Alterations of Transforming Growth Factor-β Signaling in Squamous Cell Carcinomas

  • Wen Xie
  • Michael ReissEmail author


Genetic mouse models have clearly demonstrated that either activation or attenuation of the transforming growth factor-(TGF-)β and the TGF-β signaling pathway can have a major impact on either the genesis and/or the progression of squamous cell carcinomas (SCC) in the epidermis as well as in the head-and-neck region. In general, inactivation of the TGF-β signaling pathway in stratified squamous epithelium promotes the de novo emergence of benign papillomas that have the potential to progress to invasive SCC. On the other hand, activation of TGF-β signaling in established SCC clearly favors their progression to highly invasive and metastatic SCC. Furthermore, a large number of reports of structural and functional alterations in TGF-β pathway components in human SCC cell lines as well as tumor specimens strongly support the idea that this pathway in general, and TGF-β receptors in particular, play an important role in human SCC as well. Attenuation of either Type I TGF-β receptor (TβR)-I or -II signaling promotes SCC development in mice, and mutation and/or loss of expression of TβR-I or -II receptors are commonly seen in human SCC. Thus, approximately 10–15% of head and neck squamous cell carcinoma (HNSCC) display evidence of functional inactivation of TβR receptor signaling, as defined by the absence of pSmad2 and -3 or the presence of an inactivating TGFBR gene mutation. Patients with this tumor type appear to have a particularly favorable clinical outcome. On the other hand, in approximately 40–60% of human SCC TβR expression is reduced but not eliminated. In this context, exposure of the tumor cells to bioactive TGF-β will activate a proinvasive and -metastatic gene expression program, thereby conferring a worse clinical outcome. Therefore, we would like to propose that a structural and functional analysis of the TβR receptors potentially represents a powerful prognostic tool for the management of patients with SCC.


Squamous Cell Carcinoma Esophageal Squamous Cell Carcinoma Invasive Squamous Cell Carcinoma Cervical Squamous Cell Carcinoma Squamous Cell Carcinoma Cell Line 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.





Extracellular matrix


Epithelial-to-mesenchymal transition


Human head-and-neck squamous cell carcinoma(s)




Matrix metalloproteinase


Squamous cell carcinoma(s)


