TGFβ-regulated transcriptional mechanisms in cancer

Review Article


Transforming growth factor-beta (TGFβ) has been implicated in oncogenesis for many years. The multifunctional activities of TGFβ endow it with both tumor suppressor and tumor promoting activities, depending on the stage of carcinogenesis and the responsivity of the tumor cell. In early tumor stages, TGFβ inhibits epithelial cell growth through induction of apoptosis and cell cycle arrest. During tumor development, however, many tumor cells lose their growth-inhibitory responses to TGFβ owing to genetic alterations or signaling perturbations such as oncogenic Ras signaling. Loss of TGFβ-growth inhibition is commonly associated with increased tumor cell invasion and metastasis of tumor cells that undergo an epithelial-mesenchymal transition. Interestingly, the tumor-promoting effects of TGFβ on the tumor cells are observed particularly in cells in which TGFβ-signaling remains functional despite loss of growth control by TGFβ. New insights into transcriptional mechanisms activated by TGFβ are providing a better understanding of the cellular changes involved in the switch of TGFβ from a tumor suppressor to a tumor promotor.

Key Words

TGFβ Smad TIEG epithelial-mesenchymal transdifferentiation 


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  1. 1.
    Massague J, Chen YG. Controlling TGFβ signaling. Genes Dev 2000;14:627–644.PubMedGoogle Scholar
  2. 2.
    Blobe GC, Schiemann WP, Lodish HF. Role of TGFβ in human disease. N Eng J Med 2000;342:1350–1358.CrossRefGoogle Scholar
  3. 3.
    de Caestecker MP, Piek E, Roberts AB. The role of TGFβ signaling in cancer. J Natl Cancer Inst 2000;92:1388–1402.PubMedCrossRefGoogle Scholar
  4. 4.
    Itoh S, Itoh F, Goumans MJ, et al. Signaling of TGFβ family members through Smad proteins. Eur J Biochem 2000;267:6954–6967.PubMedCrossRefGoogle Scholar
  5. 5.
    Reiss M. TGFβ and cancer. Microbes Infect 1999;1:1327–1347.PubMedCrossRefGoogle Scholar
  6. 6.
    Akhurst RJ, Balmain A. Genetic events and the role of TGFβ in epithelial tumour progression. J Pathol 1999;187:82–90.PubMedCrossRefGoogle Scholar
  7. 7.
    Portella G, Cumming SA, Liddell J, et al. Transforming growth factor beta is essential for spindle cell conversion of mouse skin carcinoma in vivo: implications for tumor invasion. Cell Growth Differ 1998;9:393–404.PubMedGoogle Scholar
  8. 8.
    Chen RH, Ebner R, Derynck R. Inactivation of the type-II receptor reveals two receptor pathways for the diverse TGFβ activities. Science 1993;260:1335–1338.PubMedCrossRefGoogle Scholar
  9. 9.
    Akhurst RJ, Derynck R. TGFβ signaling in cancer–a double-edged sword. Trends Cell Biol 2001;11:44–51.Google Scholar
  10. 10.
    Cui W, Fowlis D, Bryson S, et al. TGFβ1 inhibits the formation of benign skin tumours but enhances progression to invasive spindle cell carcinomas in transgenic mice. Cell 1996;86:531–542.PubMedCrossRefGoogle Scholar
  11. 11.
    Welch DR, Fabra A, Nakajima M, et al. TGFβ stimulates mammary adenocarcinoma cell invasion and metastatic potential. Proc Natl Acad Sci USA 1990;87:7678–7682.PubMedCrossRefGoogle Scholar
  12. 12.
    Ellenrieder V, Hendler SF, Ruhland C, et al. TGFβ induced invasiveness of pancreatic cancer cells is mediated by MMP-2 and the urokinase plasminogen activator system. Int J Cancer 2001;93:204–211.PubMedCrossRefGoogle Scholar
  13. 13.
    Massague J, Blain SW, Lo RS. TGFβ signaling in growth control, cancer, and heritable disorders. Cell 2000;103:295–309.PubMedCrossRefGoogle Scholar
  14. 14.
    Zhao J, Buick RN. Regulation of transforming growth factor beta receptors in H-ras oncogene transformed rat intestinal epithelial cells. Cancer Res 1995;55:6181–6188.PubMedGoogle Scholar
  15. 15.
    Ellenrieder V, Hendler SF, Boeck W. TGFβ1 treatment leads to an epithelial-mesenchymal-transdifferentiation of pancreatic cancer cells requiring ERK2 activation. Cancer Res 2001;61:4222–4228.PubMedGoogle Scholar
  16. 16.
