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  • Review Article
  • Published:

Targeting the TGFβ signalling pathway in disease

An Erratum to this article was published on 19 October 2012

This article has been updated

Key Points

  • Transforming growth factor-β (TGFβ) has pleiotropic effects on many cell types in vivo, mediated via multiple signalling pathways — canonical and non-canonical

  • TGFβ signalling is modulated by other signalling pathways (for example, Notch and RAS).

  • TGFβ effects are context-dependent: they are influenced by cell type, growth or differentiation status, and innate genetic variation.

  • TGFβ is potently immune-modulatory and signalling is upregulated in, and can exacerbate, many disease states, especially cancer and fibrosis.

  • Drugs for TGFβ signalling blockade have been developed that target biosynthesis, activation, ligand and receptor binding as well as downstream responses to TGFβ.

  • Drug classes include antisense oligonucleotides (ASOs), ligand traps, antibodies, small-molecule chemical inhibitors, antisense genes, pyrrole-imidazole polyamide DNA binders and gene therapy.

  • In cancer therapy, TGFβ blockade may suppress metastasis by targeting tumour-initiating cells, enhancing immune surveillance and cytotoxic T cell activity, modulating the tumour stroma and suppressing angiogenesis.

  • In fibrosis, TGFβ blockade suppresses epithelial–mesenchymal transition, inhibits myofibroblast differentiation and proliferation, and prevents excessive elaboration of the extracellular matrix.

  • Clinical trials are ongoing for applications in oncology and fibrosis.

  • In oncology, clinical trials show promise with ASOs for malignant glioblastoma and pancreatic cancer, antibodies for metastatic melanoma and renal cell carcinoma, and chemical inhibition for glioblastoma, as well as augmentation of tumour vaccines for non-small-cell lung cancer.

  • In fibrosis, clinical trials show promise for focal segmental glomerulosclerosis and diabetic kidney disease using anti-ligand antibodies, for scleroderma/skin fibrosis using a topical betaglycan mimetic peptide, and for idiopathic pulmonary fibrosis, glomerulosclerosis and diabetic kidney disease with pirfenidone.

  • Combination therapies of chemotherapy or radiation with TGFβ blockade show great promise for oncology.

  • Patient selection will be critical to obtain therapeutic efficacy and minimize side effects.

Abstract

Many drugs that target transforming growth factor-β (TGFβ) signalling have been developed, some of which have reached Phase III clinical trials for a number of disease applications. Preclinical and clinical studies indicate the utility of these agents in fibrosis and oncology, particularly in augmentation of existing cancer therapies, such as radiation and chemotherapy, as well as in tumour vaccines. There are also reports of specialized applications, such as the reduction of vascular symptoms of Marfan syndrome. Here, we consider why the TGFβ signalling pathway is a drug target, the potential clinical applications of TGFβ inhibition, the issues arising with anti-TGFβ therapy and how these might be tackled using personalized approaches to dosing, monitoring of biomarkers as well as brief and/or localized drug-dosing regimens.

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Figure 1: Schematic overview of the canonical, SMAD-dependent TGFβ signalling pathway.
Figure 2: Schematic representation of non-canonical TGFβ signalling and crosstalk with other signalling pathways.
Figure 3: Biphasic activities of the TGFβ signalling pathway during tumorigenesis: from the tumour suppressor to the tumour promoter.
Figure 4: TGFβ effects on immune cells.
Figure 5: Schematic representation of therapeutic approaches for blocking TGFβ signalling.
Figure 6: Structures of representative small-molecule inhibitors of TGFβ signalling.

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Change history

  • 19 October 2012

    On page 7 of the main text, LY2382770 was incorrectly referred to as a pan-TGFβ ligand-specific blocking antibody; it is a TGFβ1 ligand-selective blocking antibody. This has now been corrected online.

References

  1. Schmierer, B. & Hill, C. S. TGFβ–SMAD signal transduction: molecular specificity and functional flexibility. Nature Rev. Mol. Cell Biol. 8, 970–982 (2007).

    Article  CAS  Google Scholar 

  2. Derynck, R. & Miyazono, K. (eds) The TGF-β Family (Cold Spring Harbor Press, 2008).

    Google Scholar 

  3. Derynck, R. & Akhurst, R. J. Differentiation plasticity regulated by TGF-β family proteins in development and disease. Nature Cell Biol. 9, 1000–1004 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Flavell, R. A., Sanjabi, S., Wrzesinski, S. H. & Licona-Limon, P. The polarization of immune cells in the tumour environment by TGFβ. Nature Rev. Immunol. 10, 554–567 (2010).

    Article  CAS  Google Scholar 

  5. Mao, J. H. et al. Genetic variants of Tgfb1 act as context-dependent modifiers of mouse skin tumor susceptibility. Proc. Natl Acad. Sci. USA 103, 8125–8130 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Guo, X. & Wang, X. F. Signaling cross-talk between TGF-β/BMP and other pathways. Cell Res. 19, 71–88 (2009).

    Article  CAS  PubMed  Google Scholar 

  7. Conidi, A. et al. Few Smad proteins and many Smad-interacting proteins yield multiple functions and action modes in TGFβ/BMP signaling in vivo. Cytokine Growth Factor Rev. 22, 287–300 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. Akhurst, R. J. TGFβ signaling in health and disease. Nature Genet. 36, 790–792 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Freimuth, J. et al. Epistatic interactions between Tgfb1 and genetic loci, Tgfbm2 and Tgfbm3, determine susceptibility to an asthmatic stimulus. Proc. Natl Acad. Sci. USA (in the press).

  10. Anscher, M. S. et al. Small molecular inhibitor of transforming growth factor-β protects against development of radiation-induced lung injury. Int. J. Radiat. Oncol. Biol. Phys. 71, 829–837 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Neptune, E. R. et al. Dysregulation of TGF-β activation contributes to pathogenesis in Marfan syndrome. Nature Genet. 33, 407–411 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Habashi, J. P. et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 312, 117–121 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Roberts, A. B. & Wakefield, L. M. The two faces of transforming growth factor β in carcinogenesis. Proc. Natl Acad. Sci. USA 100, 8621–8623 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Massague, J. TGFβ in cancer. Cell 134, 215–230 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Levy, L. & Hill, C. S. Alterations in components of the TGF-β superfamily signaling pathways in human cancer. Cytokine Growth Factor Rev. 17, 41–58 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Hawinkels, L. J. & Ten Dijke, P. Exploring anti-TGF-β therapies in cancer and fibrosis. Growth Factors 29, 140–152 (2011).

    Article  CAS  PubMed  Google Scholar 

  17. Harradine, K. A. & Akhurst, R. J. Mutations of TGFβ signaling molecules in human disease. Ann. Med. 38, 403–414 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Millan, F. A., Denhez, F., Kondaiah, P. & Akhurst, R. J. Embryonic gene expression patterns of TGF β1, β2 and β3 suggest different developmental functions in vivo. Development 111, 131–143 (1991).

    CAS  PubMed  Google Scholar 

  19. Kulkarni, A. B. et al. Transforming growth factor β1 null mutation in mice causes excessive inflammatory response and early death. Proc. Natl Acad. Sci. USA 90, 770–774 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Shull, M. M. et al. Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease. Nature 359, 693–699 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Dickson, M. C. et al. Defective haematopoiesis and vasculogenesis in transforming growth factor-β1 knock out mice. Development 121, 1845–1854 (1995).