Single-strand conformation polymorphism

TGFBR1, Tgfbr-1

Type I TGF-β receptor gene

TGFBR2, Tgfbr-2

Type II TGF-β receptor gene


Transforming growth factor-β




Type I TGF-β receptor


Type II TGF-β receptor


  1. Andarawewa KL, Paupert J, Pal A, Barcellos-Hoff MH (2007) New rationales for using TGFbeta inhibitors in radiotherapy. Int J Radiat Biol 83:803–811PubMedCrossRefGoogle Scholar
  2. Andl CD, Fargnoli BB, Okawa T, Bowser M, Takaoka M, Nakagawa H, Klein-Szanto A, Hua X, Herlyn M, Rustgi AK (2006) Coordinated functions of E-cadherin and transforming growth factor beta receptor II in vitro and in vivo. Cancer Res 66:9878–9885PubMedCrossRefGoogle Scholar
  3. Ashcroft GS, Yang X, Glick AB, Weinstein M, Letterio JL, Mizel DE, Anzano M, Greenwell-Wild T, Wahl SM, Deng C, Roberts AB (1999) Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat Cell Biol 1:260–266PubMedCrossRefGoogle Scholar
  4. Bae DS, Blazanin N, Licata M, Lee J, Glick AB (2009) Tumor suppressor and oncogene actions of TGFbeta1 occur early in skin carcinogenesis and are mediated by Smad3. Mol Carcinog 48:441–453PubMedCrossRefGoogle Scholar
  5. Baldus SE, Schwarz E, Lohrey C, Zapatka M, Landsberg S, Hahn SA, Schmidt D, Dienes HP, Schmiegel WH, Schwarte-Waldhoff I (2005) Smad4 deficiency in cervical carcinoma cells. Oncogene 24:810–819PubMedCrossRefGoogle Scholar
  6. Barcellos-Hoff MH (1998) How do tissues respond to damage at the cellular level? The role of cytokines in irradiated tissues. Radiat Res 150:S109–S120PubMedCrossRefGoogle Scholar
  7. Bharathy S, Xie W, Yingling JM, Reiss M (2008) Cancer-associated transforming growth factor beta type II receptor gene mutant causes activation of bone morphogenic protein-Smads and invasive phenotype. Cancer Res 68:1656–1666PubMedCrossRefGoogle Scholar
  8. Bian Y, Terse A, Du J, Hall B, Molinolo A, Zhang P, Chen W, Flanders KC, Gutkind JS, Wakefield LM, Kulkarni AB (2009) Progressive tumor formation in mice with conditional deletion of TGF-beta signaling in head and neck epithelia is associated with activation of the PI3K/Akt pathway. Cancer Res 69:5918–5926PubMedCrossRefGoogle Scholar
  9. Biswas S, Guix M, Rinehart C, Dugger TC, Chytil A, Moses HL, Freeman ML, Arteaga CL (2007) Inhibition of TGF-beta with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression. J Clin Invest 117:1305–1313PubMedCrossRefGoogle Scholar
  10. Border WA, Noble NA (1994) Transforming growth factor ß in tissue fibrosis. N Engl J Med 331:1286–1292PubMedCrossRefGoogle Scholar
  11. Branton MH, Kopp JB (1999) TGF-beta and fibrosis. Microbes Infect 1:1349–1365PubMedCrossRefGoogle Scholar
  12. Chen T, Carter D, Garrigue-Antar L, Reiss M (1998) Transforming growth factor beta type I receptor kinase mutant associated with metastatic breast cancer. Cancer Res 58:4805–4810PubMedGoogle Scholar
  13. Chen T, de Vries EG, Hollema H, Yegen HA, Vellucci VF, Strickler HD, Hildesheim A, Reiss M (1999) Structural alterations of transforming growth factor-beta receptor genes in human cervical carcinoma. Int J Cancer 82:43–51PubMedCrossRefGoogle Scholar
  14. Chen T, Triplett J, Dehner B, Hurst B, Colligan B, Pemberton J, Graff JR, Carter JH (2001a) Transforming growth factor-beta receptor type i gene is frequently mutated in ovarian carcinomas. Cancer Res 61:4679–4682PubMedGoogle Scholar
  15. Chen T, Yan W, Wells RG, Rimm DL, McNiff J, Leffell D, Reiss M (2001b) Novel inactivating mutations of transforming growth factor-beta type I receptor gene in head-and-neck cancer metastases. Int J Cancer 93:653–661PubMedCrossRefGoogle Scholar
  16. Chu TY, Lai JS, Shen CY, Liu HS, Chao CF (1999) Frequent aberration of the transforming growth factor-beta receptor II gene in cell lines but no apparent mutation in pre-invasive and invasive carcinomas of the uterine cervix. Int J Cancer 80:506–510PubMedCrossRefGoogle Scholar
