Skip to main content
SpringerLink
Log in
Book cover

Transforming Growth Factor-β in Cancer Therapy, Volume II pp 553–570Cite as

TGF-β at the Crossroads Between Inflammation, Suppression and Cancer

  • Chapter

  • 1545 Accesses

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Over the past few decades, transforming growth factor-β (TGF-β) and the proteins that regulate it have come to the forefront of tumor immunology. The relationship of mutations, deletions, and amplifications of members of the TGF-β signaling pathway, as well as reductions in receptor expression, to malignancy and the identification of TGF-β receptor polymorphisms as candidate tumor susceptibility alleles confirm TGF-β’s influence on tumorigenesis and provide avenues for potential therapeutic intervention. Just as TGF-β can promote or suppress tumorigenesis, TGF-β can also promote or suppress inflammation, depending on cell type, state of differentiation/activation, and context of the microenvironment. Recent studies have rejuvenated early observations linking inflammation with cancer and have focused on the impact of TGF-β and its pro- and antiinflammatory activities on the outcome of tumor-specific immune responses. Harnessing the suppressive power of TGF-β, the regulatory T-cell counters the host antitumor immune response, posing a major mechanism for tumor immunoevasion and a significant obstacle for effective tumor immunotherapy.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   279.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Gorelik L, Flavell RA. Transforming growth factor-beta in T-cell biology. Nat Rev Immunol 2002;2:46–53.

    Article  CAS  PubMed  Google Scholar 

  2. Kulkarni AB, Thyagarajan T, Letterio JJ. Function of cytokines within the TGF-beta superfamily as determined from transgenic and gene knockout studies in mice. Curr Mol Med 2002;2:303–327.

    Article  CAS  PubMed  Google Scholar 

  3. Letterio JJ. TGF-beta signaling in T cells: roles in lymphoid and epithelial neoplasia. Oncogene 2005;24:5701–5712.

    Article  CAS  PubMed  Google Scholar 

  4. Wahl SM, Swisher J, McCartney-Francis N, Chen W. TGF-beta: the perpetrator of immune suppression by regulatory T cells and suicidal T cells. J Leukoc Biol 2004;76:15–24.

    Article  CAS  PubMed  Google Scholar 

  5. Sporn MB, Roberts AB. Autocrine growth factors and cancer. Nature 1985;313:745–747.

    Article  CAS  PubMed  Google Scholar 

  6. Akhurst RJ, Fee F, Balmain A. Localized production of TGF-beta mRNA in tumour promoterstimulated mouse epidermis. Nature 1988;331:363–365.

    Article  CAS  PubMed  Google Scholar 

  7. Wakefield LM, Roberts AB. TGF-beta signaling: positive and negative effects on tumorigenesis. Curr Opin Genet Dev 2002;12:22–29.

    Article  CAS  PubMed  Google Scholar 

  8. Yingling JM, Wang XF, Bassing CH. Signaling by the transforming growth factor-beta receptors. Biochim Biophys Acta 1995;1242:115–136.

    PubMed  Google Scholar 

  9. Kim SJ, Letterio J. Transforming growth factor-beta signaling in normal and malignant hematopoiesis. Leukemia 2003;17:1731–1737.

    Article  CAS  PubMed  Google Scholar 

  10. Sanchez-Capelo A. Dual role for TGF-beta1 in apoptosis. Cytokine Growth Factor Rev 2005;16:15–34.

    Article  CAS  PubMed  Google Scholar 

  11. Bhowmick NA, Chytil A, Plieth D, et al. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 2004;303:848–851.

    Article  CAS  PubMed  Google Scholar 

  12. Oft M, Peli J, Rudaz C, Schwarz H, Beug H, Reichmann E. TGF-beta1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells. Genes Dev 1996;10: 2462–2477.

    Article  CAS  PubMed  Google Scholar 

  13. Yin JJ, Selander K, Chirgwin JM, et al. TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J Clin Invest 1999;103:197–206.

    Article  CAS  PubMed  Google Scholar 

  14. Roberts AB, Wakefield LM. The two faces of transforming growth factor beta in carcinogenesis. Proc Natl Acad Sci USA 2003;100:8621–8623.

    Article  CAS  PubMed  Google Scholar 

  15. Elliott RL, Blobe GC. Role of transforming growth factor beta in human cancer. J Clin Oncol 2005;23: 2078–2093.

    Article  CAS  PubMed  Google Scholar 

  16. Khalil N. TGF-beta: from latent to active. Microbes Infect 1999;1:1255–1263.

    Article  CAS  PubMed  Google Scholar 

  17. Annes JP, Munger JS, Rifkin DB. Making sense of latent TGFbeta activation. J Cell Sci 2003;116: 217–224.

    Article  CAS  PubMed  Google Scholar 

  18. Feng XH, Derynck R. Specificity and versatility in TGF-beta signaling through Smads. Annu Rev Cell Dev Biol 2005;21:659–693.

