connell MJ, Nagorney DM, Thibodeau SN: Allelic imbalance and microsatellite instability in resected Duke's colorectal cancer. Diagnost Mol Pathol 6: 78–84, 1997

    Google Scholar 

  7. Ogunbiyi OA, Goodfellow PJ, Herfarth K, Gagliardi G, Swanson PE, Binbaum EH, Read TE, Fleshman JW, Kodner IJ, Moley JF: Confirmation that chromosome 18q allelic loss in colon cancer is a prognostic indicator. J Clin Onc 16: 427–433, 1998

    Google Scholar 

  8. Carethers JM, Hawn MT, Greenson JK, Hitchcock CL, Boland CR: Prognostic significance of allelic loss at chromosome 18q21 for stage II colorectal cancer. Gastroenterology 114: 1188–1195, 1998

    Google Scholar 

  9. Folkman J: New perspectives in clinical oncology from angiogenesis research. Eur J Cancer 32A: 2534–2539, 1996

    Google Scholar 

  10. Fox SB: Tumor angiogenesis and prognosis. Histopathology 30: 294–301, 1997

    Google Scholar 

  11. Viens P, Pernault-Llorca F, Jacquemier J, Gravis C, Cowen D, Bertucci F, Houvenaeghel G, Blaise D, Maraninchi D: High dose chemotherapy and haematopoietic stem cell transplantation for inflammmatory breast cancer: pathologic response and outcome. Bone Marrow Transplantation 21: 249–254, 1998

    Google Scholar 

  12. Kinzler KW, Vogelstein B: Landscaping the cancer terrain. Science 280: 1036–1037, 1998

    Google Scholar 

  13. Watson KL, Justice RW, Bryant P: Drosophila in cancer research: the first fifty tumor suppressor genes. Development 18: 19–33, 1994

    Google Scholar 

  14. Gilbert SF: Developmental Biology. Fifth edition. Massachusetts Sinauer Associates Inc. Publishers, Sunderland, 1997

    Google Scholar 

  15. Jouanneau J, Tucker GC, Boyer B, Valleś AM, Thiery JP: Epithelial cell plasticity in neoplasia. Cancer Cells 3: 525–529, 1991

    Google Scholar 

  16. Savagner P, Boyer B, Valles AM, Jouanneau J, Thiery IP: Modulations of the epithelial phenotype during embryogenesis and cancer progression. In: Dickson R, Lipmann M (eds) Mammary tumorigenesis and malignant progression. Kluwer Academic Publishers, Dordrecht, The Netherlands, 1994, pp 229–249

    Google Scholar 

  17. Birchmeier C, Birchmeier W, Brand-Saberi B: Epithelial-mesenchymal transitions in cancer progression. Acta Anat 156: 217–226, 1996

    Google Scholar 

  18. Leptin M, Casal J, Grunewald B, Reuter R: Mechanisms of early Drosophila mesoderm formation. In: Stern CD, Ingham PW (eds) Gastrulation. The Company of Biologists, 1992, pp 23–31

  19. Morize P, Christiansen AE, Costa M, Parks S, Wieschaus E: Hyperactivation of the folded gastrulation pathway induces specific cell shape changes. Development 125: 589–597, 1998

    Google Scholar 

  20. Hacker U, Perrimon N: DRhoGEF2 encodes a member of the Dbl family of oncogenes and controls cell shape changes during gastrulation in Drosophila. Genes & Development 12: 274–284, 1998

    Google Scholar 

  21. Keller R: Early embryonic development of Xenopus laevis. In: Kay KB, Peng BH (eds) Methods in Cell Biology. Xenopus laevis: practical uses in Cell and Molecular Biology. Academic Press, 1991, pp 61–113

  22. Niehrs C, Keller R, Cho KWY, De Robertis EM: The homeobox gene goosecoid controls cell migration in xenopus embryos. Cell 72: 491–503, 1993

    Google Scholar 

  23. Pannese M, Polo C, Andreazzoli M, Vignali R, Kablar B, Barsacchi G, Boncinelli E: The Xenopus homologue of Otx2 is a maternal homeobox gene that demarcates and specifies anterior body regions. Development 121: 707–720, 1995

    Google Scholar 

  24. Broders F, Thiery JP: Contribution of cadherins to directional cell migration and histogenesis in xenopus embryos. Cell Adh Com 3: 419–440, 1995

    Google Scholar 

  25. Kim S-H, Yamamoto A, Bouwmeester T, Agius E, De Robertis EM: The role of paraxial protocadherin in selective adhesion and cell movements of the mesoderm during Xenopus gastrulation. Development 125: 4681–4691, 1998