    CAS  PubMed  Google Scholar 

  22. Sanford, L. P. et al. TGFβ2 knockout mice have multiple developmental defects that are non-overlapping with other TGFβ knockout phenotypes. Development 124, 2659–2670 (1997).

    CAS  PubMed  Google Scholar 

  23. Proetzel, G. et al. Transforming growth factor-β3 is required for secondary palate fusion. Nature Genet. 11, 409–414 (1995).

    Article  CAS  PubMed  Google Scholar 

  24. Schultz-Cherry, S., Ribeiro, S., Gentry, L. & Murphy-Ullrich, J. E. Thrombospondin binds and activates the small and large forms of latent transforming growth factor-β in a chemically defined system. J. Biol. Chem. 269, 26775–26782 (1994).

    CAS  PubMed  Google Scholar 

  25. Munger, J. S. et al. The integrin αvβ6 binds and activates latent TGF β1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96, 319–328 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Shi, M. et al. Latent TGF-β structure and activation. Nature 474, 343–349 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  28. Davis-Dusenbery, B. N. & Hata, A. Smad-mediated miRNA processing: a critical role for a conserved RNA sequence. RNA Biol. 8, 71–76 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Oft, M. et al. TGF-β1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells. Genes Dev. 10, 2462–2477 (1996).

    Article  CAS  PubMed  Google Scholar 

  30. Massague, J. & Gomis, R. R. The logic of TGFβ signaling. FEBS Lett. 580, 2811–2820 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Massague, J. How cells read TGF-β signals. Nature Rev. Mol. Cell Biol. 1, 169–178 (2000).

    Article  CAS  Google Scholar 

  32. Mehra, A. & Wrana, J. L. TGF-β and the Smad signal transduction pathway. Biochem. Cell Biol. 80, 605–622 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Padua, D. & Massague, J. Roles of TGFβ in metastasis. Cell Res. 19, 89–102 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Heldin, C. H., Landstrom, M. & Moustakas, A. Mechanism of TGF-β signaling to growth arrest, apoptosis, and epithelial–mesenchymal transition. Curr. Opin. Cell Biol. 21, 166–176 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. Dooley, S. & ten Dijke, P. TGF-β in progression of liver disease. Cell Tissue Res. 347, 245–256 (2012).

    Article  CAS  PubMed  Google Scholar 

  36. Pardali, E. & Ten Dijke, P. TGFβ signaling and cardiovascular diseases. Int. J. Biol. Sci. 8, 195–213 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Derynck, R., Akhurst, R. J. & Balmain, A. TGF-β signaling in tumor suppression and cancer progression. Nature Genet. 29, 117–129 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Coffey, R. J. Jr. et al. Growth modulation of mouse keratinocytes by transforming growth factors. Cancer Res. 48, 1596–1602 (1988).

    CAS  PubMed  Google Scholar 

  39. Gomis, R. R. et al. A FoxO-Smad synexpression group in human keratinocytes. Proc. Natl Acad. Sci. USA 103, 12747–12752 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Siegel, P. M., Shu, W. & Massague, J. Mad upregulation and Id2 repression accompany transforming growth factor (TGF)-β-mediated epithelial cell growth suppression. J. Biol. Chem. 278, 35444–35450 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Akhurst, R. J. The paradoxical TGF-β vasculopathies. Nature Genet. 44, 838–839 (2012).

    Article  CAS  PubMed  Google Scholar 

  42. Heldin, C. H., Rubin, K., Pietras, K. & Ostman, A. High interstitial fluid pressure — an obstacle in cancer therapy. Nature Rev. Cancer 4, 806–813 (2004).

    Article  CAS  Google Scholar 

  43. Mani, S. A. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Salnikov, A. V. et al. Inhibition of TGF-β modulates macrophages and vessel maturation in parallel to a lowering of interstitial fluid pressure in experimental carcinoma. Lab. Invest. 85, 512–521 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Willis, B. C. et al. Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-β1: potential role in idiopathic pulmonary fibrosis. Am. J. Pathol. 166, 1321–1332 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kim, K. K. et al. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc. Natl Acad. Sci. USA 103, 13180–13185 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Goumans, M. J., van Zonneveld, A. J. & ten Dijke, P. Transforming growth factor β-induced endothelial-to-mesenchymal transition: a switch to cardiac fibrosis? Trends Cardiovasc. Med. 18, 293–298 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Sato, M., Muragaki, Y., Saika, S., Roberts, A. B. & Ooshima, A. Targeted disruption of TGF-β1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction. J. Clin. Invest. 112, 1486–1494 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lan, H. Y. Diverse roles of TGF-β/Smads in renal fibrosis and inflammation. Int. J. Biol. Sci. 7, 1056–1067 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Yao, E. H. et al. A pyrrole-imidazole polyamide targeting transforming growth factor-β1 inhibits restenosis and preserves endothelialization in the injured artery. Cardiovasc. Res. 81, 797–804 (2009). This study evaluates the potential use of a pyrrole-imidazole polyamide that targets TGFB1 expression for preventing restenosis after the use of drug-eluting stents.

    Article  CAS  PubMed  Google Scholar 

  51. Tsai, S. et al. TGF-β through Smad3 signaling stimulates vascular smooth muscle cell proliferation and neointimal formation. Am. J. Physiol. Heart Circ. Physiol. 297, H540–H549 (2009). This study demonstrates the role of the TGFβ–SMAD3 pathway in the development of intimal hyperplasia in response to endothelial injury.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Fu, K. et al. SM16, an orally active TGFβ type I receptor inhibitor prevents myofibroblast induction and vascular fibrosis in the rat carotid injury model. Arterioscler. Thromb. Vasc. Biol. 28, 665–671 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Nishimura, G. et al. δEF1 mediates TGF-β signaling in vascular smooth muscle cell differentiation. Dev. Cell 11, 93–104 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. Diebold, R. J. et al. Early-onset multifocal inflammation in the transforming growth factor β1-null mouse is lymphocyte mediated. Proc. Natl Acad. Sci. USA 92, 12215–12219 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Rubtsov, Y. P. & Rudensky, A. Y. TGFβ signalling in control of T-cell-mediated self-reactivity. Nature Rev. Immunol. 7, 443–453 (2007).

    Article  CAS  Google Scholar 

  56. Ramesh, S., Wildey, G. M. & Howe, P. H. Transforming growth factor β (TGFβ)-induced apoptosis: the rise and fall of Bim. Cell Cycle 8, 11–17 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Maruyama, T. et al. Control of the differentiation of regulatory T cells and TH17 cells by the DNA-binding inhibitor Id3. Nature Immunol. 12, 86–95 (2011).

    Article  CAS  Google Scholar 

  58. Gorelik, L. & Flavell, R. A. Immune-mediated eradication of tumors through the blockade of transforming growth factor-β signaling in T cells. Nature Med. 7, 1118–1122 (2001). This study shows that T cell-specific blockade of TGFβ signalling using a dominant negative type II receptor potentiates immune eradication of tumours in mice challenged with live tumour cells.