    Article  CAS  PubMed  Google Scholar 

  19. Shi Y, Massagué J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 2003;113:685–700.

    Article  CAS  PubMed  Google Scholar 

  20. Attisano L, Wrana JL. Signal transduction by the TGF-beta superfamily. Science 2002;296:1646–1647.

    Article  CAS  PubMed  Google Scholar 

  21. Chen W, Jin W, Tian H, et al. Requirement for transforming growth factor beta1 in controlling T cell apoptosis. J Exp Med 2001;194:439–453.

    Article  CAS  PubMed  Google Scholar 

  22. Chen W, Jin W, Hardegen N, et al. Conversion of peripheral CD4+CD25-naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 2003;198:1875–1886.

    Article  CAS  PubMed  Google Scholar 

  23. Chen W, Wahl SM. TGF-beta: the missing link in CD4+CD25+ regulatory T cell-mediated immunosuppression. Cytokine Growth Factor Rev 2003;14:85–89.

    Article  CAS  PubMed  Google Scholar 

  24. Chen ML, Pittet MJ, Gorelik L, et al. Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo. Proc Natl Acad Sci USA 2005;102:419–424.

    Article  CAS  PubMed  Google Scholar 

  25. Gregg RK, Jain R, Schoenleber SJ, et al. A sudden decline in active membrane-bound TGF-beta impairs both T regulatory cell function and protection against autoimmune diabetes. J Immunol 2004;173:7308–7316.

    CAS  PubMed  Google Scholar 

  26. Nakamura K, Kitani A, Strober W. Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med 2001; 194:629–644.

    Article  CAS  PubMed  Google Scholar 

  27. Fahlen L, Read S, Gorelik L, et al. T cells that cannot respond to TGF-beta escape control by CD4(+)CD25(+) regulatory T cells. J Exp Med 2005;201:737–746.

    Article  CAS  PubMed  Google Scholar 

  28. Feng XH, Zhang Y, Wu RY, Derynck R. The tumor suppressor Smad4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for smad3 in TGF-beta-induced transcriptional activation. Genes Dev 1998;12:2153–2163.

    Article  CAS  PubMed  Google Scholar 

  29. Shioda T, Lechleider RJ, Dunwoodie SL, et al. Transcriptional activating activity of Smad4: roles of SMAD hetero-oligomerization and enhancement by an associating transactivator. Proc Natl Acad Sci USA 1998;95:9785–9790.

    Article  CAS  PubMed  Google Scholar 

  30. Wotton D, Lo RS, Lee S, Massagué J. A Smad transcriptional corepressor. Cell 1999;97:29–39.

    Article  CAS  PubMed  Google Scholar 

  31. Kurokawa M, Mitani K, Irie K, et al. The oncoprotein Evi-1 represses TGF-beta signalling by inhibiting Smad3. Nature 1998;394:92–96.

    Article  CAS  PubMed  Google Scholar 

  32. Ghosh AK, Yuan W, Mori Y, Varga J. Smad-dependent stimulation of type I collagen gene expression in human skin fibroblasts by TGF-beta involves functional cooperation with p300/CBP transcriptional coactivators. Oncogene 2000;19:3546–3555.

    Article  CAS  PubMed  Google Scholar 

  33. 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.

    Article  CAS  PubMed  Google Scholar 

  34. Stroschein SL, Wang W, Zhou S, Zhou Q, Luo K. Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein. Science 1999;286:771–774.

    Article  CAS  PubMed  Google Scholar 

  35. Massagué J, Seoane J, Wotton D. Smad transcription factors. Genes Dev 2005;19:2783–2810.

    Article  PubMed  CAS  Google Scholar 

  36. Nakao A, Afrakhte M, Moren A, et al. Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature 1997;389:631–635.

    Article  CAS  PubMed  Google Scholar 

  37. Ulloa L, Doody J, Massagué J. Inhibition of transforming growth factor-beta/SMAD signalling by the interferon-gamma/STAT pathway. Nature 1999;397:710–713.

    Article  CAS  PubMed  Google Scholar 

  38. Bitzer M, von Gersdorff G, Liang D, et al. A mechanism of suppression of TGF-beta/SMAD signaling by NF-kappa B/RelA. Genes Dev 2000;14:187–197.

    CAS  PubMed  Google Scholar 

  39. ten Dijke P, Hill CS. New insights into TGF-beta-Smad signalling. Trends Biochem Sci 2004;29: 265–273.

    Article  PubMed  CAS  Google Scholar 

  40. Shi W, Sun C, He B, et al. GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type 1 receptor. J Cell Biol 2004;164:291–300.

    Article  CAS  PubMed  Google Scholar 

  41. Song K, Cornelius SC, Danielpour D. Development and characterization of DP-153, a nontumorigenic prostatic cell line that undergoes malignant transformation by expression of dominant-negative transforming growth factor beta receptor type II. Cancer Res 2003;63:4358–4367.

    CAS  PubMed  Google Scholar 

  42. Tang B, de Castro K., Barnes HE, et al. Loss of responsiveness to transforming growth factor beta induces malignant transformation of nontumorigenic rat prostate epithelial cells. Cancer Res 1999;59:4834–4842.