  17. Cui W, Fowlis DJ, Cousins FM, Duffie E, Bryson S, Balmain A, Akhurst RJ (1995) Concerted action of TGF-beta 1 and its type II receptor in control of epidermal homeostasis in transgenic mice. Genes Dev 9:945–955PubMedCrossRefGoogle Scholar
  18. Cui W, Fowlis DJ, Bryson S et al (1996) TGFß1 inhibits the formation of benign skin tumours but enhances progression to invasive spindle cell carcinnomas in transgenic mice. Cell 86:531–542PubMedCrossRefGoogle Scholar
  19. Daly AC, Randall RA, Hill CS (2008) TGF-{beta}-induced Smad1/5 phosphorylation in epithelial cells is mediated by novel receptor complexes and is essential for anchorage-independent growth. Mol Cell Biol 28:6889–6902PubMedCrossRefGoogle Scholar
  20. Dasgupta S, Bhattacharya-Chatterjee M, O’Malley BW Jr, Chatterjee SK (2005) Inhibition of NK cell activity through TGF-beta 1 by down-regulation of NKG2D in a murine model of head and neck cancer. J Immunol 175:5541–5550PubMedGoogle Scholar
  21. Dasgupta S, Bhattacharya-Chatterjee M, O’Malley BW Jr, Chatterjee SK (2006) Recombinant vaccinia virus expressing interleukin-2 invokes anti-tumor cellular immunity in an orthotopic murine model of head and neck squamous cell carcinoma. Mol Ther 13:183–193PubMedCrossRefGoogle Scholar
  22. Davies M, Robinson M, Smith E, Huntley S, Prime S, Paterson I (2005) Induction of an epithelial to mesenchymal transition in human immortal and malignant keratinocytes by TGF-beta1 involves MAPK, Smad and AP-1 signalling pathways. J Cell Biochem 95:918–931PubMedCrossRefGoogle Scholar
  23. D’Cruz CM, Moody SE, Master SR, Hartman JL, Keiper EA et al (2002) Persistent parity-induced changes in growth factors, TGF-beta3, and differentiation in the rodent mammary gland. Mol Endocrinol 16:2034–2051PubMedCrossRefGoogle Scholar
  24. De M, Yan W, de Jonge RR, Garrigue-Antar L, Vellucci VF, Reiss M (1998) Functional characterization of transforming growth factor beta type II receptor mutants in human cancer. Cancer Res 58:1986–1992PubMedGoogle Scholar
  25. Eisma RJ, Spiro JD, von Biberstein SE, Lindquist R, Kreutzer DL (1996) Decreased expression of transforming growth factor beta receptors on head and neck squamous cell carcinoma tumor cells. Am J Surg 172:641–645PubMedCrossRefGoogle Scholar
  26. El-Sherif AM, Seth R, Tighe PJ, Jenkins D (2000) Decreased synthesis and expression of TGF-beta1, beta2, and beta3 in epithelium of HPV 16-positive cervical precancer: a study by microdissection, quantitative RT-PCR, and immunocytochemistry. J Pathol 192:494–501PubMedCrossRefGoogle Scholar
  27. Ewan KB, Henshall-Powell RL, Ravani SA, Pajares MJ, Arteaga C, Warters R, Akhurst RJ, Barcellos-Hoff MH (2002) Transforming growth factor-beta1 mediates cellular response to DNA damage in situ. Cancer Res 62:5627–5631PubMedGoogle Scholar
  28. Faure E, Heisterkamp N, Groffen J, Kaartinen V (2000) Differential expression of TGF-beta isoforms during postlactational mammary gland involution. Cell Tissue Res 300:89–95PubMedGoogle Scholar
  29. Fukai Y, Fukuchi M, Masuda N, Osawa H, Kato H, Nakajima T, Kuwano H (2003) Reduced expression of transforming growth factor-beta receptors is an unfavorable prognostic factor in human esophageal squamous cell carcinoma. Int J Cancer 104:161–166PubMedCrossRefGoogle Scholar
  30. Fukuchi M, Fukai Y, Masuda N, Miyazaki T, Nakajima M, Sohda M, Manda R, Tsukada K, Kato H, Kuwano H (2002a) High-level expression of the Smad ubiquitin ligase Smurf2 correlates with poor prognosis in patients with esophageal squamous cell carcinoma. Cancer Res 62:7162–7165PubMedGoogle Scholar
  31. Fukuchi M, Masuda N, Miyazaki T, Nakajima M, Osawa H, Kato H, Kuwano H (2002b) Decreased Smad4 expression in the transforming growth factor-beta signaling pathway during progression of esophageal squamous cell carcinoma. Cancer 95:737–743PubMedCrossRefGoogle Scholar
