Advertisement

TGF-β Signaling Alterations in Neoplastic and Stromal Cells

  • Qinghua Zeng
  • Boris Pasche
Chapter
Part of the Cancer Genetics book series (CANGENETICS)

Abstract

Transforming growth factor beta (TGF-β) plays an central role in cell homeostasis and inherited mutations in the TGFB1 gene cause Camurati-Engelmann disease, a condition characterized by hyperostosis and sclerosis of the diaphyses of long bones (Janssens et al., 2000; Kinoshita et al., 2000). However, mutations in the TGFB genes do not appear to occur in cancer. In contrast, type I and II TGF-β receptors and their downstream effectors SMADs are often targeted by oncogenic events.

Keywords

Colorectal Cancer Cdk4 Expression TGFB Gene Human Colorectal Cancer Cell Line Adjacent Epithelial Cell 
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.

Notes

Acknowledgments

Supported by grants from CA112520, CA108741 from the NCI and AR048098-070007 from the NIH.

References

  1. Ashcroft GS, Yang X, Glick AB, Weinstein M, Letterio JJ, Mizel DE, Anzano M, Greenwell-Wild T, Wahl SM, Deng CX, Roberts AB. 1999. Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat Cell Biol 1:260–266.PubMedCrossRefGoogle Scholar
  2. Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S, Washington MK, Neilson EG, Moses HL. 2004. TGF-{beta} Signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303:848–851.PubMedCrossRefGoogle Scholar
  3. Bian Y, Knobloch TJ, Sadim M, Kaklamani V, Raji A, Yang GY, Weghorst CM, Pasche B. 2007. Somatic acquisition of TGFBR1*6A by epithelial and stromal cells during head and neck and colon cancer development. Hum Mol Genet 16:3128–3135.PubMedCrossRefGoogle Scholar
  4. Biswas S, Chytil A, Washington K, Romero-Gallo J, Gorska AE, Wirth PS, Gautam S, Moses HL, Grady WM. 2004. Transforming growth factor {beta} receptor Type II Inactivation promotes the establishment and progression of colon cancer. Cancer Res 64:4687–4692.PubMedCrossRefGoogle Scholar
  5. Bogdan C, Paik J, Vodovotz Y, Nathan C. 1992. Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10. J Biol Chem 267:23301–23308.PubMedGoogle Scholar
  6. Broderick P, Carvajal-Carmona L, Pittman AM, Webb E, Howarth K, Rowan A, Lubbe S, Spain S, Sullivan K, Fielding S, Jaeger E, Vijayakrishnan J, Kemp Z, Gorman M, Chandler I, Papaemmanuil E, Penegar S, Wood W, Sellick G, Qureshi M, Teixeira A, Domingo E, Barclay E, Martin L, Sieber O, Kerr D, Gray R, Peto J, Cazier JB, Tomlinson I, Houlston RS. 2007. A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. Nat Genet 39:1315–1317.PubMedCrossRefGoogle Scholar
  7. Cerutti JM, Ebina KN, Matsuo SE, Martins L, Maciel RM, Kimura ET. 2003. Expression of Smad4 and Smad7 in human thyroid follicular carcinoma cell lines. J Endocrinol Invest 26:516–521PubMedGoogle Scholar
  8. Cheng N, Bhowmick NA, Chytil A, Gorksa AE, Brown KA, Muraoka R, Arteaga CL, Neilson EG, Hayward SW, Moses HL. 2005. Loss of TGF-beta type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-alpha-, MSP- and HGF-mediated signaling networks. Oncogene 24:5053–5068.PubMedCrossRefGoogle Scholar
  9. Coussens LM and Werb Z. 2002. Inflammation and cancer. Nature 420:860–867.PubMedCrossRefGoogle Scholar
  10. Datto MB, Li Y, Panus JF, Howe DJ, Xiong Y, Wang XF. 1995. Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc Natl Acad Sci U S A 92:5545–5549.PubMedCrossRefGoogle Scholar
  11. Derynck R and Akhurst RJ. 2007. Differentiation plasticity regulated by TGF-[beta] family proteins in development and disease. Nat Cell Biol 9:1000–1004.PubMedCrossRefGoogle Scholar
