Role of transforming growth factor β in cancer microenvironment

  • Luis de la Cruz-Merino
  • Fernando Henao-Carrasco
  • Teresa García-Manrique
  • Pedro M. Fernández-Salguero
  • Manuel Codes-Manuel de Villena
Educational Series Molecular Targets in Oncology

Abstract

Transforming growth factor β (TGF-β) family members are polypeptidic cytokines with pleiotropic physiological properties. In relation to cancer, TGF-β exerts a dual tumour-suppressive and oncogenic effect, which is largely dependent on microenvironment stimuli. After activation of TGF-β signalling, two pathways can be activated: the canonical one through the mammalian Smad family or the non-canonical one activating, among others, the cellular mitogen-activated protein kinase (MAPK) signalling downstream, which interacts with Smad signalling. During tumorigenesis, cells of many cancer types often lose their response to the tumour-suppressive effects of TGF-β, which, in turn, has the opposite effect, acting as an autocrine tumour-promoting factor. In this review, we summarise the current knowledge about this intriguing cytokine, with special emphasis on its immunosuppressive actions.

Keywords

Transforming growth factor Cancer Microenvironment 

References

  1. 1.
    Massague J, Blain SW, Lo RS (2000) TGFβ signaling in growth control, cancer, and heritable disorders. Cell 103:295–309CrossRefPubMedGoogle Scholar
  2. 2.
    Siegel PM, Massague J (2003) Cytostatic and apoptotic actions of TGF-β in homeostasis and cancer. Nat Rev 3:807–819Google Scholar
  3. 3.
    de Caestecker M (2004) The transforming growth factor β superfamily of receptors. Cytokine Growth Factor Rev 15:1–11CrossRefPubMedGoogle Scholar
  4. 4.
    Hyytianen M, Pentinnen C, Keski-Oja J (2004) Latent TGFβ binging proteins: extracellular matrix association and roles in TGF β activation. Crit Rev Clin Lab Sci 4:233–264CrossRefGoogle Scholar
  5. 5.
    Feng XH, Derynck R (2005) Specificity and versatility in TGFβ signaling through Smads. Annu Rev Cell Dev Biol 21:659–693CrossRefPubMedGoogle Scholar
  6. 6.
    Attisano L, Lee-Hoeflich T (2001) The Smads. Genome Biol 2: REVIEWS3010CrossRefPubMedGoogle Scholar
  7. 7.
    Weinstein M, Yang X, Deng C (2000) Functions of mammalian Smads genes as revealed by targeted gene disruption in mice. Cytokine Growth Factor Rev 11:49–58CrossRefPubMedGoogle Scholar
  8. 8.
    Shi Y, Massagué J (2003) Mechanisms of TGFβ signaling from cell membrane to the nucleus. Cell 113:685–700CrossRefPubMedGoogle Scholar
  9. 9.
    Leivonen SK, Kahari VM (2007) Transforming growth factor β signaling in cancer invasion and metastasis. Int J Cancer 121:2119–2124CrossRefPubMedGoogle Scholar
  10. 10.
    Javelaud D, Mauviel A (2005) Crosstalk mechanisms between the mitogen-activated protein kinase pathways and Smad signaling downstream of TGFβ: implications for carcinogenesis. Oncogene 24:5742–5750CrossRefPubMedGoogle Scholar
  11. 11.
    Wakefield LM, Roberts AB (2002) TGF-β signaling: positive and negative effects on tumorigenesis. Curr Opin Genet Dev 12:22–29CrossRefPubMedGoogle Scholar
  12. 12.
    Derynck R, Akhurst RJ, Balmain A (2001) TGF-β signaling in tumor suppression and cancer progression. Nat Genet 29:117–129CrossRefPubMedGoogle Scholar
  13. 13.
    Cordenonsi M, Dupont S, Maretto S et al (2003) Links between tumor suppressors: p53 is required for TGF-β gene responses by cooperating with Smads. Cell 113:301–314CrossRefPubMedGoogle Scholar
  14. 14.
    Ribeiro A, Bronk SE, Roberts PJ et al (1999) The transforming growth factor β1 inducible transcription factor, TIEG1, mediated apoptosis trough oxidative stress. Hepatology 30:1490–1497CrossRefPubMedGoogle Scholar
  15. 15.
    Pardali K, Moustakas A (2007) Actions of TGF-β as tumor suppressor and pro-metastatic factor in human cancer. Biochim Biophys Acta 1775:21–62PubMedGoogle Scholar
  16. 16.
    Dumont N, Arteaga CL (2002) The tumor microenvironment: a potential arbitrator of the tumor suppressive and promoting actions of TGF-β. Differentiation 70:574–582CrossRefPubMedGoogle Scholar
  17. 17.