    Article  CAS  PubMed  Google Scholar 

  59. Yamaguchi, Y., Tsumura, H., Miwa, M. & Inaba, K. Contrasting effects of TGF-β1 and TNF-α on the development of dendritic cells from progenitors in mouse bone marrow. Stem Cells 15, 144–153 (1997).

    Article  CAS  PubMed  Google Scholar 

  60. Sato, K. et al. TGF-β1 reciprocally controls chemotaxis of human peripheral blood monocyte-derived dendritic cells via chemokine receptors. J. Immunol. 164, 2285–2295 (2000).

    Article  CAS  PubMed  Google Scholar 

  61. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Mangan, P. R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006).

    Article  CAS  PubMed  Google Scholar 

  63. Gutcher, I. et al. Autocrine transforming growth factor-β1 promotes in vivo TH17 cell differentiation. Immunity 34, 396–408 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Annunziato, F. & Romagnani, S. Mouse T helper 17 phenotype: not so different than in man after all. Cytokine 56, 112–115 (2011).

    Article  CAS  PubMed  Google Scholar 

  65. Das, J. et al. Transforming growth factor β is dispensable for the molecular orchestration of TH17 cell differentiation. J. Exp. Med. 206, 2407–2416 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ghoreschi, K. et al. Generation of pathogenic TH17 cells in the absence of TGF-β signalling. Nature 467, 967–971 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Laouar, Y., Sutterwala, F. S., Gorelik, L. & Flavell, R. A. Transforming growth factor-β controls T helper type 1 cell development through regulation of natural killer cell interferon-γ. Nature Immunol. 6, 600–607 (2005).

    Article  CAS  Google Scholar 

  68. Mantovani, A., Sozzani, S., Locati, M., Allavena, P. & Sica, A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 23, 549–555 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. Fridlender, Z. G. et al. Polarization of tumor-associated neutrophil phenotype by TGF-β: “N1” versus “N2” TAN. Cancer Cell 16, 183–194 (2009). This study shows that TGFβ blockade increases neutrophil-attracting chemokines, and 'depolarizes' the invading tumour-associated neutrophils to become more cytotoxic to tumour cells and to express higher levels of pro-inflammatory cytokines.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Schlingensiepen, R. et al. Intracerebral and intrathecal infusion of the TGF-β2-specific antisense phosphorothioate oligonucleotide AP 12009 in rabbits and primates: toxicology and safety. Oligonucleotides 15, 94–104 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. Schlingensiepen, K. H. et al. Targeted tumor therapy with the TGF-β2 antisense compound AP 12009. Cytokine Growth Factor Rev. 17, 129–139 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Jachimczak, P. et al. The effect of transforming growth factor-β2-specific phosphorothioate-anti-sense oligodeoxynucleotides in reversing cellular immunosuppression in malignant glioma. J. Neurosurg. 78, 944–951 (1993).

    Article  CAS  PubMed  Google Scholar 

  73. Schlingensiepen, K. H. et al. Transforming growth factor-β2 gene silencing with trabedersen (AP 12009) in pancreatic cancer. Cancer Sci. 102, 1193–1200 (2011).

    Article  CAS  PubMed  Google Scholar 

  74. Bogdahn, U. et al. Targeted therapy for high-grade glioma with the TGF-β2 inhibitor trabedersen: results of a randomized and controlled phase IIb study. Neuro Oncol. 13, 132–142 (2011). This is the full report of a randomized, open-label, active-controlled, dose-finding Phase IIb study to evaluate the efficacy and safety of trabedersen (AP12009) administered intra-tumourally by convection-enhanced delivery in patients with recurrent or refractory high-grade glioma.

    Article  CAS  PubMed  Google Scholar 

  75. Santiago, B. et al. Topical application of a peptide inhibitor of transforming growth factor-β1 ameliorates bleomycin-induced skin fibrosis. J. Invest. Dermatol. 125, 450–455 (2005). This is the first evidence that the peptide inhibitor P144 may be efficacious in the treatment of skin fibrosis after topical application.

    Article  CAS  PubMed  Google Scholar 

  76. Llopiz, D. et al. Peptide inhibitors of transforming growth factor-β enhance the efficacy of antitumor immunotherapy. Int. J. Cancer 125, 2614–2623 (2009).

    Article  CAS  PubMed  Google Scholar 

  77. Hermida, N. et al. A synthetic peptide from transforming growth factor-β1 type III receptor prevents myocardial fibrosis in spontaneously hypertensive rats. Cardiovascular Res. 81, 601–609 (2009). This study shows that P144 inhibits the TGFβ1-dependent signalling pathway and prevents myocardial fibrosis.

    Article  CAS  Google Scholar 

  78. Ezquerro, I. J. et al. A synthetic peptide from transforming growth factor β type III receptor inhibits liver fibrogenesis in rats with carbon tetrachloride liver injury. Cytokine 22, 12–20 (2003).

    Article  CAS  PubMed  Google Scholar 

  79. Nam, J. S. et al. An anti-transforming growth factor β antibody suppresses metastasis via cooperative effects on multiple cell compartments. Cancer Res. 68, 3835–3843 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Ganapathy, V. et al. Targeting the transforming growth factor-β pathway inhibits human basal-like breast cancer metastasis. Mol. Cancer 9, 122 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Bouquet, F. et al. TGFβ1 inhibition increases the radiosensitivity of breast cancer cells in vitro and promotes tumor control by radiation in vivo. Clin. Cancer Res. 17, 6754–6765 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Rodon Ahnert, J. et al. First human dose (FHD) study of the oral transforming growth factor-β receptor I kinase inhibitor LY2157299 in patients with treatment-refractory malignant glioma. J. Clin. Oncol. 29, Abstract 3011 (2011).

    Article  Google Scholar 

  83. Schlingensiepen, K. H., Fischer-Blass, B., Schmaus, S. & Ludwig, S. Antisense therapeutics for tumor treatment: the TGF-β2 inhibitor AP 12009 in clinical development against malignant tumors. Recent Results Cancer Res. 177, 137–150 (2008).

    Article  CAS  PubMed  Google Scholar 

  84. Oettle, H. et al. Final results of a phase I/II study in patients with pancreatic cancer, malignant melanoma, and colorectal carcinoma with trabedersen. J. Clin. Oncol. 30, Abstract 4034 (2012).

    Google Scholar 

  85. Nemunaitis, J. et al. Phase II study of belagenpumatucel-L, a transforming growth factor β-2 antisense gene-modified allogeneic tumor cell vaccine in non-small-cell lung cancer. J. Clin. Oncol. 24, 4721–4730 (2006). This paper reports the first Phase II trial of the non-viral, gene-based, allogeneic tumour cell vaccine of antisense TGFβ2-transfected NSCLC cells. This vaccine shows great promise in increasing survival rates for NSCLC.

    Article  CAS  PubMed  Google Scholar 

  86. Nemunaitis, J. et al. Phase II trial of Belagenpumatucel-L, a TGF-β2 antisense gene modified allogeneic tumor vaccine in advanced non small cell lung cancer (NSCLC) patients. Cancer Gene Ther. 16, 620–624 (2009).