  12. Derynck R, Akhurst RJ, Balmain A. 2001. TGF-beta signaling in tumor suppression and cancer progression. Nat Genet 29:117–129.PubMedCrossRefGoogle Scholar
  13. Dowdy SC, Mariani A, Reinholz MM, Keeney GL, Spelsberg TC, Podratz KC, Janknecht R. 2005. Overexpression of the TGF-beta antagonist Smad7 in endometrial cancer. Gynecol Oncol 96:368–373.PubMedCrossRefGoogle Scholar
  14. Ebisawa T, Fukuchi M, Murakami G, Chiba T, Tanaka K, Imamura T, Miyazono K. 2001. Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation. J Biol Chem 276:12477–12480.PubMedCrossRefGoogle Scholar
  15. 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 104:161–166.PubMedCrossRefGoogle Scholar
  16. 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 75:263–272.PubMedGoogle Scholar
  17. Gobbi H, Arteaga CL, Jensen RA, Simpson JF, Dupont WD, Olson SJ, Schuyler PA, Plummer WD, Page DL, david.page@mcmail.vanderbilt.edu, Benign bd, Ductal carcinoma is, Immunohistochemistry, Invasive mc, Transforming growth factor beta receptors. 2000. Loss of expression of transforming growth factor beta type II receptor correlates with high tumour grade in human breast in-situ and invasive carcinomas. Histopathology 36:168–177.PubMedCrossRefGoogle Scholar
  18. Gorelik L, Flavell RA. 2002. Transforming growth factor-beta in T-cell biology. Nat Rev Immunol 2:46–53.PubMedCrossRefGoogle Scholar
  19. Goumans MJ, Valdimarsdottir G, Itoh S, Lebrin F, Larsson J, Mummery C, Karlsson S, ten Dijke P. 2003. Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGF[beta]/ALK5 signaling. Mol Cell 12:817–828.PubMedCrossRefGoogle Scholar
  20. Grady WM and Markowitz S. 2000. Genomic instability and colorectal cancer. Current Opinion in Gastroenterology 16:62–67.PubMedCrossRefGoogle Scholar
  21. Grady WM and Markowitz SD. 2002. Genetic and epigenetic alterations in colon cancer. Annu Rev Genom Hum Genet 3:101–128.CrossRefGoogle Scholar
  22. Grady WM, Myeroff LL, Swinler SE, Rajput A, Thiagalingam S, Lutterbaugh JD, Neumann A, Brattain MG, Chang J, Kim SJ, Kinzler KW, Vogelstein B, Willson JK, Markowitz S. 1999. Mutational inactivation of transforming growth factor beta receptor type II in microsatellite stable colon cancers. Cancer Res 59:320–324.PubMedGoogle Scholar
  23. Grady WM, Willis JE, Trobridge P, Romero-Gallo J, Munoz N, Olechnowicz J, Ferguson K, Gautam S, Markowitz SD. 2006. Proliferation and Cdk4 expression in microsatellite unstable colon cancers with TGFBR2 mutations. Int J Cancer 118:600–608.PubMedCrossRefGoogle Scholar
  24. Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE. 1996. Dpc4, a candidate tumor suppressor gene at human chromosome 18q21.1. [see comments]. Science 271:350–353.PubMedCrossRefGoogle Scholar
  25. Howe JR, Roth S, Ringold JC, Summers RW, Jarvinen HJ, Sistonen P, Tomlinson IP, Houlston RS, Bevan S, Mitros FA, Stone EM, Aaltonen LA. 1998. Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science 280:1086–1088.PubMedCrossRefGoogle Scholar
  26. Ilyas M, Efstathiou JA, Straub J, Kim HC, Bodmer WF. 1999. Transforming growth factor beta stimulation of colorectal cancer cell lines: Type II receptor bypass and changes in adhesion molecule expression. Proc 96:3087–3091.Google Scholar
  27. Imamura T, Takase M, Nishihara A, Oeda E, Hanai J, Kawabata M, Miyazono K. 1997. Smad6 inhibits signalling by the tgf-beta superfamily. Nature 389:622–626.PubMedCrossRefGoogle Scholar
  28. Jaffee EM, Hruban RH, Canto M, Kern SE. 2002. Focus on pancreas cancer. Cancer Cell 2: 25–28.PubMedCrossRefGoogle Scholar
  29. Janssens K, Gershoni-Baruch R, Guanabens N, Migone N, Ralston S, Bonduelle M, Lissens W, Van ML, Vanhoenacker F, Verbruggen L, Van HW. 2000. Mutations in the gene encoding the latency-associated peptide of TGF-beta 1 cause Camurati-Engelmann disease. Nat Genet 26:273–275.PubMedCrossRefGoogle Scholar