    Massague J, Wotton D. Transcriptional control by the TGF-β/Smad signaling system. EMBO J 19:1745–1754.Google Scholar
  17. 17.
    Heldin CH, Miyazono K, ten Djike P. TGFβ signaling from cell membrane to nucleus through SMAD proteins. Nature 1997;390:465–471.PubMedCrossRefGoogle Scholar
  18. 18.
    Nakao A, Afrakhte M, Moren A, et al. Identification of Smad7, a TGFβ-inducible antagonist of TGFβ signaling. Nature 1997;389:631–635.PubMedCrossRefGoogle Scholar
  19. 19.
    Imamura T, Takase M, Nishihara A, et al. Smad6 inhibits signaling by the TGFβ superfamily. Nature 1997;389:622–626.PubMedCrossRefGoogle Scholar
  20. 20.
    He W, Cao T, Smith DA, et al. Smads mediate signaling of the TGFbeta superfamily in normal keratinocytes but are lost during skin chemical carcinogenesis. Oncogene 2001;20:471–483.PubMedCrossRefGoogle Scholar
  21. 21.
    Kleeff J, Ishiwata T, Maruyama H, et al. The TGF-beta signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer. Oncogene 1999;18:5363–5372.PubMedCrossRefGoogle Scholar
  22. 22.
    Wrana JL. Crossing Smads. Sci STKE 2000;23:RE1.Google Scholar
  23. 23.
    Zhang Y, Derynck R. Regulation of Smad signaling by protein associations and signaling crosstalk. Trends Cell Biol 1999;9:274–279.PubMedCrossRefGoogle Scholar
  24. 24.
    Piek E, Roberts AB. Suppressor and oncogenic roles of transforming growth factor-beta and its signaling pathways in tumorigenesis. Adv Cancer Res 2001;83:1–54.PubMedCrossRefGoogle Scholar
  25. 25.
    Massague J. How cells read TGF-beta signals. Nat Rev Mol Cell Biol 2000;1:169–178.PubMedCrossRefGoogle Scholar
  26. 26.
    Ellis CA, Clark G. The importance of being K-Ras. Cell Signal 2000;12:425–434.PubMedCrossRefGoogle Scholar
  27. 27.
    Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl J Med 1988;319:525–532.PubMedCrossRefGoogle Scholar
  28. 28.
    Kretzschmar M, Doody J, Timokhina I, et al. A mechanism of repression of TGFβ/Smad signaling by oncogenic Ras. Genes Dev 1999;13:804–816.PubMedCrossRefGoogle Scholar
  29. 29.
    Mulder KM: Role of Ras and MAPKs in TGFβ signaling. Cytokine Growth Factor Rev 2000;11:23–35.PubMedCrossRefGoogle Scholar
  30. 30.
    Frey RS, Mulder KM. Involvement of extracellular signal-regulated kinase 2 and stress-activated protein kinase/Jun N-terminal kinase activation by transforming growth factor beta in the negative growth control of breast cancer cells. Cancer Res 1997;57:628–633.PubMedGoogle Scholar
  31. 31.
    Calonge MJ, Massague J. Smad4/DPC4 silencing and hyperactive Ras jointly disrupt transforming growth factorbeta antiproliferative responses in colon cancer cells. J Biol Chem 1999;274:33,637–33,643.CrossRefGoogle Scholar
  32. 32.
    Wicks SJ, Lui S, Abdel-Wahab N, et al. Inactivation of smad-transforming growth factor beta signaling by Ca(2+-calmodulin-dependent protein kinase II. Mol Cell Biol 2000;20:8103–8111.PubMedCrossRefGoogle Scholar
  33. 33.
    Yakymovych I, ten Dijke P, Heldin CH, et al. Regulation of Smad signaling by protein kinase C. FASEB J 2001;15:553–555.PubMedGoogle Scholar
  34. 34.
    Engel ME, McDonnell MA, Law BK, et al. Interdependent SMAD and JNK signaling in transforming growth factorbeta-mediated transcription. J Biol Chem 1999;274:37,413–37,420.CrossRefGoogle Scholar
  35. 35.
    Brown JD, Dichiara MR, Anderson KR, et al. MEKK-1, a component of the stress (stress-activated protein kinase/c-Jun N-terminal kinase) pathway, can selectively activate Smad2-mediated transcriptional activation in endothelial cells. J Biol Chem 1999;274:8797–8805.PubMedCrossRefGoogle Scholar
  36. 36.
    Frey RS, Mulder KM. TGFβ regulation of mitogen-activated protein kinases in human breast cancer cells. Cancer Lett 1997;117:41–50.PubMedCrossRefGoogle Scholar
  37. 37.
    Shibuya H, Yamaguchi, Shirakabe K, et al. Identification of a member of the MAPKKK family as a potential mediator of TGFβ signal transduction. Science 1995;270:2008–2011.PubMedCrossRefGoogle Scholar
  38. 38.