    Article  CAS  PubMed  Google Scholar 

  87. Bazhenova, L., Carrier, E., Shawler, D. & Fakhrai, H. Long-term survival in a phase II study of belagenpumatucel-L (antisense TGFβ vaccine) in non small-cell lung cancer (NSCLC). Cancer Res. 72, Abstract 5367 (2012).

    Article  Google Scholar 

  88. Mead, A. L., Wong, T. T., Cordeiro, M. F., Anderson, I. K. & Khaw, P. T. Evaluation of anti-TGF-β2 antibody as a new postoperative anti-scarring agent in glaucoma surgery. Invest. Ophthalmol. Vis. Sci. 44, 3394–3401 (2003).

    Article  PubMed  Google Scholar 

  89. CAT-152 0201 Trabeculectomy Study Group. CAT-152 trabeculectomy study. Ophthalmology 114, 1950 (2007).

  90. Denton, C. P. et al. Recombinant human anti-transforming growth factor β1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192. Arthritis Rheum. 56, 323–333 (2007). This report evaluates CAT-192, a recombinant human antibody that neutralizes TGFβ1, in the treatment of early-stage diffuse cutaneous systemic sclerosis and concludes that there is no evidence of efficacy.

    Article  CAS  PubMed  Google Scholar 

  91. Lonning, S., Mannick, J. & McPherson, J. M. Antibody targeting of TGF-β in cancer patients. Curr. Pharm. Biotechnol. 12, 2176–2189 (2011).

    Article  CAS  PubMed  Google Scholar 

  92. Trachtman, H. et al. A phase 1, single-dose study of fresolimumab, an anti-TGF-β antibody, in treatment-resistant primary focal segmental glomerulosclerosis. Kidney Int. 79, 1236–1243 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Morris, J. C. et al. Phase I/II study of GC1008: a human anti-transforming growth factor-beta (TGFβ) monoclonal antibody (MAb) in patients with advanced malignant melanoma (MM) or renal cell carcinoma (RCC). J. Clin. Oncol. 26, Abstract 9028 (2008).

    Article  Google Scholar 

  94. Zhong, Z. et al. Anti-transforming growth factor β receptor II antibody has therapeutic efficacy against primary tumor growth and metastasis through multieffects on cancer, stroma, and immune cells. Clin. Cancer Res. 16, 1191–1205 (2010).

    Article  CAS  PubMed  Google Scholar 

  95. Van Aarsen, L. A. et al. Antibody-mediated blockade of integrin αvβ6 inhibits tumor progression in vivo by a transforming growth factor-β-regulated mechanism. Cancer Res. 68, 561–570 (2008).

    Article  CAS  PubMed  Google Scholar 

  96. Muraoka, R. S. et al. Blockade of TGF-β inhibits mammary tumor cell viability, migration, and metastases. J. Clin. Invest. 109, 1551–1559 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Lu, A., Miao, M., Schoeb, T. R., Agarwal, A. & Murphy-Ullrich, J. E. Blockade of TSP1-dependent TGF-β activity reduces renal injury and proteinuria in a murine model of diabetic nephropathy. Am. J. Pathol. 178, 2573–2586 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Yingling, J. M., Blanchard, K. L. & Sawyer, J. S. Development of TGF-β signalling inhibitors for cancer therapy. Nature Rev. Drug Discov. 3, 1011–1022 (2004).

    Article  CAS  Google Scholar 

  99. Bonafoux, D. & Lee, W. C. Strategies for TGF-β modulation: a review of recent patents. Expert Opin. Ther. Pat. 19, 1759–1769 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. Saunier, E. F. & Akhurst, R. J. TGFβ inhibition for cancer therapy. Curr. Cancer Drug Targets 6, 519–532 (2006).

    Article  Google Scholar 

  101. Akhurst, R. J. Large- and small-molecule inhibitors of transforming growth factor-beta signaling. Curr. Opin. Investig. Drugs 7, 513–521 (2006).

    CAS  PubMed  Google Scholar 

  102. Washio, H. et al. Transcriptional inhibition of hypertrophic scars by a gene silencer, pyrrole-imidazole polyamide, targeting the TGF-β1 promoter. J. Invest. Dermatol. 131, 1987–1995 (2011).

    Article  CAS  PubMed  Google Scholar 

  103. Chen, M. et al. Pretranscriptional regulation of Tgf-β1 by PI polyamide prevents scarring and accelerates wound healing of the cornea after exposure to alkali. Mol. Ther. 18, 519–527 (2010).

    Article  CAS  PubMed  Google Scholar 

  104. Chen, H. Y. et al. The protective role of Smad7 in diabetic kidney disease: mechanism and therapeutic potential. Diabetes 60, 590–601 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Kapoor, S. Smad7 gene transfer therapy: therapeutic applications beyond colonic fibrosis. Eur. J. Clin. Invest. 38, 876–877; author reply 878–880 (2008).

    Article  CAS  PubMed  Google Scholar 

  106. Sheridan, C. Gene therapy finds its niche. Nature Biotech. 29, 121–128 (2011).

    Article  CAS  Google Scholar 

  107. Foster, A. E. et al. Antitumor activity of EBV-specific T lymphocytes transduced with a dominant negative TGF-β receptor. J. Immunother. 31, 500–505 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Rainusso, N. et al. Immunotherapy targeting HER2 with genetically modified T cells eliminates tumor-initiating cells in osteosarcoma. Cancer Gene Ther. 19, 212–217 (2012).

    Article  CAS  PubMed  Google Scholar 

  109. Nakazawa, Y. et al. PiggyBac-mediated cancer immunotherapy using EBV-specific cytotoxic T-cells expressing HER2-specific chimeric antigen receptor. Mol. Ther. 19, 2133–2143 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Ahmed, N. et al. HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors. Clin. Cancer Res. 16, 474–485 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Ahmed, N. et al. Regression of experimental medulloblastoma following transfer of HER2-specific T cells. Cancer Res. 67, 5957–5964 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Laverty, H. G. et al. Effects of avotermin (transforming growth factor β3) in a clinically relevant pig model of long, full-thickness incisional wounds. J. Cutan. Med. Surg. 14, 223–232 (2010).

    Article  CAS  PubMed  Google Scholar 

  113. Cohn, R. D. et al. Angiotensin II type 1 receptor blockade attenuates TGF-β-induced failure of muscle regeneration in multiple myopathic states. Nature Med. 13, 204–210 (2007).

    Article  CAS  PubMed  Google Scholar 

  114. Podowski, M. et al. Angiotensin receptor blockade attenuates cigarette smoke-induced lung injury and rescues lung architecture in mice. J. Clin. Invest. 122, 229–240 (2012).

    Article  CAS  PubMed  Google Scholar 

  115. Lanz, T. V. et al. Angiotensin II sustains brain inflammation in mice via TGF-β. J. Clin. Invest. 120, 2782–2794 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Zhou, H., Latham, C. W., Zander, D. S., Margolin, S. B. & Visner, G. A. Pirfenidone inhibits obliterative airway disease in mouse tracheal allografts. J. Heart Lung Transplant. 24, 1577–1585 (2005).

    Article  PubMed  Google Scholar 

  117. Taniguchi, H. et al. The clinical significance of 5% change in vital capacity in patients with idiopathic pulmonary fibrosis: extended analysis of the pirfenidone trial. Respir. Res. 12, 93 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Noble, P. W. et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 377, 1760–1769 (2011).