    CAS  PubMed  Google Scholar 

  43. Guo Y, Kyprianou N. Overexpression of transforming growth factor (TGF) betal type II receptor restores TGF-betal sensitivity and signaling in human prostate cancer cells. Cell Growth Differ 1998;9:185–193.

    CAS  PubMed  Google Scholar 

  44. Sun L, Wu G, Willson JK, et al. Expression of transforming growth factor beta type II receptor leads to reduced malignancy in human breast cancer MCF-7 cells. J Biol Chem 1994;269:26,449–26,455.

    CAS  PubMed  Google Scholar 

  45. Bierie B, Moses HL. TGF-beta and cancer. Cytokine Growth Factor Rev 2006;17:29–40.

    Article  CAS  PubMed  Google Scholar 

  46. Pasche B, Kolachana P, Nafa K, et al. TbetaR-I(6A) is a candidate tumor susceptibility allele. Cancer Res 1999;59:5678–5682.

    CAS  PubMed  Google Scholar 

  47. Kaklamani VG, Hou N, Bian Y, et al. TGFBR1*6A and cancer risk: a meta-analysis of seven case-control studies. J Clin Oncol 2003;21:3236–3243.

    Article  CAS  PubMed  Google Scholar 

  48. Pasche B, Kaklamani V, Hou N, et al. TGFBR1*6A and cancer: a meta-analysis of 12 case-control studies. J Clin Oncol 2004;22:756–758.

    Article  PubMed  Google Scholar 

  49. Schiemann WP, Pfeifer WM, Levi E, Kadin ME, Lodish HF. A deletion in the gene for transforming growth factor beta type I receptor abolishes growth regulation by transforming growth factor beta in a cutaneous T-cell lymphoma. Blood 1999;94:2854–2861.

    CAS  PubMed  Google Scholar 

  50. Knaus PI, Lindemann D, DeCoteau JF, et al. A dominant inhibitory mutant of the type II transforming growth factor beta receptor in the malignant progression of a cutaneous T-cell lymphoma. Mol Cell Biol 1996;16:3480–3489.

    CAS  PubMed  Google Scholar 

  51. Imai Y, Kurokawa M, Izutsu K, et al. Mutations of the Smad4 gene in acute myelogeneous leukemia and their functional implications in leukemogenesis. Oncogene 2001;20:88–96.

    Article  CAS  PubMed  Google Scholar 

  52. Kaklamani VG, Pasche B. Role of TGF-beta in cancer and the potential for therapy and prevention. Expert Rev Anticancer Ther 2004;4:649–661.

    Article  CAS  PubMed  Google Scholar 

  53. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet 2001;357:539–545.

    Article  CAS  PubMed  Google Scholar 

  54. Karin M, Lawrence T, Nizet V. Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell 2006;124:823–835.

    Article  CAS  PubMed  Google Scholar 

  55. Balkwill F, Charles KA, Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 2005;7:211–217.

    Article  CAS  PubMed  Google Scholar 

  56. Kuper H, Adami HO, Trichopoulos D. Infections as a major preventable cause of human cancer. J Intern Med 2000;248:171–183.

    Article  CAS  PubMed  Google Scholar 

  57. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001;2:533–543.

    Article  CAS  PubMed  Google Scholar 

  58. Parsonnet J, Friedman GD, Vandersteen DP, et al. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med 1991;325:1127–1131.

    CAS  PubMed  Google Scholar 

  59. Houghton J, Stoicov C, Nomura S, et al. Gastric cancer originating from bone marrow-derived cells. Science 2004;306:1568–1571.

    Article  CAS  PubMed  Google Scholar 

  60. Castellsague X, Bosch FX, Munoz N. Environmental co-factors in HPV carcinogenesis. Virus Res 2002;89:191–199.

    Article  CAS  PubMed  Google Scholar 

  61. Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000. The global picture. Eur J Cancer 37 Suppl 2001;8:S4–66.

    Article  Google Scholar 

  62. Block TM, Mehta AS, Fimmel CJ, Jordan R. Molecular viral oncology of hepatocellular carcinoma. Oncogene 2003;22:5093–5107.

    Article  CAS  PubMed  Google Scholar 

  63. Rosin MP, Anwar WA, Ward AJ. Inflammation, chromosomal instability, and cancer: the schistosomiasis model. Cancer Res 1994;54:1929s–1933s.

    CAS  PubMed  Google Scholar 

  64. Mostafa MH, Sheweita SA, O’Connor PJ. Relationship between schistosomiasis and bladder cancer. Clin Microbiol Rev 1999;12:97–111.

    CAS  PubMed  Google Scholar 

  65. Lin EY, Pollard JW. Macrophages: modulators of breast cancer progression. Novartis Found Symp 2004;256:158–168; discussion 168–172:259–169.