  30. Joseph H, Gorska AE, Sohn P, Moses HL, Serra R. 1999. Overexpression of a kinase-deficient transforming growth factor-beta type II receptor in mouse mammary stroma results in increased epithelial branching. Molecular Biology of the Cell 10:1221–1234.PubMedGoogle Scholar
  31. Kim IY, Ahn HJ, Zelner DJ, Shaw JW, Lang S, Kato R, Oefelein MG, Miyazono K, Nemeth JA, Kozlowski JM, Lee C. 1996. Loss of expression of transforming growth factor beta type i and type ii receptors correlates with tumor grade in human prostate cancer. Clin Cancer Res 2:1255–1261.PubMedGoogle Scholar
  32. Kim IY, Ahn HJ, Lang S, Oefelein MG, Oyasu R, Kozlowski JM, Lee C. 1998. Loss of expression of transforming growth factor-beta receptors is associated with poor prognosis in prostate cancer patients. Clini Cancer Res 4:1625–1630.Google Scholar
  33. Kim WS, Park C, Jung YS, Kim HS, Han JH, Park CH, Kim K, Kim J, Shim YM, Park K. 1999. Reduced transforming growth factor-beta type II receptor (TGF-beta RII) expression in adenocarcinoma of the lung. Anticancer Res 19:301–306.PubMedGoogle Scholar
  34. Kim BG, Li C, Qiao W, Mamura M, Kasperczak B, Anver M, Wolfraim L, Hong S, Mushinski E, Potter M, Kim SJ, Fu XY, Deng C, Letterio JJ. 2006. Smad4 signalling in T cells is required for suppression of gastrointestinal cancer. Nature 441:1015–1019.PubMedCrossRefGoogle Scholar
  35. Kinoshita A, Saito T, Tomita H, Makita Y, Yoshida K, Ghadami M, Yamada K, Kondo S, Ikegawa S, Nishimura G, Fukushima Y, Nakagomi T, Saito H, Sugimoto T, Kamegaya M, Hisa K, Murray JC, Taniguchi N, Niikawa N, Yoshiura K. 2000. Domain-specific mutations in TGFB1 result in Camurati-Engelmann disease. Nat Genet 26:19–20.PubMedCrossRefGoogle Scholar
  36. Kirkbride KC, Blobe GC. 2003. Inhibiting the TGF-beta signalling pathway as a means of cancer immunotherapy. Expert Opin Biol Ther 3:251–261.PubMedGoogle Scholar
  37. Ku JL, Park SH, Yoon KA, Shin YK, Kim KH, Choi JS, Kang HC, Kim IJ, Han IO, Park JG. 2007. Genetic alterations of the TGF-beta signaling pathway in colorectal cancer cell lines: A novel mutation in Smad3 associated with the inactivation of TGF-beta-induced transcriptional activation. Cancer Lett 247:283–292.PubMedCrossRefGoogle Scholar
  38. Letterio JJ. 2005. TGF-beta signaling in T cells: Roles in lymphoid and epithelial neoplasia. Oncog 24:5701–5712.CrossRefGoogle Scholar
  39. Levy L, Hill CS. 2005. Smad4 dependency defines two classes of transforming growth factor {beta} (TGF-{beta}) target genes and distinguishes TGF-{beta}-induced epithelial-mesenchymal transition from its antiproliferative and migratory responses. Mol Cell Biol 25:8108–8125.PubMedCrossRefGoogle Scholar
  40. Lynch MA, Nakashima R, Song H, Degroff VL, Wang D, Enomoto T, Weghorst CM. 1998. Mutational analysis of the transforming growth factor beta receptor type II gene in human ovarian carcinoma. Cancer Res 58:4227–4232.PubMedGoogle Scholar
  41. Maggio-Price L, Treuting P, Zeng W, Tsang M, Bielefeldt-Ohmann H, Iritani BM. 2006. Helicobacter Infection Is Required for Inflammation and Colon Cancer in Smad3-Deficient Mice. Cancer Res 66:828–838.PubMedCrossRefGoogle Scholar
  42. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA. 2008. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133:704–715.PubMedCrossRefGoogle Scholar
  43. Massague J. 1998. TGF-beta signal transduction. Annu Rev Biochem 67:753–791.PubMedCrossRefGoogle Scholar
  44. Massague J. 2008. TGF-beta in Cancer. Cell 134:215–230.PubMedCrossRefGoogle Scholar