    Article  CAS  PubMed  Google Scholar 

  119. Grainger, D. J. et al. The serum concentration of active transforming growth factor-β is severely depressed in advanced atherosclerosis. Nature Med. 1, 74–79 (1995).

    Article  CAS  PubMed  Google Scholar 

  120. Cui, W. et al. TGFβ1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice. Cell 86, 531–542 (1996).

    Article  CAS  PubMed  Google Scholar 

  121. Bierie, B. & Moses, H. L. Gain or loss of TGFβ signaling in mammary carcinoma cells can promote metastasis. Cell Cycle 8, 3319–3327 (2009).

    Article  CAS  PubMed  Google Scholar 

  122. Bierie, B. et al. Abrogation of TGF-β signaling enhances chemokine production and correlates with prognosis in human breast cancer. J. Clin. Invest. 119, 1571–1582 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Larsson, J. et al. Abnormal angiogenesis but intact hematopoietic potential in TGF-β type I receptor-deficient mice. EMBO J. 20, 1663–1673 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Akhurst, R. J. TGF-β antagonists: why suppress a tumor suppressor? J. Clin. Invest. 109, 1533–1536 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Yang, Y. A. et al. Lifetime exposure to a soluble TGF-β antagonist protects mice against metastasis without adverse side effects. J. Clin. Invest. 109, 1607–1615 (2002). This is the first demonstration that long-term exposure to a TGFβ antagonist in mice does not manifest any major adverse effects.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Anderton, M. J. et al. Induction of heart valve lesions by small-molecule ALK5 inhibitors. Toxicol. Pathol. 39, 916–924 (2011).

    Article  CAS  PubMed  Google Scholar 

  127. Frazier, K. et al. Inhibition of ALK5 signaling induces physeal dysplasia in rats. Toxicol. Pathol. 35, 284–295 (2007).

    Article  CAS  PubMed  Google Scholar 

  128. Goudie, D. R. et al. Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1. Nature Genet. 43, 365–369 (2011).

    Article  CAS  PubMed  Google Scholar 

  129. Chapman, P. B. et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507–2516 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Arnault, J. P. et al. Keratoacanthomas and squamous cell carcinomas in patients receiving sorafenib. J. Clin. Oncol. 27, e59–e61 (2009).

    Article  PubMed  Google Scholar 

  131. Esser, A. C., Abril, A., Fayne, S. & Doyle, J. A. Acute development of multiple keratoacanthomas and squamous cell carcinomas after treatment with infliximab. J. Am. Acad. Dermatol. 50, S75–S77 (2004).

    Article  PubMed  Google Scholar 

  132. Su, F. et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N. Engl. J. Med. 366, 207–215 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Arnault, J. P. et al. Skin tumors induced by sorafenib; paradoxic RAS-RAF pathway activation and oncogenic mutations of HRAS, TP53, and TGFBR1. Clin. Cancer Res. 18, 263–272 (2012).

    Article  CAS  PubMed  Google Scholar 

  134. Singh, A. & Settleman, J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29, 4741–4751 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Shipitsin, M. et al. Molecular definition of breast tumor heterogeneity. Cancer Cell 11, 259–273 (2007).

    Article  CAS  PubMed  Google Scholar 

  136. Ikushima, H. et al. Autocrine TGF-β signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors. Cell Stem Cell 5, 504–514 (2009).

    Article  CAS  PubMed  Google Scholar 

  137. Anido, J. et al. TGF-β receptor inhibitors target the CD44high/Id1high glioma-initiating cell population in human glioblastoma. Cancer Cell 18, 655–668 (2010). This is a demonstration of the targeting of tumour-initiating cells by TGFβ blockade in a mouse model of glioblastoma.

    Article  CAS  PubMed  Google Scholar 

  138. Penuelas, S. et al. TGF-β increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma. Cancer Cell 15, 315–327 (2009).

    Article  CAS  PubMed  Google Scholar 

  139. Naka, K. et al. TGF-β–FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature 463, 676–680 (2010). This is a demonstration of the targeting of leukaemia-initiating cells by TGFβ blockade in a mouse model of chronic myeloid leukaemia.

    Article  CAS  PubMed  Google Scholar 

  140. Bragado, P. et al. Microenvironmental signals dictate disseminated tumor cells (DTCs) fate through regulation of TGFβII and p38α. Cancer Res. 72 (Suppl. 1), Abstract 5234 (2012).

    Article  Google Scholar 

  141. Biswas, T., Yang, J., Zhao, L. & Sun, L. Z. Development of murine models of breast cancer metastasis for the evaluation of the efficacy of TGF-β inhibitors as therapeutic agents. Cancer Res. 72 (Suppl. 1), Abstract 1366 (2012).

    Article  Google Scholar 

  142. Ohmori, T., Yang, J. L., Price, J. O. & Arteaga, C. L. Blockade of tumor cell transforming growth factor-βs enhances cell cycle progression and sensitizes human breast carcinoma cells to cytotoxic chemotherapy. Exp. Cell Res. 245, 350–359 (1998).

    Article  CAS  PubMed  Google Scholar 

  143. Ehata, S. et al. Transforming growth factor-β decreases the cancer-initiating cell population within diffuse-type gastric carcinoma cells. Oncogene 30, 1693–1705 (2011).

    Article  CAS  PubMed  Google Scholar 

  144. Tang, B. et al. Transforming growth factor-β can suppress tumorigenesis through effects on the putative cancer stem or early progenitor cell and committed progeny in a breast cancer xenograft model. Cancer Res. 67, 8643–8652 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Quante, M. et al. Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell 19, 257–272 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Hayashi, T. et al. Transforming growth factor β receptor I kinase inhibitor down-regulates cytokine secretion and multiple myeloma cell growth in the bone marrow microenvironment. Clin. Cancer Res. 10, 7540–7546 (2004). This is the first report of a chemical inhibitor of TβRI showing antitumour effects via activity on the tumour microenvironment in a mouse model of multiple myeloma.

    Article  CAS  PubMed  Google Scholar 

  147. Bandyopadhyay, A. et al. Doxorubicin in combination with a small TGFβ inhibitor: a potential novel therapy for metastatic breast cancer in mouse models. PLoS ONE 5, e10365 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Takeuchi, K. et al. TGF-β inhibition restores terminal osteoblast differentiation to suppress myeloma growth. PLoS ONE 5, e9870 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Yin, J. J. et al. TGF-β signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J. Clin. Invest. 103, 197–206 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Shinto, O. et al. Combination effect of a TGF-β receptor kinase inhibitor with 5-FU analog S1 on lymph node metastasis of scirrhous gastric cancer in mice. Cancer Sci. 101, 1846–1852 (2010).

    Article  CAS  PubMed  Google Scholar 

  151. Kano, M. R. et al. Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-β signaling. Proc. Natl Acad. Sci. USA 104, 3460–3465 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Liu, Y. & Zeng, G. Cancer and innate immune system interactions: translational potentials for cancer immunotherapy. J. Immunother. 35, 299–308 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Wang, L. et al. Immunotherapy for human renal cell carcinoma by adoptive transfer of autologous transforming growth factor β-insensitive CD8+ T cells. Clin. Cancer Res. 16, 164–173 (2010).