    Article  CAS  PubMed  Google Scholar 

  66. Condeelis J, Pollard JW. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 2006;124:263–266.

    Article  CAS  PubMed  Google Scholar 

  67. Wahl SM, Hunt DA, Wakefield LM, et al. Transforming growth factor type beta induces monocyte chemotaxis and growth factor production. Proc Natl Acad Sci USA 1987;84:5788–5792.

    Article  CAS  PubMed  Google Scholar 

  68. Bingle L, Brown NJ, Lewis CE. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol 2002;196:254–265.

    Article  CAS  PubMed  Google Scholar 

  69. Nakayama Y, Nagashima N, Minagawa N, et al. Relationships between tumor-associated macrophages and clinicopathological factors in patients with colorectal cancer. Anticancer Res 2002;22:4291–4296.

    PubMed  Google Scholar 

  70. Funada Y, Noguchi T, Kikuchi R, Takeno S, Uchida Y, Gabbert HE. Prognostic significance of CD8+ T cell and macrophage peritumoral infiltration in colorectal cancer. Oncol Rep 2003;10:309–313.

    PubMed  Google Scholar 

  71. McCartney-Francis N Wahl SM. TGF-beta and macrophages in the rise and fall of inflammation. In: TGF-beta and Related Cytokines in Inflammation. Breit SN, Wahl SM, eds.. Birkhauser Verlag, Basel, 2001; p. 65–89.

    Google Scholar 

  72. Janeway CA, Jr., Medzhitov R. Innate immune recognition. Annu Rev Immunol 2002;20:197–216.

    Article  CAS  PubMed  Google Scholar 

  73. Nathan C. Nitric oxide as a secretory product of mammalian cells. FASEB J 1992;6:3051–3064.

    CAS  PubMed  Google Scholar 

  74. Mangan PR, Harrington LE, O’Quin DB, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 2006;411:231–234.

    Article  CAS  Google Scholar 

  75. McCartney-Francis NL, Song X, Mizel DE, Wahl SM. Selective inhibition of inducible nitric oxide synthase exacerbates erosive joint disease. J Immunol 2001;166:2734–2740.

    CAS  PubMed  Google Scholar 

  76. Wahl SM, McCartney-Francis N, Chan J, Dionne R, Ta L, Orenstein JM. Nitric oxide in experimental joint inflammation. Benefit or detriment? Cells Tissues Organs 2003;174:26–33.

    Article  CAS  PubMed  Google Scholar 

  77. Ekmekcioglu S, Tang CH, Grimm EA. NO news is not necessarily good news in cancer. Curr Cancer Drug Targets 2005;5:103–115.

    Article  CAS  PubMed  Google Scholar 

  78. Wahl SM, Wen J, Moutsopoulos N. TGF-beta-a mobile purveyor of immune privilege. Immunolog Rev 2006;213:213–227.

    Article  CAS  Google Scholar 

  79. Lucas PJ, McNeil N, Hilgenfeld E, et al. Transforming growth factor-beta pathway serves as a primary tumor suppressor in CD8+ T cell tumorigenesis. Cancer Res 2004;64:6524–6529.

    Article  CAS  PubMed  Google Scholar 

  80. Lucas PJ, Kim SJ, Melby SJ, Gress RE. Disruption of T cell homeostasis in mice expressing a T cell-specific dominant negative transforming growth factor beta II receptor. J Exp Med 2000;191:1187–1196.

    Article  CAS  PubMed  Google Scholar 

  81. Gorelik L, Flavell RA. Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 2000;12:171–181.

    Article  CAS  PubMed  Google Scholar 

  82. Gorelik L, Flavell RA. Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med 2001;7:1118–1122.

    Article  CAS  PubMed  Google Scholar 

  83. Wahl SM. TGF-beta in the evolution and resolution of inflammatory and immune processes. Introduction. Microbes Infect 1999;1:1247–1249.

    Article  CAS  PubMed  Google Scholar 

  84. McCartney-Francis NL, Frazier-Jessen M, Wahl SM. TGF-beta: a balancing act. Int Rev Immunol 1998;16:553–580.

    Article  CAS  PubMed  Google Scholar 

  85. Kulkarni AB, Huh CG, Becker D, et al. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA 1993;90:770–774.

    Article  CAS  PubMed  Google Scholar 

  86. Shull MM, Ormsby I, Kier AB, et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 1992;359:693–699.

    Article  CAS  PubMed  Google Scholar 

  87. Vodovotz Y, Geiser AG, Chesler L, et al. Spontaneously increased production of nitric oxide and aberrant expression of the inducible nitric oxide synthase in vivo in the transforming growth factor beta 1 null mouse. J Exp Med 1996;183:2337–2342.

    Article  CAS  PubMed  Google Scholar 

  88. McCartney-Francis NL, Wahl SM. Dysregulation of IFN-gamma signaling pathways in the absence of TGF-beta 1. J Immunol 2002;169:5941–5947.

    CAS  PubMed  Google Scholar 

  89. McCartney-Francis N, Jin W, Wahl SM. Aberrant Toll receptor expression and endotoxin hyper-sensitivity in mice lacking a functional TGF-beta 1 signaling pathway. J Immunol 2004;172:3814–3821.