    Atfi A, Djelloul S, Chastre E, et al. Evidence for a role of Rho-like GTPases and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in transforming growth factor beta-mediated signaling. J Biol Chem 1997;272:1429–1432.PubMedCrossRefGoogle Scholar
  39. 39.
    Hanafusa H, Ninomiya-Tsuji J, Masuyama N, et al. Involvement of the p38 mitogen-activated protein kinase pathway in transforming growth factor beta induced gene expression. J Biol Chem 1999;274:27,161–27,167.CrossRefGoogle Scholar
  40. 40.
    Zhang Y, Feng XH, Derynck R. Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta-induced transcription. Nature 1998;394:909–913.PubMedCrossRefGoogle Scholar
  41. 41.
    Moustakas A, Kardassis D. Regulation of the human p21/WAF1/Cip1 promoter in hepatic cells by functional interactions between Sp1 and Smad family members. Proc Natl Acad Sci USA 1998;95:6733–6738.PubMedCrossRefGoogle Scholar
  42. 42.
    Chen X, Rubock MJ, Whitman M. A transcriptional partner for MAD proteins in TGFbeta signaling. Nature 1996;383:691–696.PubMedCrossRefGoogle Scholar
  43. 43.
    Yanagisawa J, Yanagi Y, Masuhiro Y, et al. Convergence of transforming growth factor beta and vitamin D signaling pathways on Smad transcriptional coactivators. Science 1999;283:1317–1321.PubMedCrossRefGoogle Scholar
  44. 44.
    Feng XH, Zhang Y, Wu RY, et al. The tumor suppressor Smad4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for Smad3 in TGFβ-induced transcriptional activation. Genes Dev 1998;12:2153–2163.PubMedCrossRefGoogle Scholar
  45. 45.
    Janknecht R, Wells NJ, Hunter T. TGFβ-stimulated cooperation of Smad proteins with the coactivators CBP/p300. Genes Dev 1998;12:2114–2119.PubMedCrossRefGoogle Scholar
  46. 46.
    Wotton D, Lo RS, Lee S, et al. A Smad transcriptional corepressor. Cell 1999;97:29–39.PubMedCrossRefGoogle Scholar
  47. 47.
    Stroschein SL, Wang W, Zhou S, et al. Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein. Science 1999;286:771–774.PubMedCrossRefGoogle Scholar
  48. 48.
    Izutsu K, Kurokawa M, Imai Y, et al. The corepressor CtBP interacts with Evi-1 to repress transforming growth factor beta signaling. Blood 2001;97:2815–2822.PubMedCrossRefGoogle Scholar
  49. 49.
    Recio JA, Merlino G. Hepatocyte growth factor/scatter factor activates proliferation in melanoma cells through p38 MAPK, ATF-2 and cyclin D1. Oncogene 2002;21:1000–1008.PubMedCrossRefGoogle Scholar
  50. 50.
    van Dam H, Castellazzi M. Distinct roles of Jun:Fos and Jun:ATF dimers in oncogenesis. Oncogene 2001;20:2453–2464.PubMedCrossRefGoogle Scholar
  51. 51.
    Luo K, Stroschein SL, Wang W, et al. The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling. Genes Dev 1999;13:2196–2206.PubMedCrossRefGoogle Scholar
  52. 52.
    Goggins M, Shekher M, Turnacioglu K, et al. Genetic alterations of the transforming growth factor beta receptor genes in pancreatic and biliary adenocarcinomas. Cancer Res 1998;58:5329–5332.PubMedGoogle Scholar
  53. 53.
    Hahn SA, Schutte M, Hoque AT, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 1996;271:350–353.PubMedCrossRefGoogle Scholar
  54. 54.
    Schutte M, Hruban RH, Hedrick L, et al. DPC4 in various tumor types. Cancer Res 1996;56:2527–2530.PubMedGoogle Scholar
  55. 55.
    Eppert K, Scherer SW, Ozcelik H, et al. MADR2 maps to 18q21 and encodes a TGFβ-regulated MAD-related protein that is functionally mutated in colorectal carcinomas. Cell 1996;86:543–552.PubMedCrossRefGoogle Scholar
  56. 56.
    Donovan J, Slingerland J. Transforming growth factor-beta and breast cancer: Cell cycle arrest by transforming growth factor-beta and its disruption in cancer. Breast Cancer Res 2000;2:116–124.PubMedCrossRefGoogle Scholar
  57. 57.
    Seoane J, Pouponnot C, Staller P, et al. TGFbeta influences Myc, Miz-1 and Smad to control the CDK inhibitor p151NK4b. Nat Cell Biol 2001;3:400–408.PubMedCrossRefGoogle Scholar
  58. 58.
    Amati B. Integrating Myc and TGF-beta signalling in cell-cycle control. Nat Cell Biol 2001;3:112–113.CrossRefGoogle Scholar
  59. 59.