    Article  CAS  PubMed  Google Scholar 

  154. Zhang, Q. et al. Blockade of transforming growth factor-β signaling in tumor-reactive CD8+ T cells activates the antitumor immune response cycle. Mol. Cancer Ther. 5, 1733–1743 (2006).

    Article  CAS  PubMed  Google Scholar 

  155. Wallace, A. et al. Transforming growth factor-β receptor blockade augments the effectiveness of adoptive T-cell therapy of established solid cancers. Clin. Cancer Res. 14, 3966–3974 (2008). This is the first demonstration of the use of a chemical TGFβ receptor inhibitor augmenting adoptive T cell therapy via its immunomodulatory effects.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Connolly, E. C. et al. Outgrowth of drug-resistant carcinomas expressing markers of tumor aggression after long term TβRI/II kinase inhibition with LY2109761. Cancer Res. 71, 1–11 (2011).

    Article  CAS  Google Scholar 

  157. Zhang, M. et al. Blockade of TGF-β signaling by the TGFβR-I kinase inhibitor LY2109761 enhances radiation response and prolongs survival in glioblastoma. Cancer Res. 71, 7155–7167 (2011).

    Article  CAS  PubMed  Google Scholar 

  158. Barcellos-Hoff, M. H. & Akhurst, R. J. Transforming growth factor-β in breast cancer: too much, too late. Breast Cancer Res. 11, 202 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Kirshner, J. et al. Inhibition of transforming growth factor-β1 signaling attenuates ataxia telangiectasia mutated activity in response to genotoxic stress. Cancer Res. 66, 10861–10869 (2006).

    Article  PubMed  Google Scholar 

  160. Zhou, L. et al. Reduced SMAD7 leads to overactivation of TGF-β signaling in MDS that can be reversed by a specific inhibitor of TGF-β receptor I kinase. Cancer Res. 71, 955–963 (2011).

    Article  CAS  PubMed  Google Scholar 

  161. Cerri, S., Spagnolo, P., Luppi, F. & Richeldi, L. Management of idiopathic pulmonary fibrosis. Clin. Chest Med. 33, 85–94 (2012).

    Article  PubMed  Google Scholar 

  162. Sheppard, D. Transforming growth factor β: a central modulator of pulmonary and airway inflammation and fibrosis. Proc. Am. Thorac. Soc. 3, 413–417 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Katsumoto, T. R., Violette, S. M. & Sheppard, D. Blocking TGFβ via inhibition of the αvβ6 integrin: a possible therapy for systemic sclerosis interstitial lung disease. Int. J. Rheumatol. 2011, 208219 (2011). This report summarizes the inhibition of αVβ6 integrin as an attractive therapeutic option for systemic sclerosis and interstitial lung disease mediated by TGFβ.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Chapman, H. A. Epithelial-mesenchymal interactions in pulmonary fibrosis. Annu. Rev. Physiol. 73, 413–435 (2011).

    Article  CAS  PubMed  Google Scholar 

  165. Azuma, A. Pirfenidone treatment of idiopathic pulmonary fibrosis. Ther. Adv. Respir. Dis. 6, 107–114 (2012). This report summarizes the outcome of a number of clinical trials of pirfenidone, which is the first antifibrotic agent to be approved for the treatment of IPF.

    Article  CAS  PubMed  Google Scholar 

  166. Yamada, M. et al. Gene transfer of soluble transforming growth factor type II receptor by in vivo electroporation attenuates lung injury and fibrosis. J. Clin. Pathol. 60, 916–920 (2007).

    Article  PubMed  Google Scholar 

  167. Arribillaga, L. et al. Therapeutic effect of a peptide inhibitor of TGF-β on pulmonary fibrosis. Cytokine 53, 327–333 (2011).

    Article  CAS  PubMed  Google Scholar 

  168. Crunkhorn, S. Deal watch: Biogen acquires Stromedix to pursue novel fibrosis therapy. Nature Rev. Drug Discov. 11, 260 (2012).

    Article  CAS  Google Scholar 

  169. Allison, M. Stromedix acquisition signals growing interest in fibrosis. Nature Biotech. 30, 375–376 (2012).

    Article  CAS  Google Scholar 

  170. Liu, Y. Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int. 69, 213–217 (2006).

    Article  CAS  PubMed  Google Scholar 

  171. Fragiadaki, M. & Mason, R. M. Epithelial-mesenchymal transition in renal fibrosis — evidence for and against. Int. J. Exp. Pathol. 92, 143–150 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Alan, C., Kocoglu, H., Altintas, R., Alici, B. & Resit Ersay, A. Protective effect of decorin on acute ischaemia-reperfusion injury in the rat kidney. Arch. Med. Sci. 7, 211–216 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Terada, Y. et al. Gene transfer of Smad7 using electroporation of adenovirus prevents renal fibrosis in post-obstructed kidney. Kidney Int. 61, S94–S98 (2002). This report indicates that genetic transfer of Smad7 prevents unilateral ureteral obstruction-induced renal fibrosis, suggesting that SMAD7 may be applicable for the treatment of renal fibrosis.

    Article  PubMed  Google Scholar 

  174. Lim, D. S. et al. Angiotensin II blockade reverses myocardial fibrosis in a transgenic mouse model of human hypertrophic cardiomyopathy. Circulation 103, 789–791 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. van Rooij, E. & Olson, E. N. Searching for miR-acles in cardiac fibrosis. Circ. Res. 104, 138–140 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Merkel, P. A. et al. Validity, reliability, and feasibility of durometer measurements of scleroderma skin disease in a multicenter treatment trial. Arthritis Rheum. 59, 699–705 (2008).

    Article  PubMed  Google Scholar 

  177. McCaffrey, T. A. TGF-β signaling in atherosclerosis and restenosis. Front. Biosci. (Schol. Ed.) 1, 236–245 (2009).

    Article  Google Scholar 

  178. Friedl, R. et al. Intimal hyperplasia and expression of transforming growth factor-β1 in saphenous veins and internal mammary arteries before coronary artery surgery. Ann. Thorac. Surg. 78, 1312–1318 (2004).

    Article  PubMed  Google Scholar 

  179. Ranjzad, P., Salem, H. K. & Kingston, P. A. Adenovirus-mediated gene transfer of fibromodulin inhibits neointimal hyperplasia in an organ culture model of human saphenous vein graft disease. Gene Ther. 16, 1154–1162 (2009).

    Article  CAS  PubMed  Google Scholar 

  180. Kapur, N. K. et al. Inhibition of transforming growth factor-β restores endothelial thromboresistance in vein grafts. J. Vasc. Surg. 54, 1117–1123.e1 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  181. Ramirez, F. & Dietz, H. C. Marfan syndrome: from molecular pathogenesis to clinical treatment. Curr. Opin. Genet. Dev. 17, 252–258 (2007).

    Article  CAS  PubMed  Google Scholar 

  182. Holm, T. M. et al. Noncanonical TGFβ signaling contributes to aortic aneurysm progression in Marfan syndrome mice. Science 332, 358–361 (2011). This report demonstrates a significant contribution of the non-canonical TGFβ signalling pathway to aortic aneurysm progression in MFS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Siriwardena, D. et al. Human antitransforming growth factor β2 monoclonal antibody — a new modulator of wound healing in trabeculectomy: a randomized placebo controlled clinical study. Ophthalmology 109, 427–431 (2002).