    CAS  PubMed  Google Scholar 

  90. Marie JC, Letterio JJ, Gavin M, Rudensky AY. TGF-beta 1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J Exp Med 2005;201:1061–1067.

    Article  CAS  PubMed  Google Scholar 

  91. Longenecker G, Thyagarajan T, Nagineni CN, et al. Endocrine expression of the active form of TGF-beta1 in the TGF-beta1 null mice fails to ameliorate lethal phenotype. Cytokine 2002;18:43–50.

    Article  CAS  PubMed  Google Scholar 

  92. Kobayashi S, Yoshida K, Ward JM, et al. Beta 2-microglobulin-deficient background ameliorates lethal phenotype of the TGF-beta 1 null mouse. J Immunol 1999;163:4013–4019.

    CAS  PubMed  Google Scholar 

  93. Letterio JJ, Geiser AG, Kulkarni AB, et al. Autoimmunity associated with TGF-beta1-deficiency in mice is dependent on MHC class II antigen expression. J Clin Invest 1996;98:2109–2119.

    Article  CAS  PubMed  Google Scholar 

  94. Yang X, Li C, Xu X, Deng C. The tumor suppressor SMAD4/DPC4 is essential for epiblast proliferation and mesoderm induction in mice. Proc Natl Acad Sci USA 1999;95:3667–3672.

    Article  Google Scholar 

  95. Datto MB, Frederick JP, Pan L, Borton AJ, Zhuang Y, Wang XF. Targeted disruption of Smad3 reveals an essential role in transforming growth factor beta-mediated signal transduction. Mol Cell Biol 1999;19:2495–2504.

    CAS  PubMed  Google Scholar 

  96. Ashcroft GS, Yang X, Glick AB, et al. Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat Cell Biol 1999;1:260–266.

    Article  CAS  PubMed  Google Scholar 

  97. Kehrl JH, Wakefied LM, Roberts AB, et al. Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth. J Exp Med 1986;163:1037–1050.

    Article  CAS  PubMed  Google Scholar 

  98. Wahl SM, Hunt DA, Wong HL, et al. Transforming growth factor-beta is a potent immunosuppressive agent that inhibits IL-1-dependent lymphocyte proliferation. J Immunol 1988;140:3026–3032.

    CAS  PubMed  Google Scholar 

  99. Sad S, Mosmann TR. Single IL-2-secreting precursor CD4 T cell can develop into either Th1 or Th2 cytokine secretion phenotype. J Immunol 1994;153:3514–3522.

    CAS  PubMed  Google Scholar 

  100. Hoehn P, Goedert S, Germann T, et al. Opposing effects of TGF-beta 2 on the Th1 cell development of naive CD4+ T cells isolated from different mouse strains. J Immunol 1995;155:3788–3793.

    CAS  PubMed  Google Scholar 

  101. Swain SL, Huston G, Tonkonogy S, Weinberg A. Transforming growth factor-beta and IL-4 cause helper T cell precursors to develop into distinct effector helper cells that differ in lymphokine secretion pattern and cell surface phenotype. J Immunol 1991;147:2991–3000.

    CAS  PubMed  Google Scholar 

  102. Ranges GE, Figari IS, Espevik T, Palladino MA, Jr. Inhibition of cytotoxic T cell development by transforming growth factor beta and reversal by recombinant tumor necrosis factor alpha. J Exp Med 1987;166:991–998.

    Article  CAS  PubMed  Google Scholar 

  103. Coffey RJ Jr., Bascom CC, Sipes NJ, Graves-Deal R, Weissman BE, Moses HL. Selective inhibition of growth-related gene expression in murine keratinocytes by transforming growth factor beta. Mol Cell Biol 1988;8:3088–3093.

    CAS  PubMed  Google Scholar 

  104. Hannon GJ, Beach D. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature 1994;371:257–261.

    Article  CAS  PubMed  Google Scholar 

  105. Datto MB, Li Y, Panus JF, Howe DJ, Xiong Y, Wang XF. Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc Natl Acad Sci USA 1995;92:5545–5549.

    Article  CAS  PubMed  Google Scholar 

  106. Polyak K, Kato JY, Solomon MJ, et al. p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev 1994;8:9–22.

    Article  CAS  PubMed  Google Scholar 

  107. Gorelik L, Constant S, Flavell RA. Mechanism of transforming growth factor beta-induced inhibition of T helper type 1 differentiation. J Exp Med 2002;195:1499–1505.

    Article  CAS  PubMed  Google Scholar 

  108. Gorham JD, Guler ML, Fenoglio D, Gubler U, Murphy KM. Low dose TGF-beta attenuates IL-12 responsiveness in murine Th cells. J Immunol 1998;161:1664–1670.

    CAS  PubMed  Google Scholar 

  109. Gorelik L, Fields PE, Flavell RA. Cutting edge: TGF-beta inhibits Th type 2 development through inhibition of GATA-3 expression. J Immunol 2000;165:4773–4777.

