Skip to main content

Advertisement

Log in

The TGFß pathway as a therapeutic target in cancer

  • Educational Series
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

The TGFß pathway has recently emerged as a putative therapeutic target against cancer. However, TGFß has a complex and dual role in cancer. In normal epithelial cells and early tumours, TGFß acts as a tumour suppressor. In contrast, during tumour progression TGFß becomes an oncogenic factor inducing proliferation, angiogenesis, invasion and metastasis, as well as suppressing the anti-tumoral immune response. The role of TGFß in oncogenesis requires the precise understanding of the TGFß pathway in order to design optimal therapeutic approaches and select the patient population that may benefit from an anti-TGFß therapy. Here we review the rationale for evaluating TGFß signalling inhibitors as cancer therapeutics, and the progress made in the preclinical and clinical testing of anti-TGFß compounds.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Siegel PM, Massague J (2003) Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nat Rev Cancer 3:807–821

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  5. Shi Y, Massague J (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113:685–700

    Article  PubMed  CAS  Google Scholar 

  6. Massague J, Seoane J, Wotton D (2005) Smad transcription factors. Genes Dev 19:2783–2810

    Article  PubMed  CAS  Google Scholar 

  7. Inman, GJ, Hill CS (2002) Stoichiometry of active smad-transcription factor complexes on DNA. J Biol Chem 277:51008–51016

    Article  PubMed  CAS  Google Scholar 

  8. Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425:577–584

    Article  PubMed  CAS  Google Scholar 

  9. Moustakas A, Heldin CH (2005) Non-Smad TGF-beta signals. J Cell Sci 118:3573–3584

    Article  PubMed  CAS  Google Scholar 

  10. Mulder KM (2000) Role of Ras and Mapks in TGFbeta signaling. Cytokine Growth Factor Rev 11:23–35

    Article  PubMed  CAS  Google Scholar 

  11. Bhowmick NA, Ghiassi M, Bakin A et al (2001) Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol Biol Cell 12:27–36

    PubMed  CAS  Google Scholar 

  12. Edlund S, Landstrom M, Heldin CH, Aspenstrom P (2002) Transforming growth factor-beta-induced mobilization of actin cytoskeleton requires signaling by small GTPases Cdc42 and RhoA. Mol Biol Cell 13:902–914

    Article  PubMed  CAS  Google Scholar 

  13. Muraoka-Cook RS, Shin I, Yi JY et al (2005) Activated type I TGFbeta receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression. Oncogene 25:3408–3423

    Article  PubMed  Google Scholar 

  14. Wilkes MC, Mitchell H, Penheiter SG et al (2005) Transforming growth factor-beta activation of phosphatidylinositol 3-kinase is independent of Smad2 and Smad3 and regulates fibroblast responses via p21-activated kinase-2. Cancer Res 65:10431–10440

    Article  PubMed  CAS  Google Scholar 

  15. Ozdamar B, Bose R, Barrios-Rodiles M et al (2005) Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science 307:1603–1609

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  17. Derynck R, Akhurst RJ, Balmain A (2001) TGF-beta signaling in tumor suppression and cancer progression. Nat Genet 29:117–129

    Article  PubMed  CAS  Google Scholar 

  18. Bierie B, Moses HL (2006) Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer 6:506–520

    Article  PubMed  CAS  Google Scholar 

  19. Seoane J (2006) Escaping from the TGFbeta antiproliferative control. Carcinogenesis 27:2148–2156

    Article  PubMed  CAS  Google Scholar 

  20. Levy L, Hill CS (2006) Alterations in components of the TGF-beta superfamily signaling pathways in human cancer. Cytokine Growth Factor Rev 17:41–58

    Article  PubMed  CAS  Google Scholar 

  21. Bruna A, Darken RS, Rojo F et al (2007) High TGFbeta-Smad activity confers poor prognosis in glioma patients and promotes cell proliferation depending on the methylation of the PDGF-B gene. Cancer Cell 11:147–160

    Article  PubMed  CAS  Google Scholar 

  22. Pertovaara L, Kaipainen A, Mustonen T et al (1994) Vascular endothelial growth factor is induced in response to transforming growth factor-beta in fibroblastic and epithelial cells. J Biol Chem 269:6271–6274

    PubMed  CAS  Google Scholar 

  23. Janda E, Lehmann K, Killisch I et al (2002) Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol 156:299–313

    Article  PubMed  CAS  Google Scholar 

  24. Peinado H, Quintanilla M, Cano A (2003) Transforming growth factor beta-1 induces snail transcription factor in epithelial cell lines: mechanisms for epithelial mesenchymal transitions. J Biol Chem 278:21113–21123