    Claassen GF, Hann SR (2000) A role for transcriptional repression of p21CIP1 by c-myc in overcoming transforming growth factor β induced cell cycle arrest. Proc Natl Acad Sci USA 97:9498–9503CrossRefPubMedGoogle Scholar
  18. 18.
    Cohen MM (2003) TGF β/Smad signaling system and its pathological correlates. Am J Med Genet A 116:1–10CrossRefGoogle Scholar
  19. 19.
    Zavadil J, Bottinger EP (2005) TGF-β and epithelial to mesenchymal transitions. Oncogene 24:5764–5774CrossRefPubMedGoogle Scholar
  20. 20.
    Gupta GP, Perk J, Acharyya S et al (2007) ID genes mediate tumor reinitiation during breast cancer lung metastasis. Proc Natl Acad Sci USA 104:19506–19511CrossRefPubMedGoogle Scholar
  21. 21.
    Restifo NP, Robbins PF, Rosenberg SA (2008) Principles of immunotherapy. In: DeVita VT, Lawrence TS, Rosenberg SA (eds) Cancer: principles and practice of oncology, 8th Edn. Lippincott Williams & Wilkins, Philadelphia, pp 351–368Google Scholar
  22. 22.
    De la Cruz-Merino L, Grande-Pulido E, Albero-Tamarit A, Codes-Manuel de Villena (2008) Cancer and immune response: old and new evidence for future challenges. Oncologist 13:1246–1254CrossRefPubMedGoogle Scholar
  23. 23.
    Alexander WS, Hilton DJ (2004) The role of suppressors of cytokine signaling in regulation of the immune response. Annu Rev Immunol 22:503–529CrossRefPubMedGoogle Scholar
  24. 24.
    Li MO, Wan YY, Sanjabi S et al (2006) Transforming growth factor β regulation of immune responses. Annu Rev Immunol 24:99–146CrossRefPubMedGoogle Scholar
  25. 25.
    Howe PH (2003) Transforming growth factor β. In: Thompson AW, Lotze MT (eds) The cytokine handbook, 4th ed. Academic Press, San Diego, CA, pp 1119–1152Google Scholar
  26. 26.
    Lu T, Tian L, Han Y et al (2007) Dose dependent cross talk between the TGF-βand interleukin-1 signaling pathways. Proc Natl Acad Sci USA 14:4365–4370CrossRefGoogle Scholar
  27. 27.
    Teicher BA (2007) TGF-β and the immune response to malignant disease. Clin Cancer Res 13:6247–6251CrossRefPubMedGoogle Scholar
  28. 28.
    Tian M, Schiemann WP (2009) The TGF-β paradox in human cancer: an update. Future Oncol 5:259–271CrossRefPubMedGoogle Scholar
  29. 29.
    Langer LF, Clay TM, Morse MA (2007) Update on anti-CTLA-4 antibodies in clinical trials. Expert Opin Biol Ther 7:1245–1256CrossRefPubMedGoogle Scholar
  30. 30.
    Pyzic M, Piccirillo CA (2007) TGF-β 1 modulates Foxp3 expression and regulatory activity in distinct BCD4+ T cell subsets. J Leukoc Biol 82:335–346CrossRefGoogle Scholar
  31. 31.
    Zou W (2006) Regulatory T cells, tumor immunity and immunotherapy. Nat Rev Immunol 6:295–307CrossRefPubMedGoogle Scholar
  32. 32.
    Selvaraj RK, Geiger TL (2007) A kinetic and dynamic analysis of Foxp3 induced in T cells by TGF-β. J Immunol 178:7667–7677PubMedGoogle Scholar
  33. 33.
    Yingling JM, Blanchard KL, Sawyer JS (2004) Development of TGF β signalling inhibitors for cancer therapy. Nat Rev Drug Discov 3:1011–1022CrossRefPubMedGoogle Scholar
  34. 34.
    Akhurst RJ (2006) Large and small molecule inhibitors of transforming growth factor β signaling. Curr Opin Investig Drugs 7:513–521PubMedGoogle Scholar
  35. 35.
    Prud’Homme GJ (2007) Pathobiology of transforming growth factor β in cancer, fibrosis and immunologic disease, and therapeutic considerations. Lab Invest 87:1077–1091CrossRefPubMedGoogle Scholar
  36. 36.
    Schlingensiepen KH, Schligensiepen R, Steinbrecher A et al (2006) Targeted tumor therapy with the TGF-beta 2 antisense compound AP 12009. Cytokine Growth Factor Rev 17:129–139CrossRefPubMedGoogle Scholar

Copyright information

© Feseo 2009

Authors and Affiliations

  • Luis de la Cruz-Merino
    • 1
  • Fernando Henao-Carrasco
    • 1
  • Teresa García-Manrique
    • 1
  • Pedro M. Fernández-Salguero
    • 2
  • Manuel Codes-Manuel de Villena
    • 1
  1. 1.Servicio de Oncología MédicaHospital Universitario Virgen MacarenaSevillaSpain
  2. 2.Departamento de Bioquímica y Biología Molecular Facultad de CienciasUniversidad de ExtremaduraBadajozSpain

Personalised recommendations