  32. Fukuchi M, Nakajima M, Miyazaki T, Masuda N, Osawa H, Manda R, Tsukada K, Kato H, Kuwano H (2006) Lack of activated Smad2 in transforming growth factor-beta signaling is an unfavorable prognostic factor in patients with esophageal squamous cell carcinoma. J Surg Oncol 94:51–56PubMedCrossRefGoogle Scholar
  33. Garrigue-Antar L, Munoz-Antonia T, Antonia SJ, Gesmonde J, Vellucci VF, Reiss M (1995) Missense mutations of the transforming growth factor beta type II receptor in human head and neck squamous carcinoma cells. Cancer Res 55:3982–3987PubMedGoogle Scholar
  34. Garrigue-Antar L, Souza RF, Vellucci VF, Meltzer SJ, Reiss M (1996) Loss of transforming growth factor-beta type II receptor gene expression in primary human esophageal cancer. Lab Invest 75:263–272PubMedGoogle Scholar
  35. Ge R, Rajeev V, Subramanian G, Reiss KA, Liu D, Higgins L, Joly A, Dugar S, Chakravarty J, Henson M, McEnroe G, Schreiner G, Reiss M (2004) Selective inhibitors of type I receptor kinase block cellular transforming growth factor-beta signaling. Biochem Pharmacol 68:41–50PubMedCrossRefGoogle Scholar
  36. Glick AB, Kulkarni AB, Tennenbaum T, Hennings H, Flanders KC, O’Reilly M, Sporn MB, Karlsson S, Yuspa SH (1993) Loss of expression of transforming growth factor beta in skin and skin tumors is associated with hyperproliferation and a high risk for malignant conversion. Proc Natl Acad Sci USA 90:6076–6080PubMedCrossRefGoogle Scholar
  37. Glick AB, Lee MM, Darwiche N, Kulkarni AB, Karlsson S, Yuspa SH (1994) Targeted deletion of the TGF-beta 1 gene causes rapid progression to squamous cell carcinoma. Genes Dev 8:2429–2440PubMedCrossRefGoogle Scholar
  38. Glick AB, Weinberg WC, Wu IH, Quan W, Yuspa SH (1996) Transforming growth factor beta 1 suppresses genomic instability independent of a G1 arrest, p53, and Rb. Cancer Res 56:3645–3650PubMedGoogle Scholar
  39. Glick A, Popescu N, Alexander V, Ueno H, Bottinger E, Yuspa SH (1999) Defects in transforming growth factor-beta signaling cooperate with a Ras oncogene to cause rapid aneuploidy and malignant transformation of mouse keratinocytes. Proc Natl Acad Sci USA 96:14949–14954PubMedCrossRefGoogle Scholar
  40. Gold LI (1999) The role for transforming growth factor-beta (TGF-beta) in human cancer. Crit Rev Oncog 10:303–360PubMedGoogle Scholar
  41. Guasch G, Schober M, Pasolli HA, Conn EB, Polak L, Fuchs E (2007) Loss of TGFbeta signaling destabilizes homeostasis and promotes squamous cell carcinomas in stratified epithelia. Cancer Cell 12:313–327PubMedCrossRefGoogle Scholar
  42. Hagedorn H, Elbertzhagen A, Ruoss I, Sauer U, Nerlich AG (2001) Immunohistochemical analysis of major TGF-beta isoforms and their receptors in laryngeal carcinomas. Virchows Arch 439:531–539PubMedCrossRefGoogle Scholar
  43. Han G, Lu SL, Li AG, He W, Corless CL, Kulesz-Martin M, Wang XJ (2005) Distinct mechanisms of TGF-beta1-mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis. J Clin Invest 115:1714–1723PubMedCrossRefGoogle Scholar
  44. Herzog CR, Crist KA, Sabourin CL, Kelloff GJ, Boone CW, Stoner GD, You M (2001) Chromo­some 3p tumor-suppressor gene alterations in cervical carcinomas. Mol Carcinog 30:159–168PubMedCrossRefGoogle Scholar
  45. Hoot KE, Lighthall J, Han G, Lu SL, Li A, Ju W, Kulesz-Martin M, Bottinger E, Wang XJ (2008) Keratinocyte-specific Smad2 ablation results in increased epithelial-mesenchymal transition during skin cancer formation and progression. J Clin Invest 118:2722–2732PubMedGoogle Scholar
  46. Hummer BT, Bartlett C, Henry E, Weissman BE (2003) Expression of Smad4 in the FaDu cell line partially restores TGF-beta growth inhibition but is not sufficient to regulate fibronectin expression or suppress tumorigenicity. J Cell Physiol 194:289–302PubMedCrossRefGoogle Scholar