    CAS  PubMed  Google Scholar 

  110. Heath VL, Murphy EE, Crain C, Tomlinson MG, O’Garra A. TGF-beta1 down-regulates Th2 development and results in decreased IL-4-induced STAT5 activation and GATA-3 expression. Eur J Immunol 2000;30:2639–2649.

    Article  CAS  PubMed  Google Scholar 

  111. Wahl SM, Vazquez N, Chen W. Regulatory T cells and transcription factors: gatekeepers in allergic inflammation. Curr Opin Immunol 2004;16:768–774.

    Article  CAS  PubMed  Google Scholar 

  112. Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector T(H)17 and regulatory T cells. Nature 2006;441:235–238.

    Article  CAS  PubMed  Google Scholar 

  113. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006;24:179–189.

    Article  CAS  PubMed  Google Scholar 

  114. Laouar Y, Sutterwala FS, Gorelik L, Flavell RA. Transforming growth factor-beta controls T helper type 1 cell development through regulation of natural killer cell interferon-gamma. Nat Immunol 2005;6:600–607.

    Article  CAS  PubMed  Google Scholar 

  115. Wahl SM, Wen J, Moutsopoulos NM. The kiss of death: interrupted by NK-cell close encounters of another kind. Trends Immunol 2006;27:161–164.

    Article  CAS  PubMed  Google Scholar 

  116. Hamerman JA, Ogasawara K, Lanier LL. NK cells in innate immunity. Curr Opin Immunol 2005;17:29–35.

    Article  CAS  PubMed  Google Scholar 

  117. Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 2000;100:655–669.

    Article  CAS  PubMed  Google Scholar 

  118. Lala PK, Chakraborty C. Role of nitric oxide in carcinogenesis and tumour progression. Lancet Oncol 2001;2:149–156.

    Article  CAS  PubMed  Google Scholar 

  119. Engle SJ, Hoying JB, Boivin GP, Ormsby I, Gartside PS, Doetschman T. Transforming growth factor betal suppresses nonmetastatic colon cancer at an early, stage of tumorigenesis. Cancer Res 1999;59:3379–3386.

    CAS  PubMed  Google Scholar 

  120. Chakravarthy D, Green AR, Green VL, Kerin MJ, Speirs V. Expression and secretion of TGF-beta isoforms and expression of TGF-beta-receptors I, II and III in normal and neoplastic human breast. Int J Oncol 1999;15:187–194.

    CAS  PubMed  Google Scholar 

  121. van Roozendaal CE, Klijn JG, van Ooijen B, et al. Transforming growth factor beta secretion from primary breast cancer fibroblasts. Mol Cell Endocrinol 1995;111:1–6.

    Article  PubMed  Google Scholar 

  122. Chen W, Frank ME, Jin W, Wahl SM. TGF-beta released by apoptotic T cells contributes to an immunosuppressive milieu. Immunity 2001;14:715–725.

    Article  CAS  PubMed  Google Scholar 

  123. Chen W, Wahl SM. TGF-beta: receptors, signaling pathways and autoimmunity. Curr Dir Autoimmun 2002;5:62–91.

    Article  CAS  PubMed  Google Scholar 

  124. Geske FJ, Monks J, Lehman L, Fadok VA. The role of the macrophage in apoptosis: hunter, gatherer, and regulator. Int J Hematol 2002;76:16–26.

    Article  PubMed  Google Scholar 

  125. Nakamura K, Kitani A, Fuss I, et al. TGF-beta 1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice. J Immunol 2004;172:834–842.

    CAS  PubMed  Google Scholar 

  126. Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY Henson PM. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/ paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest 1998;101:890–898.

    Article  CAS  PubMed  Google Scholar 

  127. Yehualaeshet T, O’Connor R, Green-Johnson J, et al. Activation of rat alveolar macrophage-derived latent transforming growth factor beta-1 by plasmin requires interaction with thrombospondin-1 and its cell surface receptor, CD36. Am J Pathol 1999;155:841–851.

    CAS  PubMed  Google Scholar 

  128. Huynh ML, Fadok VA, Henson PM. Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation. J Clin Invest 2002;109:41–50.

    CAS  PubMed  Google Scholar 

  129. Wahl SM, Orenstein JM, Chen W. TGF-beta influences the life and death decisions of T lymphocytes. Cytokine Growth Factor Rev 2000;11:71–79.

    Article  CAS  PubMed  Google Scholar 

  130. Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 2004;22:531–562.

    Article  CAS  PubMed  Google Scholar 

  131. Itoh M, Takahashi T, Sakaguchi N, et al. Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J Immunol 1999;162:5317–5326.

    CAS  PubMed  Google Scholar 

  132. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995;155:1151–1164.

    CAS  PubMed  Google Scholar 

  133. Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 2005;6:345–352.