  45. Massague J, Blain SW, Lo RS. 2000. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell 103:295–309.PubMedCrossRefGoogle Scholar
  46. Massague J, Seoane J, Wotton D. 2005. Smad transcription factors. Genes Dev 19:2783–2810.PubMedCrossRefGoogle Scholar
  47. Matsuzaki K. 2006. Smad3 phosphoisoform-mediated signaling during sporadic human colorectal carcinogenesis. Histol Histopathol 21:645–662.PubMedGoogle Scholar
  48. Matsuzaki K, Seki T, Okazaki K. 2006. TGF-beta during human colorectal carcinogenesis: The shift from epithelial to mesenchymal signaling. Inflammopharmacology 14:198–203.PubMedCrossRefGoogle Scholar
  49. Mishra L, Shetty K, Tang Y, Stuart A, Byers SW. 2005. The role of TGF-beta and Wnt signaling in gastrointestinal stem cells and cancer. Oncog 24:5775–5789.CrossRefGoogle Scholar
  50. Moses HL, Robinson RA. 1982. Growth factors, growth factor receptors, and cell cycle control mechanisms in chemically transformed cells. Fed Proc 41:3008–3011.PubMedGoogle Scholar
  51. Nakamura K, Kitani A, Strober W. 2001. Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med 194:629–644.PubMedCrossRefGoogle Scholar
  52. Ozdamar B, Bose R, Barrios-Rodiles M, Wang HR, Zhang Y, Wrana JL. 2005. Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science 307:1603–1609.PubMedCrossRefGoogle Scholar
  53. Pasche B, Kaklamani VG, Hou N, Young T, Rademaker A, Peterlongo P, Ellis N, Offit K, Caldes T, Reiss M, Zheng T. 2004. TGFBR1*6A and cancer: A meta-analysis of 12 case-control studies. J Clin Oncol 22:756–758.PubMedCrossRefGoogle Scholar
  54. Pasche B, Knobloch TJ, Bian Y, Liu J, Phukan S, Rosman D, Kaklamani V, Baddi L, Siddiqui FS, Frankel W, Prior TW, Schuller DE, Agrawal A, Lang J, Dolan ME, Vokes EE, Lane WS, Huang CC, Caldes T, Di Cristofano A, Hampel H, Nilsson I, von Heijne G, Fodde R, Murty VVVS, de la Chapelle A, Weghorst CM. 2005. Somatic acquisition and signaling of TGFBR1*6A in cancer. JAMA 294:1634–1646.PubMedCrossRefGoogle Scholar
  55. Riedl E, Strobl H, Majdic O, Knapp W. 1997. Tgf-beta-1 promotes in vitro generation of dendritic cells by protecting progenitor cells from apoptosis. J Immunol 158:1591–1597.PubMedGoogle Scholar
  56. Roberts AB and Wakefield LM. 2003. The two faces of transforming growth factor {beta} in carcinogenesis. PNAS 100:8621.PubMedCrossRefGoogle Scholar
  57. Roberts AB, Lamb LC, Newton DL, Sporn MB, De Larco JE, Todaro GJ. 1980. Transforming growth factors: isolation of polypeptides from virally and chemically transformed cells by acid/ethanol extraction. Proc Natl Acad Sci U S A 77:3494–3498.PubMedCrossRefGoogle Scholar
  58. Rosman DS, Phukan S, Huang CC, Pasche B. 2008. TGFBR1*6A enhances the migration and invasion of MCF-7 breast cancer cells through RhoA activation. Cancer Res 68:1319–1328.PubMedCrossRefGoogle Scholar
  59. Seton-Rogers SE, Lu Y, Hines LM, Koundinya M, LaBaer J, Muthuswamy SK, Brugge JS. 2004. Cooperation of the ErbB2 receptor and transforming growth factor beta in induction of migration and invasion in mammary epithelial cells. Proc Natl Acad Sci U S A 101:1257–1262.PubMedCrossRefGoogle Scholar
  60. Shi Y and Massague J. 2003. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113:685–700.PubMedCrossRefGoogle Scholar
  61. Shi W, Sun C, He B, Xiong W, Shi X, Yao D, Cao X. 2004. GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor. J Cell Biol 164:291–300.PubMedCrossRefGoogle Scholar
  62. Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J, Nikolskaya T, Serebryiskaya T, Beroukhim R, Hu M, Halushka MK, Sukumar S, Parker LM, Anderson KS, Harris LN, Garber JE, Richardson AL, Schnitt SJ, Nikolsky Y, Gelman RS, Polyak K. 2007. Molecular definition of breast tumor heterogeneity. Cancer Cell 11:259–273.PubMedCrossRefGoogle Scholar