    Google Scholar 

  26. Le Douarin N: The Neural Crest. Cambridge University Press, 1982.

  27. Thiery JP, Duband JL, Dufour S: Adhesion systems in morphogenesis and cell migration during avian embryogenesis. In: Morphoregulatory Molecules. John Wiley and Sons, New York, 1990, pp 597–625

    Google Scholar 

  28. Duband JL, Monier F, Delannet M, Newgreen D: Epithelium-mesenchyme transition during neural crest development. Acta Anat 154: 63–78, 1996

    Google Scholar 

  29. Nieto AM, Sargent MC, Wilkinson DG, Cooke J: Control of cell behavior during vertebrate development by Slug, a zinc finger gene. Science 264: 835–839, 1994

    Google Scholar 

  30. Mancilla A, Mayor R: Neural crest formation in Xenopus laevis: mechanisms of Xslug induction. Dev Biol 177: 580–589, 1996

    Google Scholar 

  31. Glazer L, Shilo B-Z: The Drosophila FGF-R homolog is expressed in the embryonic tracheal system and appears to be required for directed tracheal cell expension. Gene Dev 5: 697–705, 1991

    Google Scholar 

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

    Google Scholar 

  33. Bellusci S, Grindley J, Emoto H, Itoh N, Hogan BL: Fibroblast growth factor 10 (FGF10) and branching morphogenesis in the embryonic mouse lung. Development 124: 4867–4878, 1997

    Google Scholar 

  34. Peters K, Werner S, Liao X, Wert S, Whitsett J, Williams L: Targeted expression of a dominant negative FGF receptor blocks branching morphogenesis and epithelial differentiation of the mouse lung. EMBO J 13: 3296–3301, 1994

    Google Scholar 

  35. Niemann C, Brinkmann V, Spitzer E, Hartmann G, Sachs M, Naundorf H, Birchmeier W: Reconstitution of mammary gland development in vitro: requirement of c-met and c-erbB2 signaling for branching and alveolar morphogenesis. J Cell Biol 143: 533–545, 1998

    Google Scholar 

  36. Boccaccio C, Ando M, Tamagnone L, Bardelli A, Michieli P, Battistini C, Comoglio PM: Induction of epithelial tubules by growth factor HGF depends on the STAT pathway. Nature 391: 285–288, 1998

    Google Scholar 

  37. Tchao R: Novel forms of epithelial cell motility on collagen and on glass surfaces. Cell Motil 4: 333–341, 1982

    Google Scholar 

  38. Boyer B, Tucker GC, Vallés AM, Gavrilovic J, Thiery JP: Reversible transition towards a fibroblastic phenotype in a rat carcinoma cell line. Int J Cancer 4: 69–75, 1989

    Google Scholar 

  39. Vallés AM, Tucker G, Thiery JP, Boyer B: Alternative patterns of mitogenesis and cell scattering induced by acidic FGF as a function of cell density in a rat bladder carcinoma cell line. Cell Regulation 4: 975–988, 1990

    Google Scholar 

  40. Vallés AM, Boyer B, Tucker GC, Badet J, Barritault D, Thiery JP: Acidic fibroblast growth factor is a modulator of epithelial plasticity in a rat bladder carcinoma cell line. Proc Natl Acad Sci USA 87: 1124–1128, 1990

    Google Scholar 

  41. Gavrilovic J, Moens G, Thiery JP, Jouanneau J: Expression of TGFα induces a motile fibroblast-like phenotype with extracellular matrix-degrading potential in a rat bladder carcinoma cell line. Cell Regulation 1: 1003–1014, 1990

    Google Scholar 

  42. Bellusci S, Moens G, Gaudino G, Comoglio P, Nakamura T, Thiery JP, Jouanneau J: Creation of an hepatocyte growth factor/scatter factor autocrine loop in carcinoma cells induces invasive properties associated with increased oncogenic potential. Oncogene 9: 1091–1099, 1994

    Google Scholar 

  43. Boyer B, Valles AM, Thiery JP: Model systems of epithelium-mesenchyme transition. Acta Anat 156: 227–239, 1996

    Google Scholar 

  44. Savagner P, Vallés AM, Jouanneau J, Yamada K, Thiery JP: 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

    Google Scholar 

  45. Boyer B, Dufour S, Thiery JP: E-cadherin expression during the acidic FGF-induced dispersion of a rat bladder carcinoma cell line. Exp Cell Res 201: 347–357, 1992

    Google Scholar 

  46. Boyer B, Thiery JP: Cyclic AMP Distinguishes between two functions of acidic FGF in a rat bladder carcinoma cell line. J Cell Biol 120: 767–776, 1993

    Google Scholar 

  47. Rodier JM, Valles AM, Denoyelle M, Thiery JP, Boyer B: pp60c-Src is a positive regulator of growth factor-induced cell scattering in a rat bladder carcinoma cell line. J Cell Biol 131: 761–773, 1995