    Chen CR, Kang Y, Massague J. Defective repression of c-myc in breast cancer cells: A loss at the core of the transforming growth factor beta growth arrest program. Proc Natl Acad Sci USA 2001;98:992–999.PubMedCrossRefGoogle Scholar
  60. 60.
    Cook T, Urrutia R. TIEG proteins join the Smads as TGF-beta-regulated transcription factors that control pancreatic cell growth. Am J Physiol Gastrointest Liver Physiol 2000;278:513–521.Google Scholar
  61. 61.
    Tachibana I, Imoto M, Adjei PN, et al. Overexpression of the TGFbeta-regulated zinc finger encoding gene, TIEG, induces apoptosis in pancreatic epithelial cells. J Clin Invest 1997;99:2365–2374.PubMedCrossRefGoogle Scholar
  62. 62.
    Cook T, Gebelein B, Mesa K, et al. Molecular cloning and characterization of TIEG2 reveals a new subfamily of transforming growth factor-beta-inducible Sp1-like zinc finger encoding genes involved in the regulation of cell growth. J Biol Chem 1998;273:25,929–25,936.CrossRefGoogle Scholar
  63. 63.
    Ellenrieder V, Fernandez-Zapico M, Urrutia R. TGFβ-mediated signaling and transcriptional regulation in pancreatic development and cancer. Curr Opin Gastroenterol 2001;17:434–440.PubMedCrossRefGoogle Scholar
  64. 64.
    Zhang JS, Moncrieffe MC, Kaczynski J, et al. A conserved alpha-helical motif mediates the interaction of Sp1-like transcriptional repressors with the corepressor mSin3A. Mol Cell Biol 2001;21:5041–5049.PubMedCrossRefGoogle Scholar
  65. 65.
    Ellenrieder V, Zhang JS, Kaczynski J, et al. Signaling disrupts mSin3A binding to the Mad1-like Sin3 interacting domain of TIEG2, an Sp1-like repressor. EMBO J 2002;21:2451–2460.PubMedCrossRefGoogle Scholar
  66. 66.
    Ellenrieder V, Adler G, Gress TM. Invasion and metastasis in pancreatic cancer. Ann Oncol 1999;4:46–50.CrossRefGoogle Scholar
  67. 67.
    Oft M, Heider KH, Beug H. TGFbeta signaling is necessary for carcinoma cell invasiveness and metastasis. Curr Biol 1998;8:1243–1252.PubMedCrossRefGoogle Scholar
  68. 68.
    Oft M, Peli J, Rudaz C, et al. TGF-beta1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells. Genes Dev 1996;10:2462–2477.PubMedCrossRefGoogle Scholar
  69. 69.
    Miettinen PJ, Ebner R, Lopez AR, et al. TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors. J Cell Biol 1994;127:2021–2036.PubMedCrossRefGoogle Scholar
  70. 70.
    Malats N, Porta M, Corominas JM, et al. Ki-ras mutations in exocrine pancreatic cancer: association with clinicopathological characteristics and with tobacco and alcohol consumption. PANK-ras I Project Investigators. Int J Cancer 1997;17:661–667.CrossRefGoogle Scholar
  71. 71.
    Lemoine NR, Jain S, Hughes CM, et al. Ki-ras oncogene activation in preinvasive pancreatic cancer. Gastroenterology 1992;102:230–236.PubMedGoogle Scholar
  72. 72.
    Wagner M, Kleeff J, Friess H, et al. Enhanced expression of the type II transforming growth factor-beta receptor is associated with decreased survival in human pancreatic cancer. Pancreas 1999;19:370–376.PubMedCrossRefGoogle Scholar
  73. 73.
    Friess H, Yamanaka Y, Buchler M, et al. Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology 1993;105:1846–1856.PubMedGoogle Scholar
  74. 74.
    Geng MM, Ellenrieder V, Wallrapp C, et al. Use of representational difference analysis to study the effect of TGFβ on the expression profile of a pancreatic cancer cell line. Genes Chromosomes Cancer 1999;26:70–79.PubMedCrossRefGoogle Scholar
  75. 75.
    Janda E, Lehmann K, Killisch I, et al. Ras and TGFβ cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol 2002;156:299–313.PubMedCrossRefGoogle Scholar
  76. 76.
    Lehmann K, Janda E, Pierreux CE, et al. Raf induces TGF-beta production while blocking its apoptotic but not invasive responses: a mechanism leading to increased malignancy in epithelial cells. Genes Dev 2000; 14:2610–2622.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2002

Authors and Affiliations

  • Volker Ellenrieder
    • 1
  • Anita Buck
    • 1
  • Thomas M. Gress
    • 1
  1. 1.Department of Internal Medicine IUniversity of UlmUlmGermany

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