    Article  PubMed  Google Scholar 

  184. Khaw, P. et al. A phase III study of subconjunctival human anti-transforming growth factor β2 monoclonal antibody (CAT-152) to prevent scarring after first-time trabeculectomy. Ophthalmology 114, 1822–1830 (2007). This study reports the results from a Phase III study examining the efficacy of CAT-152, a monoclonal antibody to TGFβ2, in preventing the progression of fibrosis in patients undergoing first-time trabeculectomy. The study found no difference between CAT-152 and placebo in preventing the failure of trabeculectomy.

    Article  PubMed  Google Scholar 

  185. Fukuda, K., Chikama, T., Takahashi, M. & Nishida, T. Long-term follow-up after lamellar keratoplasty in a patient with bilateral idiopathic corneal keloid. Cornea 30, 1491–1494 (2011).

    Article  PubMed  Google Scholar 

  186. Benzinou, M. et al. Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia. Nature Commun. 3, 616 (2012).

    Article  CAS  Google Scholar 

  187. Bonyadi, M. et al. Mapping of a major genetic modifier of embryonic lethality in TGFβ1 knockout mice. Nature Genet. 15, 207–211 (1997).

    Article  CAS  PubMed  Google Scholar 

  188. Farrington, D. L. et al. Development and validation of a phosphorylated SMAD ex vivo stimulation assay. Biomarkers 12, 313–330 (2007).

    Article  CAS  PubMed  Google Scholar 

  189. Liu, W. et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J. Exp. Med. 203, 1701–1711 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. McClymont, S. A. et al. Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes. J. Immunol. 186, 3918–3926 (2011).

    Article  CAS  PubMed  Google Scholar 

  191. You, S. et al. Adaptive TGF-β-dependent regulatory T cells control autoimmune diabetes and are a privileged target of anti-CD3 antibody treatment. Proc. Natl Acad. Sci. USA 104, 6335–6340 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Clay, T. M., Hobeika, A. C., Mosca, P. J., Lyerly, H. K. & Morse, M. A. Assays for monitoring cellular immune responses to active immunotherapy of cancer. Clin. Cancer Res. 7, 1127–1135 (2001).

    CAS  PubMed  Google Scholar 

  193. Baselga, J. et al. TGF-β signalling-related markers in cancer patients with bone metastasis. Biomarkers 13, 217–236 (2008).

    Article  CAS  PubMed  Google Scholar 

  194. Bornstein, S. et al. Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation. J. Clin. Invest. 119, 3408–3419 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Lu, S. L. et al. Loss of transforming growth factor-β type II receptor promotes metastatic head-and-neck squamous cell carcinoma. Genes Dev. 20, 1331–1342 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Gomis, R. R., Alarcon, C., Nadal, C., Van Poznak, C. & Massague, J. C/EBPβ at the core of the TGFβ cytostatic response and its evasion in metastatic breast cancer cells. Cancer Cell 10, 203–214 (2006).

    Article  CAS  PubMed  Google Scholar 

  197. Micalizzi, D. S. et al. The Six1 homeoprotein induces human mammary carcinoma cells to undergo epithelial-mesenchymal transition and metastasis in mice through increasing TGF-β signaling. J. Clin. Invest. 119, 2678–2690 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Hannigan, A. et al. Epigenetic downregulation of human disabled homolog 2 switches TGF-β from a tumor suppressor to a tumor promoter. J. Clin. Invest. 120, 2842–2857 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Law, B. K. et al. Rapamycin potentiates transforming growth factor β-induced growth arrest in nontransformed, oncogene-transformed, and human cancer cells. Mol. Cell. Biol. 22, 8184–8198 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Engelman, J. A. & Settleman, J. Acquired resistance to tyrosine kinase inhibitors during cancer therapy. Curr. Opin. Genet. Dev. 18, 73–79 (2008).

    Article  CAS  PubMed  Google Scholar 

  201. Corcoran, R. B. et al. BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. Sci. Signal. 3, ra84 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Acharya, M. et al. αv Integrin expression by DCs is required for TH17 cell differentiation and development of experimental autoimmune encephalomyelitis in mice. J. Clin. Invest. 120, 4445–4452 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Melton, A. C. et al. Expression of αvβ8 integrin on dendritic cells regulates TH17 cell development and experimental autoimmune encephalomyelitis in mice. J. Clin. Invest. 120, 4436–4444 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Yadav, H. et al. Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling. Cell Metab. 14, 67–79 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  206. Keller, B. et al. Interaction of TGFβ and BMP signaling pathways during chondrogenesis. PLoS ONE 6, e16421 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Montero, J. A., Lorda-Diez, C. I., Ganan, Y., Macias, D. & Hurle, J. M. Activin/TGFβ and BMP crosstalk determines digit chondrogenesis. Dev. Biol. 321, 343–356 (2008).

    Article  CAS  PubMed  Google Scholar 

  208. Goumans, M. J. et al. Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFβ/ALK5 signaling. Mol. Cell 12, 817–828 (2003). This study demonstrates that TGFβ regulates the activation state of the endothelium via two opposing type I receptors, ALK1 and TβRI (also known as ALK5).

    Article  CAS  PubMed  Google Scholar 

  209. Hau, P. et al. Inhibition of TGF-β2 with AP 12009 in recurrent malignant gliomas: from preclinical to phase I/II studies. Oligonucleotides 17, 201–212 (2007).

    Article  CAS  PubMed  Google Scholar 

  210. Chamberlain, M. C. Convection-enhanced delivery of a transforming growth factor-β2 inhibitor trabedersen for recurrent high-grade gliomas: efficacy real or imagined?, in reference to Bogdahn et al. (Neuro-Oncology 2011;13:132–142). Neuro Oncol. 13, 558–559; author reply 561–552 (2011).

    Article  Google Scholar 

  211. Wick, W. & Weller, M. Trabedersen to target transforming growth factor-β: when the journey is not the reward, in reference to Bogdahn et al. (Neuro-Oncology 2011;13:132–142). Neuro Oncol. 13, 559–560; author reply 561–552 (2011).

    Article  CAS  Google Scholar 

  212. Roldan Urgoiti, G. B., Singh, A. D. & Easaw, J. C. Extended adjuvant temozolomide for treatment of newly diagnosed glioblastoma multiforme. J. Neurooncol. 108, 173–177 (2012).

    Article  CAS  PubMed  Google Scholar 

  213. Azaro, A. et al. The oral transforming growth factor-β (TGF-β) receptor I kinase inhibitor LY2157299 plus lomustine in patients with treatment-refractory malignant glioma: the first human dose study. J. Clin. Oncol. 30, Abstract 2042 (2012).

    Google Scholar 

  214. Occleston, N. L. et al. Discovery and development of avotermin (recombinant human transforming growth factor β3): a new class of prophylactic therapeutic for the improvement of scarring. Wound Repair Regen. 19 (Suppl. 1), S38–S48 (2011).