    Google Scholar 

  48. Boyer B, Roche S, Denoyelle M, Thiery JP: Src and ras are involved in separate pathways in epithelial cell scattering. EMBO J 16: 5904–5943, 1997

    Google Scholar 

  49. Savagner P, Yamada KM, Thiery JP: The zinc-finger protein slug causes desmosome dissociation, an initial and necessary step for growth factor-induced epithelial-mesenchymal transition. J Cell Biol 137: 1403–1419, 1997

    Google Scholar 

  50. Tucker GC, Delouvée A, Jouanneau J, Gavrilovic J, Moens G, Vallés AM, Thiery JP: Amplification of invasiveness in organotypic cultures after NBT-II rat bladder carcinoma stimulation with in vitro scattering factors. Cell Adh Com 11: 297–309, 1991

    Google Scholar 

  51. Jouanneau J, Moens G, Bourgeois Y, Poupon MF, Thiery JP: A minority of carcinoma cells producing acidic fibroblast growth factor induces a community effect for tumor progression. Proc Natl Acad Sci USA 91: 286–290, 1994

    Google Scholar 

  52. Gurdon JB, Lemaire P, Kato K: Community effects in related phenomena in development. Cell 75: 831–834, 1993

    Google Scholar 

  53. Jouanneau J, Plouet J, Moens G, Thiery JP: FGF-2 and FGF-1 expressed in rat bladder carcinoma cells have similar angiogenic potential but different tumorigenic properties in vivo. Oncogene 14: 671–676, 1997

    Google Scholar 

  54. Bellusci S, Moens G, Thiery JP, Jouanneau J: A scatter factor-like factor is produced by a metastatic variant of a bladder carcinoma line. J Cell Science 107: 1277–1287, 1994

    Google Scholar 

  55. Aaronson SA: Growth factors and cancer. Science 254: 1146–1152, 1991

    Google Scholar 

  56. Fan Z, Mendelsohn J: Therapeutic application of antigrowth factor receptor antibodies. Curr Op Oncology 10: 67–73, 1998

    Google Scholar 

  57. Chodak GW, Hospelhorn V, Judge SM, Mayforth R, Koeppen H, Sasse J: Increased levels of fibroblast growth factor-like activity in urine from patients with bladder or kidney cancer. Cancer Res 48: 2083–2088, 1988

    Google Scholar 

  58. Chopin DK, Caruelle JP, Colombel M, Palcy S, Ravery V, Caruelle D, Abbou C, Barritault D: Increased immunodetection of acidic fibroblast growth factor in bladder cancer, detectable in urine. J Urol 150: 1126–1130, 1993

    Google Scholar 

  59. Nguyen M, Watanabe H, Budson AE, Richie JP, Folkman J: Elevated levels of the angiogenic peptide basic fibroblast growth factor in urine of bladder cancer patients. J Natl Cancer Inst 85: 241–242, 1993

    Google Scholar 

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

    Google Scholar 

  61. Yamaguchi F, Saya H, Bruner JM, Morrison RS: Differential expression of two fibroblast growth factor-receptor genes is associated with malignant progression in human astrocytomas. Proc Natl Acad Sci USA 91: 484–488, 1994

    Google Scholar 

  62. Nakagawara A, Arima-Nakagawara M, Azar CG, Scavarda NJ, Brodeur GM: Clinical significance of expression of neurotrophic factors and their receptors in neuroblastoma. Progress of clinical and biological research 385: 155–161, 1994

    Google Scholar 

  63. Kim IY, Ahn HJ, Lang S, Oefelein MG, Osyasu R, Kolowski KM, Lee C: Loss of expression of transforming growth factor beta receptors is associated with poor prognosis in prostate cancer patients. Clin Cancer Res 4: 1625–1630, 1998

    Google Scholar 

  64. Werner S, Weinberg W, Liao X, Peters KG, Blessing M, Yuspa SH, Weiner RL, Williams LT: Targeted expression of a dominant-negative FGF receptor mutant in the epidermis of transgenic mice reveals arole of FGF in keratinocyte organization and differentiation. EMBO J 12: 2635–2643, 1993

    Google Scholar 

  65. Werner S, Smola H, Liao X, Longaker MT, Krieg T, Hofschneider PH, Williams LT: The function of KGF in morphogenesis of epithelium and reepitheliasation of wounds. Science 266: 819–822, 1994

    Google Scholar 

  66. Itoh H, Hattori Y, Sakamoto H, Ishii H, Kishi T, Sasaki H, Yoshida T, Koono M, Sugimura T, Terada M: Preferential alternative splicing in cancer generates a K-sam messenger RNA with higher transforming activity. Cancer Res 54: 3237–3241, 1994