  47. Huntley SP, Davies M, Matthews JB, Thomas G, Marshall J, Robinson CM, Eveson JW, Paterson IC, Prime SS (2004) Attenuated type II TGF-beta receptor signalling in human malignant oral keratinocytes induces a less differentiated and more aggressive phenotype that is associated with metastatic dissemination. Int J Cancer 110:170–176PubMedCrossRefGoogle Scholar
  48. Janda E, Lehmann K, Killisch I, Jechlinger M, Herzig M, Downward J, Beug H, Grunert S (2002) Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol 156:299–313PubMedCrossRefGoogle Scholar
  49. Kang SH, Bang YJ, Im YH, Yang HK, Lee DA, Lee HY, Lee HS, Kim NK, Kim SJ (1999) Transcriptional repression of the transforming growth factor-beta type I receptor gene by DNA methylation results in the development of TGF-beta resistance in human gastric cancer [in process citation]. Oncogene 18:7280–7286PubMedCrossRefGoogle Scholar
  50. Kang JS, Saunier EF, Akhurst RJ, Derynck R (2008) The type I TGF-beta receptor is covalently modified and regulated by sumoylation. Nat Cell Biol 10:654–664PubMedCrossRefGoogle Scholar
  51. Kareddula A, Zachariah E, Notterman D, Reiss M (2008) Transforming growth factor-β signaling strength determines target gene expression profile in human keratinocytes. J Epithel Biol Pharmacol 1:40–94CrossRefGoogle Scholar
  52. Kim SK, Fan Y, Papadimitrakopoulou V, Clayman G, Hittelman WN, Hong WK, Lotan R, Mao L (1996) DPC4, a candidate tumor suppressor gene, is altered infrequently in head and neck squamous cell carcinoma. Cancer Res 56:2519–2521PubMedGoogle Scholar
  53. Kirshner J, Jobling MF, Pajares MJ, Ravani SA, Glick AB, Lavin MJ, Koslov S, Shiloh Y, Barcellos-Hoff MH (2006) Inhibition of transforming growth factor-beta1 signaling attenuates ataxia telangiectasia mutated activity in response to genotoxic stress. Cancer Res 66:10861–10869PubMedCrossRefGoogle Scholar
  54. Kloth JN, Kenter GG, Spijker HS, Uljee S, Corver WE, Jordanova ES, Fleuren GJ, Gorter A (2008) Expression of Smad2 and Smad4 in cervical cancer: absent nuclear Smad4 expression correlates with poor survival. Mod Pathol 21:866–875PubMedCrossRefGoogle Scholar
  55. Knobloch TJ, Lynch MA, Song H, DeGroff VL, Casto BC, Adams EM, Alam KY, Lang JC, Schuller DE, Weghorst CM (2001) Analysis of TGF-beta type I receptor for mutations and polymorphisms in head and neck cancers. Mutat Res 479:131–139PubMedGoogle Scholar
  56. Konig HG, Kogel D, Rami A, Prehn JH (2005) TGF-{beta}1 activates two distinct type I receptors in neurons: implications for neuronal NF-{kappa}B signaling. J Cell Biol 168:1077–1086PubMedCrossRefGoogle Scholar
  57. Lebrin F, Deckers M, Bertolino P, Ten Dijke P (2005) TGF-beta receptor function in the endothelium. Cardiovasc Res 65:599–608PubMedCrossRefGoogle Scholar
  58. Lehmann K, Janda E, Pierreux CE, Rytomaa M, Schulze A, McMahon M, Hill CS, Beug H, Downward J (2000) Raf induces TGFbeta production while blocking its apoptotic but not invasive responses: a mechanism leading to increased malignancy in epithelial cells. Genes Dev 14:2610–2622PubMedCrossRefGoogle Scholar
  59. Li MO, Flavell RA (2008) TGF-beta: a master of all T cell trades. Cell 134:392–404PubMedCrossRefGoogle Scholar
  60. Liss C, Fekete MJ, Hasina R, Lam CD, Lingen MW (2001) Paracrine angiogenic loop between head-and-neck squamous-cell carcinomas and macrophages. Int J Cancer 93:781–785PubMedCrossRefGoogle Scholar
  61. Liu IM, Schilling SH, Knouse KA, Choy L, Derynck R, Wang XF (2009) TGFbeta-stimulated Smad1/5 phosphorylation requires the ALK5 L45 loop and mediates the pro-migratory TGFbeta switch. EMBO J 28:88–98PubMedCrossRefGoogle Scholar
  62. Logullo AF, Nonogaki S, Miguel RE, Kowalski LP, Nishimoto IN, Pasini FS, Federico MH, Brentani RR, Brentani MM (2003) Transforming growth factor beta1 (TGFbeta1) expression in head and neck squamous cell carcinoma patients as related to prognosis. J Oral Pathol Med 32:139–145PubMedCrossRefGoogle Scholar