  63. Siegel PM and Massague J. 2003. Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nat Rev Cancer 3:807–820.PubMedCrossRefGoogle Scholar
  64. Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JKV, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE. 2006. The consensus coding sequences of human breast and colorectal cancers. Science 314:268–274.PubMedCrossRefGoogle Scholar
  65. Sweet K, Willis J, Zhou XP, Gallione C, Sawada T, Alhopuro P, Khoo SK, Patocs A, Martin C, Bridgeman S, Heinz J, Pilarski R, Lehtonen R, Prior TW, Frebourg T, Teh BT, Marchuk DA, Aaltonen LA, Eng C. 2005. Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis. JAMA 294:2465–2473.PubMedCrossRefGoogle Scholar
  66. Takayama T, Miyanishi K, Hayashi T, Sato Y, Niitsu Y. 2006. Colorectal cancer: Genetics of development and metastasis. J Gastroenterol 41:185–192.PubMedCrossRefGoogle Scholar
  67. Thiery JP. 2003. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 15:740–746.PubMedCrossRefGoogle Scholar
  68. Thuault S, Valcourt U, Petersen M, Manfioletti G, Heldin CH, Moustakas A. 2006. Transforming growth factor-{beta} employs HMGA2 to elicit epithelial-mesenchymal transition. J Cell Biol 174:175–183.PubMedCrossRefGoogle Scholar
  69. Thuault S, Tan EJ, Peinado H, Cano A, Heldin CH, Moustakas A. 2008. HMGA2 and Smads co-regulate SNAIL1 expression during induction of epithelial-to-mesenchymal transition. J Biol Chem 283:33437–33446.PubMedCrossRefGoogle Scholar
  70. Valle L, Serena-Acedo T, Liyanarachchi S, Hampel H, Comeras I, Li Z, Zeng Q, Zhang HT, Pennison MJ, Sadim M, Pasche B, Tanner SM, de la Chapelle A. 2008. Germline allele-specific expression of TGFBR1 confers an increased risk of colorectal cancer. Science 115 9397.Google Scholar
  71. Yamagata H, Matsuzaki K, Mori S, Yoshida K, Tahashi Y, Furukawa F, Sekimoto G, Watanabe T, Uemura Y, Sakaida N, Yoshioka K, Kamiyama Y, Seki T, Okazaki K. 2005. Acceleration of Smad2 and Smad3 phosphorylation via c-Jun NH2-terminal kinase during human colorectal carcinogenesis. Cancer Res 65:157–165.PubMedGoogle Scholar
  72. Yang X, Letterio JJ, Lechleider RJ, Chen L, Hayman R, Gu H, Roberts AB, Deng CX. 1999. Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta. EMBO Journal 18:1280–1291.PubMedCrossRefGoogle Scholar
  73. Zeng Q, Phukan S, Xu Y, Sadim M, Rosman DS, Pennison M, Liao J, Yang GY, Huang CC, Valle L, Di Cristofano A, de la Chapelle A, Pasche B. 2009. Tgfbr1 haploinsufficiency is a potent modifier of colorectal cancer development. Cancer Res 69:678–686.PubMedCrossRefGoogle Scholar
  74. Zhang HT, Chen XF, Wang MH, Wang JC, Qi QY, Zhang RM, Xu WQ, Fei QY, Wang F, Cheng QQ, Chen F, Zhu CS, Tao SH, Luo Z. 2004. Defective expression of transforming growth factor {beta} receptor type II is associated with CpG methylated promoter in primary non-small cell lung cancer. Clin Cancer Res 10:2359–2367.PubMedCrossRefGoogle Scholar
  75. Zhu YA, Richardson JA, Parada LF, Graff JM. 1998. Smad3 mutant mice develop metastatic colorectal cancer. Cell 94:703–714.PubMedCrossRefGoogle Scholar
  76. Zhu Q, Krakowski AR, Dunham EE, Wang L, Bandyopadhyay A, Berdeaux R, Martin GS, Sun L, Luo K. 2007. Dual role of SnoN in mammalian tumorigenesis. Mol Cell Biol 27:324–339.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Division of Hematology/Oncology, Department of Medicine and UAB Comprehensive Cancer CenterThe University of Alabama at BirminghamBirminghamUSA

Personalised recommendations