    Google Scholar 

  67. 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

    Google Scholar 

  68. Ornitz DM, Leder P: Ligand specificity and heparin dependence of fibroblast growth factor receptors 1 and 3. J Biol Chem 267: 16305–16311, 1992

    Google Scholar 

  69. Kanai M, Goke M, Tsunekawa S, Podolsky D: Signal transduction pathway of human fibroblast growth factor receptor 3. Identification of anovel 66-kDaphosphoprotein. J Biol Chem 272: 6621–6628, 1997

    Google Scholar 

  70. Naski MC, Wang Q, Xu J, Ornitz DM: Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia. Nature Genet 13: 233–237, 1996

    Google Scholar 

  71. Webster M, D'Avis PY, Robertson SC, Donhogue DJ: Profound ligand-independent kinase activation of fibroblast growth factor receptor 3 by the activation loop mutation responsible for a lethal skeletal dysplasia, thanatophoric dysplasia type II. Mol Cell Biol 16: 4081–4087, 1996a

    Google Scholar 

  72. Webster M, Donhogue DJ: Consitutive activation of fibroblast growth factor receptor 3 by the transmembrane domain mutation found in achondroplasia. EMBO J 15: 520–527, 1996b

    Google Scholar 

  73. Colvin JS, Bohne BA, Harding GW, McEwen DG, Ornitz DM: Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nature Genet 12: 390–397, 1996

    Google Scholar 

  74. Deng C, Wynshaw-Boris A, Zhou F, Kuo A, Leder P: Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell 84: 911–921, 1996

    Google Scholar 

  75. Ricol D, Cappellen D, El Marjou A, Gil-Diez de Medina S, Girault J-M, Ferry G, Tucker G, Poupon M-F, Chopin D, Thiery JP, Radvanyi F: Tumour suppressive properties of fibroblast growth factor receptor 2-IIIb in human bladder cancer. Oncogene (in press) 1999

  76. Birchmeier W, Behrens J: Cadherin expression in carcinomas: role in the formation of cell junction and the prevention of invasiveness. Biochem Biophys Acta 1198: 11–26, 1994

    Google Scholar 

  77. Gil-Diez de Medina S, Popov Z, Chopin DK, Southgate J, Tucker G, Delouvée A, Thiery JP, Radvanyi F: Relationship between E-cadherin and Fibroblast Growth Factor Receptor 2b expression in bladder carcinomas. Oncogene (in press) 1999

  78. Schmidt L et al.: Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nature Genet 16: 68–73, 1997

    Google Scholar 

  79. Kolibaba KS, Druker BJ: Protein tyrosine kinases and cancer. Biochimica et Biophysica Acta 1333: 217–248, 1997

    Google Scholar 

  80. Ravery V, Colombel M, Popov Z, Bastuji S, Patard JJ, Bellot J, Abbou CC, Fradet Y, Chopin DK: Prognostic value of epidermal growth factor-receptor, T138 and T43 expression in bladder cancer. Br J Cancer 71: 196–200, 1995

    Google Scholar 

  81. Kobrin MS, Yamanaka Y, Friess H, Lopez ME, Korc M: Aberrant expression of type I fibroblast growth factor receptor in human pancreatic adenocarcinomas. Cancer Res 53: 4741–4744, 1993

    Google Scholar 

  82. Jacquemier J, Adelaide J, Parc P, Penault-Llorca F, Planche J, DeLapeyriere O, Birnbaum D: Expression of the FGFR1 gene in human breast carcinoma cells. Int J Cancer 59: 373–378, 1994

    Google Scholar 

  83. 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

    Google Scholar 

  84. Feng S, Wang F, Matsubara A, Kan M, McKeehan WL: Fibroblast growth factor receptor 2 limits and receptor 1 accelerates tumorigenicity of prostate epithelial cells. Cancer Res 57: 5369–5378, 1997

    Google Scholar 

  85. El Marjou A, Delouvee A, Thiery JP, Radvanyi F: A positive autocrine loop EGF-R/ligands is involved in chemically-inducedmousebladder tumourprogression. Submitted 1999

  86. Boyer B, Thiery JP: Epithelium-mesenchyme interconversion as example of epithelial plasticity. Apmis 101: 257–268, 1993

    Google Scholar 

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  1. UMR 144 CNRS, Laboratoire de Morphogenèse Cellulaire et Progression Tumorale, Institut Curie, Paris, France

    Jean Paul Thiery & Dominique Chopin

  2. Groupe d'Etude des Tumeurs Urologiques et Service d'Urologie, Centre Hospitalier Henri Mondor, Créteil, France

    Jean Paul Thiery

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Thiery, J.P., Chopin, D. Epithelial Cell Plasticity in Development and Tumor Progression. Cancer Metastasis Rev 18, 31–42 (1999). https://doi.org/10.1023/A:1006256219004

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