  63. Lu SL, Reh D, Li AG, Woods J, Corless CL, Kulesz-Martin M, Wang XJ (2004) Overexpression of transforming growth factor beta1 in head and neck epithelia results in inflammation, angiogenesis, and epithelial hyperproliferation. Cancer Res 64:4405–4410PubMedCrossRefGoogle Scholar
  64. Lu SL, Herrington H, Reh D, Weber S, Bornstein S, Wang D, Li AG, Tang CF, Siddiqui Y, Nord J, Andersen P, Corless CL, Wang XJ (2006) Loss of transforming growth factor-beta type II receptor promotes metastatic head-and-neck squamous cell carcinoma. Genes Dev 20:1331–1342PubMedCrossRefGoogle Scholar
  65. Maliekal TT, Antony ML, Nair A, Paulmurugan R, Karunagaran D (2003) Loss of expression, and mutations of Smad 2 and Smad 4 in human cervical cancer. Oncogene 22:4889–4897PubMedCrossRefGoogle Scholar
  66. Massague J (2008) TGFbeta in cancer. Cell 134:215–230PubMedCrossRefGoogle Scholar
  67. Mincione G, Di Marcantonio MC, Artese L, Vianale G, Piccirelli A, Piccirilli M, Perrotti V, Rubini C, Piattelli A, Muraro R (2008) Loss of expression of TGF-beta1, TbetaRI, and TbetaRII correlates with differentiation in human oral squamous cell carcinomas. Int J Oncol 32:323–331PubMedGoogle Scholar
  68. Muro-Cacho CA, Anderson M, Cordero J, Munoz-Antonia T (1999) Expression of transforming growth factor beta type II receptors in head and neck squamous cell carcinoma. Clin Cancer Res 5:1243–1248PubMedGoogle Scholar
  69. Muro-Cacho CA, Rosario-Ortiz K, Livingston S, Munoz-Antonia T (2001) Defective transforming growth factor beta signaling pathway in head and neck squamous cell carcinoma as evidenced by the lack of expression of activated Smad2. Clin Cancer Res 7:1618–1626PubMedGoogle Scholar
  70. Natsugoe S, Xiangming C, Matsumoto M, Okumura H, Nakashima S, Sakita H, Ishigami S, Baba M, Takao S, Aikou T (2002) Smad4 and transforming growth factor beta1 expression in patients with squamous cell carcinoma of the esophagus. Clin Cancer Res 8:1838–1842PubMedGoogle Scholar
  71. Nerlich AG, Sauer U, Ruoss I, Hagedorn HG (2003) High frequency of TGF-beta-receptor-II mutations in microdissected tissue samples from laryngeal squamous cell carcinomas. Lab Invest 83:1241–1251PubMedCrossRefGoogle Scholar
  72. Oft M, Akhurst RJ, Balmain A (2002) Metastasis is driven by sequential elevation of H-ras and Smad2 levels. Nat Cell Biol 4:487–494PubMedCrossRefGoogle Scholar
  73. Osawa H, Shitara Y, Shoji H, Mogi A, Kuwano H, Hagiwara K, Takenoshita S (2000) Mutation analysis of transforming growth factor beta type II receptor, Smad2, Smad3 and Smad4 in esophageal squamous cell carcinoma. Int J Oncol 17:723–728PubMedGoogle Scholar
  74. Osawa H, Nakajima M, Kato H, Fukuchi M, Kuwano H (2004) Prognostic value of the expression of Smad6 and Smad7, as inhibitory Smads of the TGF-beta superfamily, in esophageal squamous cell carcinoma. Anticancer Res 24:3703–3709PubMedGoogle Scholar
  75. Pardali E, ten Dijke P (2009) Transforming growth factor-beta signaling and tumor angiogenesis. Front Biosci 14:4848–4861PubMedGoogle Scholar
  76. Paterson IC, Matthews JB, Huntley S, Robinson CM, Fahey M, Parkinson EK, Prime SS (2001) Decreased expression of TGF-beta cell surface receptors during progression of human oral squamous cell carcinoma. J Pathol 193:458–467PubMedCrossRefGoogle Scholar
  77. Peng SB, Yan L, Xia X, Watkins SA, Brooks HB, Beight D, Herron DK, Jones ML, Lampe JW, McMillen WT, Mort N, Sawyer JS, Yingling JM (2005) Kinetic characterization of novel pyrazole TGF-beta receptor I kinase inhibitors and their blockade of the epithelial-mesenchymal transition. Biochemistry 44:2293–2304PubMedCrossRefGoogle Scholar
  78. Portella G, Cumming SA, Liddell J, Cui W, Ireland H, Akhurst RJ, Balmain A (1998) Transforming growth factor beta is essential for spindle cell conversion of mouse skin carcinoma in vivo: implications for tumor invasion. Cell Growth Differ 9:393–404PubMedGoogle Scholar