    Article  PubMed  CAS  Google Scholar 

  25. Wrzesinski SH, Wan YY, Flavell RA (2007) Transforming growth factor-beta and the immune response: implications for anticancer therapy. Clin Cancer Res 13:5262–5270

    Article  PubMed  CAS  Google Scholar 

  26. Tsushima H, Ito N, Tamura S et al (2001) Circulating transforming growth factor beta 1 as a predictor of liver metastasis after resection in colorectal cancer. Clin Cancer Res 7:1258–1262

    PubMed  CAS  Google Scholar 

  27. Pangas SA, Matzuk MM (2004) Genetic models for transforming growth factor beta superfamily signaling in ovarian follicle development. Mol Cell Endocrinol 225:83–91

    Article  PubMed  CAS  Google Scholar 

  28. Mizuguchi T, Collod-Beroud G, Akiyama T et al (2004) Heterozygous TGFBR2 mutations in Marfan syndrome. Nat Genet 36:855–860

    Article  PubMed  CAS  Google Scholar 

  29. Loeys BL, Chen J, Neptune ER et al (2005) A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet 37:275–281

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  31. Kanzler S, Meyer E, Lohse AW et al (2001) Hepatocellular expression of a dominant-negative mutant TGF-beta type II receptor accelerates chemically induced hepatocarcinogenesis. Oncogene 20:5015–5024

    Article  PubMed  CAS  Google Scholar 

  32. Im YH, Kim HT, Kim IY et al (2001) Heterozygous mice for the transforming growth factor-beta type II receptor gene have increased susceptibility to hepatocellular carcinogenesis. Cancer Res 61:6665–6668

    PubMed  CAS  Google Scholar 

  33. Gorska AE, Jensen RA, Shyr Y et al (2003) Transgenic mice expressing a dominant-negative mutant type II transforming growth factor-beta receptor exhibit impaired mammary development and enhanced mammary tumor formation. Am J Pathol 163:1539–1549

    PubMed  CAS  Google Scholar 

  34. Yingling JM, Blanchard KL, Sawyer JS (2004) Development of TGF-beta signalling inhibitors for cancer therapy. Nat Rev Drug Discov 3: 1011–1022

    Article  PubMed  CAS  Google Scholar 

  35. Dumont N, Arteaga CL (2003) Targeting the TGF beta signaling network in human neoplasia. Cancer Cell 3:531–536

    Article  PubMed  CAS  Google Scholar 

  36. Akhurst RJ (2006) Large-and small-molecule inhibitors of transforming growth factor-beta signaling. Curr Opin Investig Drugs 7:513–521

    PubMed  CAS  Google Scholar 

  37. Saunier EF, Akhurst RJ (2006) TGF beta inhibition for cancer therapy. Curr Cancer Drug Targets 6:565–578

    Article  PubMed  CAS  Google Scholar 

  38. Hau P, Jachimczak P, Schlingensiepen R et al (2007) Inhibition of TGF-beta2 with AP 12009 in recurrent malignant gliomas: from preclinical to phase I/II studies. Oligonucleotides 17:201–212

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  40. Schlingensiepen, R, Goldbrunner M, Szyrach MN et al (2005) Intracerebral and intrathecal infusion of the TGF-beta 2-specific antisense phosphorothioate oligonucleotide AP 12009 in rabbits and primates: toxicology and safety. Oligonucleotides 15:94–104

    Article  PubMed  CAS  Google Scholar 

  41. Mead AL, Wong TT, Cordeiro MF et al (2003) Evaluation of anti-TGF-beta2 antibody as a new postoperative anti-scarring agent in glaucoma surgery. Invest Ophthalmol Vis Sci 44:3394–3401

    Article  PubMed  Google Scholar 

  42. Benigni A, Zoja C, Corna D et al (2003) Add-on anti-TGF-beta antibody to ACE inhibitor arrests progressive diabetic nephropathy in the rat. J Am Soc Nephrol 14:1816–1824

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  44. Inman GJ, Nicolas FJ, Callahan JF et al (2002) SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7. Mol Pharmacol 62:65–74

    Article  PubMed  CAS  Google Scholar 

  45. Uhl M, Aulwurm S, Wischhusen J et al (2004) SD-208, a novel transforming growth factor beta receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitro and in vivo. Cancer Res 64:7954–7961

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Joan Seoane.

Additional information

Supported by an unrestricted educational grant from Pfizer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Seoane, J. The TGFß pathway as a therapeutic target in cancer. Clin Transl Oncol 10, 14–19 (2008). https://doi.org/10.1007/s12094-008-0148-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-008-0148-2

Keywords

Navigation