    Article  PubMed  Google Scholar 

  215. Platten, M. et al. N−[3,4-dimethoxycinnamoyl]-anthranilic acid (tranilast) inhibits transforming growth factor-β relesase and reduces migration and invasiveness of human malignant glioma cells. Int. J. Cancer 93, 53–61 (2001).

    Article  CAS  PubMed  Google Scholar 

  216. Isaji, M. et al. Inhibitory effects of tranilast on the proliferation and functions of human pterygium-derived fibroblasts. Cornea 19, 364–368 (2000).

    Article  CAS  PubMed  Google Scholar 

  217. Schlingensiepen, K. H. et al. The TGF-β1 antisense oligonucleotide AP 11014 for the treatment of non-small cell lung, colorectal and prostate cancer: preclinical studies. J. Clin. Oncol. 22, Abstract 3132 (2004).

    Article  Google Scholar 

  218. Nam, J. S. et al. Bone sialoprotein mediates the tumor cell-targeted prometastatic activity of transforming growth factor β in a mouse model of breast cancer. Cancer Res. 66, 6327–6335 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Melisi, D. et al. LY2109761, a novel transforming growth factor β receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. Mol. Cancer Ther. 7, 829–840 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Fransvea, E., Angelotti, U., Antonaci, S. & Giannelli, G. Blocking transforming growth factor-β up-regulates E-cadherin and reduces migration and invasion of hepatocellular carcinoma cells. Hepatology 47, 1557–1566 (2008).

    Article  CAS  PubMed  Google Scholar 

  221. Mazzocca, A., Fransvea, E., Lavezzari, G., Antonaci, S. & Giannelli, G. Inhibition of transforming growth factor β receptor I kinase blocks hepatocellular carcinoma growth through neo-angiogenesis regulation. Hepatology 50, 1140–1151 (2009).

    Article  CAS  PubMed  Google Scholar 

  222. Zhang, B., Halder, S. K., Zhang, S. & Datta, P. K. Targeting transforming growth factor-β signaling in liver metastasis of colon cancer. Cancer Lett. 277, 114–120 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Inman, G. J. et al. SB-431542 is a potent and specific inhibitor of transforming growth factor-β superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7. Mol. Pharmacol. 62, 65–74 (2002).

    Article  CAS  PubMed  Google Scholar 

  224. Hjelmeland, M. D. et al. SB-431542, a small molecule transforming growth factor-β-receptor antagonist, inhibits human glioma cell line proliferation and motility. Mol. Cancer Ther. 3, 737–745 (2004).

    CAS  PubMed  Google Scholar 

  225. DaCosta Byfield, S., Major, C., Laping, N. J. & Roberts, A. B. SB-505124 is a selective inhibitor of transforming growth factor-β type I receptors ALK4, ALK5, and ALK7. Mol. Pharmacol. 65, 744–752 (2004).

    Article  PubMed  Google Scholar 

  226. Uhl, M. et al. SD-208, a novel transforming growth factor β 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 (2004). This is the first report of the use of a chemical inhibitor of TβRI showing efficacy in reduced tumour growth and invasion as well as increased immunogenicity in a mouse model of glioblastoma.

    Article  CAS  PubMed  Google Scholar 

  227. Ge, R. et al. Inhibition of growth and metastasis of mouse mammary carcinoma by selective inhibitor of transforming growth factor-β type I receptor kinase in vivo. Clin. Cancer Res. 12, 4315–4330 (2006).

    Article  CAS  PubMed  Google Scholar 

  228. Suzuki, E. et al. A novel small-molecule inhibitor of transforming growth factor β type I receptor kinase (SM16) inhibits murine mesothelioma tumor growth in vivo and prevents tumor recurrence after surgical resection. Cancer Res. 67, 2351–2359 (2007).

    Article  CAS  PubMed  Google Scholar 

  229. Kim, S. et al. Systemic blockade of transforming growth factor-β signaling augments the efficacy of immunogene therapy. Cancer Res. 68, 10247–10256 (2008). This is the first demonstration of the use of a chemical TGFβ receptor inhibitor, acting via its immunomodulatory effects, to enhance the efficacy of an adenovirus expressing IFNβ-based immunotherapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Gellibert, F. et al. Discovery of 4-{4-[3-(pyridin-2-yl)-1H-pyrazol-4-yl]pyridin-2-yl}-N-(tetrahydro-2H- pyran-4-yl)benzamide (GW788388): a potent, selective, and orally active transforming growth factor-β type I receptor inhibitor. J. Med. Chem. 49, 2210–2221 (2006).

    Article  CAS  PubMed  Google Scholar 

  231. Petersen, M. et al. Oral administration of GW788388, an inhibitor of TGF-β type I and II receptor kinases, decreases renal fibrosis. Kidney Int. 73, 705–715 (2008).

    Article  CAS  PubMed  Google Scholar 

  232. Tan, S. M., Zhang, Y., Connelly, K. A., Gilbert, R. E. & Kelly, D. J. Targeted inhibition of activin receptor-like kinase 5 signaling attenuates cardiac dysfunction following myocardial infarction. Am. J. Physiol. Heart Circ. Physiol. 298, H1415–H1425 (2010).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors give thanks to J. Dotor, J. McPherson and J. Yingling for useful discussions. Work in the authors' laboratories is funded by grants from the US National Cancer Institute, the US National Heart, Lung and Blood Institute (NHLBI), the US National Institute of Arthritis and Musculoskeletal and Skin Diseases, the US National Institute of General Medical Sciences, the Bouque Foundation and the Helen Diller Family Comprehensive Cancer Center to R.J.A., and from the NHLBI, the American Heart Association and the LeDucq Foundation to A.H. We apologize to all colleagues whose work could not be cited owing to space restrictions.

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Glossary

Epithelial–mesenchymal transition

(EMT). The transformation of a keratin-expressing epithelial cell into one with fibroblastic properties that express mesenchymal markers.

Extracellular matrix

(ECM). Matrix that supports connective tissue and is composed of proteoglycans, hyaluronic acid and fibrillar proteins secreted from the cell and rich in bound growth factors.

Fibrosis

The excess accumulation of fibroblasts and associated extracellular matrix.

Metastasis

The dissemination of tumour cells and re-establishment of tumours at a secondary site.

SMAD

Signal transduction component of the canonical transforming growth factor-β signalling pathway.

microRNA

(miRNA). Small (20–23 nucleotides long) non-coding RNA involved in post- translational regulation of gene expression. miRNAs bind to the partially complementary sequence in the 3′-untranslated region (3′-UTR) of mRNAs and negatively regulate their expression either through translational inhibition or promotion of mRNA degradation.

Myofibroblast

A contractile fibroblast that expresses smooth muscle actin and myosin, and contributes to disease progression in cancer and fibrosis.

Antisense oligonucleotides

(ASOs). Short chemically modified oligonucleotides complementary to a specific mRNA that can be used to cause specific knockdown of targeted gene expression.

Tumour-initiating cells

(TICs). The putative cancer stem cells that have the ability to maintain tumour growth, differentiate into all cell types of a heterogenous tumour, and to re-establish secondary tumours with exceedingly high efficiency.

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Akhurst, R., Hata, A. Targeting the TGFβ signalling pathway in disease. Nat Rev Drug Discov 11, 790–811 (2012). https://doi.org/10.1038/nrd3810

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