  79. Prime SS, Eveson JW, Stone AM, Huntley SP, Davies M, Paterson IC, Robinson CM (2004) Metastatic dissemination of human malignant oral keratinocyte cell lines following orthotopic transplantation reflects response to TGF-beta 1. J Pathol 203:927–932PubMedCrossRefGoogle Scholar
  80. Qiu W, Schonleben F, Li X, Su GH (2007) Disruption of transforming growth factor beta-Smad signaling pathway in head and neck squamous cell carcinoma as evidenced by mutations of SMAD2 and SMAD4. Cancer Lett 245:163–170PubMedCrossRefGoogle Scholar
  81. Reiss M, Sartorelli AC (1987) Regulation of growth and differentiation of human keratinocytes by type beta transforming growth factor and epidermal growth factor. Cancer Res 47:6705–6709PubMedGoogle Scholar
  82. Reiss M, Stash EB (1990) High frequency of resistance of human squamous carcinoma cells to the anti-proliferative action of transforming growth factor beta. Cancer Commun 2:363–369PubMedGoogle Scholar
  83. Reiss M, Pitman SW, Sartorelli AC (1985) Modulation of the terminal differentiation of human squamous carcinoma cells in vitro by all-trans-retinoic acid. J Natl Cancer Inst 74:1015–1023PubMedGoogle Scholar
  84. Reiss M, Santoro V, de Jonge RR, Vellucci VF (1997) Transfer of chromosome 18 into human head and neck squamous carcinoma cells: evidence for tumor suppression by Smad4/DPC4. Cell Growth Differ 8:407–415PubMedGoogle Scholar
  85. Riggins GJ, Kinzler KW, Vogelstein B, Thiagalingam S (1997) Frequency of Smad gene mutations in human cancers. Cancer Res 57:2578–2580PubMedGoogle Scholar
  86. Roberts AB, Sporn MB (1993) Physiological actions and clinical applications of transforming growth factor-beta (TGF-beta). Growth Factors 8:1–9PubMedCrossRefGoogle Scholar
  87. Roberts AB, Piek E, Bottinger EP, Ashcroft G, Mitchell JB, Flanders KC (2001) Is Smad3 a major player in signal transduction pathways leading to fibrogenesis? Chest 120:43S–47SPubMedCrossRefGoogle Scholar
  88. Roberts AB, Tian F, Byfield SD, Stuelten C, Ooshima A, Saika S, Flanders KC (2006) Smad3 is key to TGF-beta-mediated epithelial-to-mesenchymal transition, fibrosis, tumor suppression and metastasis. Cytokine Growth Factor Rev 17:19–27PubMedCrossRefGoogle Scholar
  89. Roop DR, Lowy DR, Tambourin PE, Strickland J, Harper JR, Balaschak M, Spangler EF, Yuspa SH (1986) An activated Harvey ras oncogene produces benign tumours on mouse epidermal tissue. Nature 323:822–824PubMedCrossRefGoogle Scholar
  90. Schipper JH, Frixen UH, Behrens J, Unger A, Jahnke K, Birchmeier W (1991) E-cadherin expression in squamous cell carcinomas of head and neck: inverse correlation with tumor dedifferentiation and lymph node metastasis. Cancer Res 51:6328–6337PubMedGoogle Scholar
  91. Schutte M, Hruban RH, Hedrick L, Cho KR, Nadasdy GM, Weinstein CL, Bova GS, Isaacs WB, Cairns P, Nawroz H, Sidransky D, Casero RA Jr, Meltzer PS, Hahn SA, Kern SE (1996) DPC4 gene in various tumor types. Cancer Res 56:2527–2530PubMedGoogle Scholar
  92. Sterner-Kock A, Thorey IS, Koli K, Wempe F, Otte J, Bangsow T, Kuhlmeier K, Kirchner T, Jin S, Keski-Oja J, von Melchner H (2002) Disruption of the gene encoding the latent transforming growth factor-beta binding protein 4 (LTBP-4) causes abnormal lung development, cardiomyopathy, and colorectal cancer. Genes Dev 16:2264–2273PubMedCrossRefGoogle Scholar
  93. Tanaka S, Mori M, Mafune K, Ohno S, Sugimachi K (2000) A dominant negative mutation of transforming growth factor-beta receptor type II gene in microsatellite stable oesophageal carcinoma [in process citation]. Br J Cancer 82:1557–1560PubMedCrossRefGoogle Scholar
  94. Torng PL, Chan WY, Lin CT, Huang SC (2003) Decreased expression of human papillomavirus E2 protein and transforming growth factor-beta1 in human cervical neoplasia as an early marker in carcinogenesis. J Surg Oncol 84:17–23PubMedCrossRefGoogle Scholar