    Article  CAS  PubMed  Google Scholar 

  134. Weiner HL. Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunol Rev 2001;182:207–214.

    Article  CAS  PubMed  Google Scholar 

  135. Ueda H, Howson JM, Esposito L, et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 2003;423:506–511.

    Article  CAS  PubMed  Google Scholar 

  136. McHugh RS, Whitters MJ, Piccirillo CA, et al. CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 2002;16:311–323.

    Article  CAS  PubMed  Google Scholar 

  137. Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S. Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 2002;3:135–142.

    Article  CAS  PubMed  Google Scholar 

  138. Stassen M, Fondel S, Bopp T, et al. Human CD25+ regulatory T cells: two subsets defined by the integrins alpha 4 beta 7 or alpha 4 beta 1 confer distinct suppressive properties upon CD4+ T helper cells. Eur J Immunol 2004;34:1303–1311.

    Article  CAS  PubMed  Google Scholar 

  139. Schubert LA, Jeffery E, Zhang Y, Ramsdell F, Ziegler SF. Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation. J Biol Chem 2001;276:37,672–37,679.

    Article  CAS  PubMed  Google Scholar 

  140. Brunkow ME, Jeffery EW, Hjerrild KA, et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 2001;27:68–73.

    Article  CAS  PubMed  Google Scholar 

  141. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003;4:330–336.

    Article  CAS  PubMed  Google Scholar 

  142. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003;299:1057–1061.

    Article  CAS  PubMed  Google Scholar 

  143. Wahl SM, Chen W. Transforming growth factor-beta-induced regulatory T cells referee inflammatory and autoimmune diseases. Arthritis Res Ther 2005;7:62–68.

    Article  CAS  PubMed  Google Scholar 

  144. Wildin RS, Ramsdell F, Peake J, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 2001;27:18–20.

    Article  CAS  PubMed  Google Scholar 

  145. Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 2003;4:337–342.

    Article  CAS  PubMed  Google Scholar 

  146. Christ M, McCartney-Francis NL, Kulkarni AB, et al. Immune dysregulation in TGF-beta 1-deficient mice. J Immunol 1994;153:1936–1946.

    CAS  PubMed  Google Scholar 

  147. Tivol EA, Borriello F, Schweitzer AN, et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995;3:541–547.

    Article  CAS  PubMed  Google Scholar 

  148. Waterhouse P, Penninger JM, Timms E, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 1995;270:985–988.

    Article  CAS  PubMed  Google Scholar 

  149. Hori S, Takahashi T, Sakaguchi S. Control of autoimmunity by naturally arising regulatory CD4+ T cells. Adv Immunol 2003;81:331–371.

    Article  CAS  PubMed  Google Scholar 

  150. Khattri R, Kasprowicz D, Cox T, et al. The amount of scurfin protein determines peripheral T cell number and responsiveness. J Immunol 2001;167:6312–6320.

    CAS  PubMed  Google Scholar 

  151. Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 2006;6:295–307.

    Article  CAS  PubMed  Google Scholar 

  152. Huber S, Schramm C, Lehr HA, et al. Cutting edge: TGF-beta signaling is required for the in vivo expansion and immunosuppressive capacity of regulatory CD4+CD25+ T cells. J Immunol 2004;173:6526–6531.

    CAS  PubMed  Google Scholar 

  153. Peng Y, Laouar Y, Li MO, Green EA, Flavell RA. TGF-beta regulates in vivo expansion of Foxp3-expressing CD4+CD25+ regulatory T cells responsible for protection against diabetes. Proc Natl Acad Sci USA 2004;101:4572–4577.

    Article  CAS  PubMed  Google Scholar 

  154. Schlingensiepen KH, Schlingensiepen R, Steinbrecher A, et al. Targeted tumor therapy with the TGF-beta2 antisense compound AP 12009. Cytokine Growth Factor Rev 2006;17:129–139.

    Article  CAS  PubMed  Google Scholar 

  155. Curiel TJ, Coukos G, Zou L, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004;10:942–949.

    Article  CAS  PubMed  Google Scholar 

  156. Su L, Creusot RJ, Gallo EM, et al. Murine CD4+CD25+ regulatory T cells fail to undergo chromatin remodeling across the proximal promoter region of the IL-2 gene. J Immunol 2004;173:4994–5001.

    CAS  PubMed  Google Scholar 

  157. Duthoit CT, Mekala DJ, Alli RS, Geiger TL. Uncoupling of IL-2 signaling from cell cycle progression in naive CD4+ T cells by regulatory CD4+CD25+ T lymphocytes. J Immunol 2005;174:155–163.

    CAS  PubMed  Google Scholar 

  158. Bettelli, Dastrenge M, Oukka M. Foxp3 interects with nuclear factor of activated T cells and NF-kappa B to repress cytokine gene expression and effector functions of T helper cells. Proc Natl Acad Sci USA 2005;102:5138–5143.

    Article  CAS  PubMed  Google Scholar 

  159. Ghiringhelli F, Menard C, Terme M, et al. CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner. J Exp Med 2005;202:1075–1085.