  95. Valcourt U, Kowanetz M, Niimi H, Heldin CH, Moustakas A (2005) TGF-beta and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. Mol Biol Cell 16:1987–2002PubMedCrossRefGoogle Scholar
  96. Wan YY, Flavell RA (2008) TGF-beta and regulatory T cell in immunity and autoimmunity. J Clin Immunol 28:647–659PubMedCrossRefGoogle Scholar
  97. Wang D, Song H, Evans JA, Lang JC, Schuller DE, Weghorst CM (1997a) Mutation and downregulation of the transforming growth factor beta type II receptor gene in primary squamous cell carcinomas of the head and neck. Carcinogenesis 18:2285–2290PubMedCrossRefGoogle Scholar
  98. Wang XJ, Greenhalgh DA, Bickenbach JR, Jiang A, Bundman DS, Krieg T, Derynck R, Roop DR (1997b) Expression of a dominant-negative type II transforming growth factor beta (TGF-beta) receptor in the epidermis of transgenic mice blocks TGF-beta-mediated growth inhibition. Proc Natl Acad Sci USA 94:2386–2391PubMedCrossRefGoogle Scholar
  99. Wang XJ, Liefer KM, Tsai S, O’Malley BW, Roop DR (1999) Development of gene-switch transgenic mice that inducibly express transforming growth factor beta1 in the epidermis. Proc Natl Acad Sci USA 96:8483–8488PubMedCrossRefGoogle Scholar
  100. Wang X, Sun W, Bai J, Ma L, Yu Y, Geng J, Qi J, Shi Z, Fu S (2009) Growth inhibition induced by transforming growth factor-beta1 in human oral squamous cell carcinoma. Mol Biol Rep 36:861–869PubMedCrossRefGoogle Scholar
  101. Wieser R, Attisano L, Wrana JL, Massagué J (1993) Signaling activity of transforming growth factor ß type II receptors lacking specific domains in the cytoplasmic region. Mol Cell Biol 13:7239–7247PubMedGoogle Scholar
  102. Wrzesinski SH, Wan YY, Flavell RA (2007) Transforming growth factor-{beta} and the immune response: implications for anticancer therapy. Clin Cancer Res 13:5262–5270PubMedCrossRefGoogle Scholar
  103. Xie W, Aisner S, Baredes S, Sreepada G, Shah R, Chen W, Foran DF, Reiss M (submitted) TGFß signaling in human head-&-neck squamous carcinoma: distinct prognostic significance of receptor and post-receptor pathway alterations. Clin Cancer ResGoogle Scholar
  104. Xie W, Bharathy S, Kim D, Haffty BG, Rimm DL, Reiss M (2003) Frequent alterations of Smad signaling in human head and neck squamous cell carcinomas: a tissue microarray analysis. Oncol Res 14:61–73PubMedGoogle Scholar
  105. Xu XC, Mitchell MF, Silva E, Jetten A, Lotan R (1999) Decreased expression of retinoic acid receptors, transforming growth factor beta, involucrin, and cornifin in cervical intraepithelial neoplasia. Clin Cancer Res 5:1503–1508PubMedGoogle Scholar
  106. Xu J, Lamouille S, Derynck R (2009) TGF-beta-induced epithelial to mesenchymal transition. Cell Res 19:156–172PubMedCrossRefGoogle Scholar
  107. Yan W, Vellucci VF, Reiss M (2000) Smad protein expression and activation in transforming growth factor-beta refractory human squamous cell carcinoma cells. Oncol Res 12:157–167PubMedGoogle Scholar
  108. Yang YA, Tang B, Robinson G, Hennighausen L, Brodie SG, Deng CX, Wakefield LM (2002) Smad3 in the mammary epithelium has a nonredundant role in the induction of apoptosis, but not in the regulation of proliferation or differentiation by transforming growth factor-beta. Cell Growth Differ 13:123–130PubMedGoogle Scholar
  109. Zavadil J, Bitzer M, Liang D, Yang YC, Massimi A, Kneitz S, Piek E, Bottinger EP (2001) Genetic programs of epithelial cell plasticity directed by transforming growth factor-beta. Proc Natl Acad Sci USA 98:6686–6691PubMedCrossRefGoogle Scholar
  110. Zavadil J, Cermak L, Soto-Nieves N, Bottinger EP (2004) Integration of TGF-beta/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. EMBO J 23:1155–1165PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Division of Medical Oncology, Department of Internal Medicine, The Cancer Institute of New JerseyUMDNJ-Robert Wood Johnson Medical SchoolNew BrunswickUSA

Personalised recommendations