    Article  CAS  PubMed  Google Scholar 

  160. Smyth MJ, Teng MW, Swann J, Kyparissoudis K, Godfrey DI, Hayakawa Y. CD4+CD25+ T regulatory cells suppress NK cell-mediated immunotherapy of cancer. J Immunol 2006;176:1582–1587.

    CAS  PubMed  Google Scholar 

  161. Takahashi T, Kuniyasu Y, Toda M, et al. Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Int Immunol 1998;10:1969–1980.

    Article  CAS  PubMed  Google Scholar 

  162. Thornton AM, Shevach EM. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 1998;188:287–296.

    Article  CAS  PubMed  Google Scholar 

  163. Annunziato F, Cosmi L, Liotta F, et al. Phenotype, localization, and mechanism of suppression of CD4(+)CD25(+) human thymocytes. J Exp Med 2002;196:379–387.

    Article  CAS  PubMed  Google Scholar 

  164. Thompson C, Powrie F. Regulatory T cells. Curr Opin Pharmacol 2004;4:408–414.

    Article  CAS  PubMed  Google Scholar 

  165. Powrie F, Carlino J, Leach MW, Mauze S, Coffman RL. A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4+ T cells. J Exp Med 1996;183:2669–2674.

    Article  CAS  PubMed  Google Scholar 

  166. Green EA, Gorelik L, McGregor CM, Tran EH, Flavell RA. CD4+CD25+ T regulatory cells control anti-islet CD8+ T cells through TGF-beta-TGF-beta receptor interactions in type 1 diabetes. Proc Natl Acad Sci USA 2003;100:10,878–10,883.

    Article  CAS  PubMed  Google Scholar 

  167. Shevach EM. CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2002;2:389–400.

    CAS  PubMed  Google Scholar 

  168. Erdman SE, Sohn JJ, Rao VP, et al. CD4+CD25+ regulatory lymphocytes induce regression of intestinal tumors in ApcMin/+ mice. Cancer Res 2005;65:3998–4004.

    Article  CAS  PubMed  Google Scholar 

  169. Khazaie K, von Boehmer H. The impact of CD4+CD25+ Treg on tumor specific CD8+ T cell cytotoxicity and cancer. Semin Cancer Biol 2006;16:124–136.

    Article  CAS  PubMed  Google Scholar 

  170. Baecher-Allan C, Anderson DE. Immune regulation in tumor-bearing hosts. Curr Opin Immunol 2006;18:214–219.

    Article  CAS  PubMed  Google Scholar 

  171. Belkaid Y, Rouse BT. Natural regulatory T cells in infectious disease. Nat Immunol 2005;6:353–360.

    Article  CAS  PubMed  Google Scholar 

  172. Lahn M, Kloeker S, Berry BS. TGF-beta inhibitors for the treatment of cancer. Expert Opin Invest Drugs 2005;14:629–643.

    Article  CAS  Google Scholar 

  173. Yang YA, Dukhanina O, Tang B, et al. Lifetime exposure to a soluble TGF-beta antagonist protects mice against metastasis without adverse side effects. J Clin Invest 2002;109:1607–1615.

    CAS  PubMed  Google Scholar 

  174. Kontani K, Kajino K, Huangi CL, et al. Spontaneous elicitation of potent antitumor immunity and eradication of established tumors by administration of DNA encoding soluble transforming growth factor-beta II receptor without active antigen-sensitization. Cancer Immunol Immunother 2006;55:579–587.

    Article  PubMed  Google Scholar 

  175. Azuma H, Ehata S, Miyazaki H, et al. Effect of Smad7 expression on metastasis of mouse mammary carcinoma JygMC(A) cells. J Natl Cancer Inst 2005;97:1734–1746.

    Article  CAS  PubMed  Google Scholar 

  176. Fakhrai H, Dorigo O, Shawler DL, et al. Eradication of established intracranial rat gliomas by transforming growth factor beta antisense gene therapy. Proc Natl Acad Sci USA 1996;93:2909–2914.

    Article  CAS  PubMed  Google Scholar 

  177. Kattan MW, Shariat SF, Andrews B, et al. The addition of interleukin-6 soluble receptor and transforming growth factor beta1 improves a preoperative nomogram for predicting biochemical progression in patients with clinically localized prostate cancer. J Clin Oncol 2003;21:3573–3579.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, The National Institutes of Health, Bethesda, MD, USA

    Nancy L. McCartney-Francis PhD & Sharon M. Wahl PhD

Authors
  1. Nancy L. McCartney-Francis PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sharon M. Wahl PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Cancer Training Branch, Office of Centers, Training and Resources, National Cancer Institute, Bethesda, MD

    Sonia B. Jakowlew PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Humana Press Inc., Totowa, NJ

About this chapter

Cite this chapter

McCartney-Francis, N.L., Wahl, S.M. (2008). TGF-β at the Crossroads Between Inflammation, Suppression and Cancer. In: Jakowlew, S.B. (eds) Transforming Growth Factor-β in Cancer Therapy, Volume II. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-293-9_34

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-293-9_34

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-715-0

  • Online ISBN: 978-1-59745-293-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation