Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Cytostatic and apoptotic actions of TGF-β in homeostasis and cancer

Nature Reviews Cancer volume 3, pages 807–820 (2003)Cite this article

Key Points

  • Members of the transforming growth factor-β (TGF-β) family maintain homeostasis in many organ systems under normal physiological conditions.

  • Antiproliferative and apoptotic responses to TGF-β in epithelial, endothelial, neuronal and haematopoietic cells effectively limit the growth of these cell lineages.

  • The importance of TGF-β as a growth suppressor is demonstrated by the disruption of TGF-β signalling components in human cancers.

  • Certain tumours develop resistance to TGF-β growth-suppressive effects in the absence of mutations that disrupt the core TGF-β pathway.

  • TGF-β induces epithelial–mesenchymal transitions (EMT) in cancer cells, and pro-angiogenic and immunosuppressive effects on the tumour microenvironment, all of which promote cancer progression.

  • TGF-β acts as an important mediator of metastasis to specific organ sites — such as breast cancer metastasis to the bone — by increasing the expression of tissue-specific metastasis genes.

Abstract

The cytostatic and apoptotic functions of transforming growth factor-β (TGF-β) help restrain the growth of mammalian tissues; loss of these effects leads to hyperproliferative disorders and is common in cancer. However, tumour cells that are relieved from TGF-β growth constraints might then overproduce this cytokine to create a local immunosuppressive environment that fosters tumour growth and exacerbates the invasive and metastatic behaviour of the tumour cells themselves. For these reasons, there is a growing interest in understanding and therapeutically _targeting TGF-β-mediated processes in cancer progression.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: TGF-β _targets and its actions in mature tissues.
Figure 2: A schematic diagram of the TGF-β signalling pathway.
Figure 3: Gene responses of the TGF-β cytostatic programme that are shared by skin, lung and mammary epithelial cells.
Figure 4: A schematic diagram illustrating signalling intermediates and transcriptional _targets involved in TGF-β induced apoptosis.
Figure 5: Points of TGF-β action during cancer progression.

Similar content being viewed by others

References

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

    Article  CAS  PubMed  Google Scholar 

  2. Tsukazaki, T., Chiang, T. A., Davison, A. F., Attisano, L. & Wrana, J. L. SARA, a FYVE domain protein that recruits Smad2 to the TGFβ receptor. Cell 95, 779–791 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. Xu, L., Kang, Y., Col, S. & Massagué, J. Smad2 nucleocytoplasmic shuttling by nucleoporins CAN/Nup214 and Nup153 feeds TGFβ signaling complexes in the cytoplasm and nucleus. Mol. Cell 10, 271–282 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. Xiao, Z., Liu, X., Henis, Y. I. & Lodish, H. F. A distinct nuclear localization signal in the N terminus of Smad 3 determines its ligand-induced nuclear translocation. Proc. Natl Acad. Sci. USA 97, 7853–7858 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wu, J. W., Fairman, R., Penry, J. & Shi, Y. Formation of a stable heterodimer between Smad2 and Smad4. J. Biol. Chem. 276, 20688–20694 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Wu, J. W. et al. Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-β signaling. Mol. Cell 8, 1277–1289 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Inman, G. J. & Hill, C. S. Stoichiometry of active smad-transcription factor complexes on DNA. J. Biol. Chem. 277, 51008–51016 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Chen, X., Rubock, M. J. & Whitman, M. A transcriptional partner for MAD proteins in TGF-β signalling. Nature 383, 691–696 (1996).

    Article  CAS  PubMed  Google Scholar 

  9. Hata, A. et al. OAZ uses distinct DNA- and protein-binding zinc fingers in separate BMP-Smad and Olf signaling pathways. Cell 100, 229–240 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Zavadil, J. et al. Genetic programs of epithelial cell plasticity directed by transforming growth factor-β. Proc. Natl Acad. Sci. USA 98, 6686–6691 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kang, Y., Chen, C. R. & Massagué, J. A self-enabling TGFβ response coupled to stress signaling. Smad engages stress response factor ATF3 for Id1 repression in epithelial cells. Mol. Cell 11, 915–926 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Massagué, J. & Wotton, D. Transcriptional control by the TGF-β/Smad signaling system. EMBO J. 19, 1745–1754 (2000).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Chen, C. R., Kang, Y., Siegel, P. M. & Massagué, J. E2F4/5 and p107 as Smad cofactors linking the TGFβ receptor to c-myc repression. Cell 110, 19–32 (2002). Identifies a preformed cytoplasmic complex — containing E2F4/5, p107 and SMAD3 — that mediates the rapid downregulation of c-MYC and functions upstream of CDK activity and independently of cell-cycle arrest.

    Article  CAS  PubMed  Google Scholar 

  14. Ten Dijke, P., Goumans, M. J., Itoh, F. & Itoh, S. Regulation of cell proliferation by Smad proteins. J. Cell Physiol. 191, 1–16 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Inman, G. J., Nicolas, F. J. & Hill, C. S. Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-β receptor activity. Mol. Cell 10, 283–294 (2002). This study demonstrates that activated SMAD proteins undergo rapid dephosphorylation and TGF-β-receptor-mediated rephosphorylation, and reveals a mechanism that determines the duration of the TGF-β signal.

    Article  CAS  PubMed  Google Scholar 

  16. Ebisawa, T. et al. Smurf1 interacts with transforming growth factor-β type I receptor through Smad7 and induces receptor degradation. J. Biol. Chem. 276, 12477–12480 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Tajima, Y. et al. Chromosomal region maintenance 1 (CRM1)-dependent nuclear export of Smad ubiquitin regulatory factor 1 (Smurf1) is essential for negative regulation of transforming growth factor-β signaling by Smad7. J. Biol. Chem. 278, 10716–10721 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Di Guglielmo, G. M., Le Roy, C., Goodfellow, A. F. & Wrana, J. L. Distinct endocytic pathways regulate TGF-β receptor signalling and turnover. Nature Cell Biol. 5, 410–421 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Zhu, H., Kavsak, P., Abdollah, S., Wrana, J. L. & Thomsen, G. H. A SMAD ubiquitin ligase _targets the BMP pathway and affects embryonic pattern formation. Nature 400, 687–693 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Lo, R. S. & Massagué, J. Ubiquitin-dependent degradation of TGF-β-activated smad2. Nature Cell Biol. 1, 472–478 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Engel, M. E., McDonnell, M. A., Law, B. K. & Moses, H. L. Interdependent SMAD and JNK signaling in transforming growth factor-β-mediated transcription. J. Biol. Chem. 274, 37413–37420 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Hocevar, B. A., Brown, T. L. & Howe, P. H. TGF-β induces fibronectin synthesis through a c-Jun N-terminal kinase-dependent, Smad4-independent pathway. EMBO J. 18, 1345–1356 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yu, L., Hebert, M. C. & Zhang, Y. E. TGF-β receptor-activated p38 MAP kinase mediates Smad-independent TGF-β responses. EMBO J. 21, 3749–3759 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Itoh, S. et al. Elucidation of Smad requirement in transforming growth factor-β type I receptor-induced responses. J. Biol. Chem. 278, 3751–3761 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Yamaguchi, K. et al. Identification of a member of the MAPKKK family as a potential mediator of TGF-β signal transduction. Science 270, 2008–2011 (1995).

    Article  CAS  PubMed  Google Scholar 

  26. Bhowmick, N. A. et al. Transforming growth factor-β1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol. Biol. Cell 12, 27–36 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Takekawa, M. et al. Smad-dependent GADD45β expression mediates delayed activation of p38 MAP kinase by TGF-β. EMBO J. 21, 6473–6482 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Petritsch, C., Beug, H., Balmain, A. & Oft, M. TGF-β inhibits p70 S6 kinase via protein phosphatase 2A to induce G1 arrest. Genes Dev. 14, 3093–3101 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kretzschmar, M., Doody, J. & Massagué, J. Opposing BMP and EGF signalling pathways converge on the TGF-β family mediator Smad1. Nature 389, 618–622 (1997).

    Article  CAS  PubMed  Google Scholar 

  30. Kretzschmar, M., Doody, J., Timokhina, I. & Massagué, J. A mechanism of repression of TGFβ/Smad signaling by oncogenic Ras. Genes Dev. 13, 804–816 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lehmann, K. et al. Raf induces TGFβ production while blocking its apoptotic but not invasive responses: a mechanism leading to increased malignancy in epithelial cells. Genes Dev. 14, 2610–2622 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Janda, E. et al. Ras and TGFβ cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J. Cell Biol. 156, 299–313 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Saha, D., Datta, P. K. & Beauchamp, R. D. Oncogenic ras represses transforming growth factor-β/Smad signaling by degrading tumor suppressor Smad4. J. Biol. Chem. 276, 29531–29537 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Foletta, V. C. et al. Direct signaling by the BMP Type II Receptor via the cytoskeletal regulator LIMK1. J. Cell Biol. 16, 1089–1098 (2003).

    Article  CAS  Google Scholar 

  35. Shull, M. M. et al. _targeted disruption of the mouse transforming growth factor-β 1 gene results in multifocal inflammatory disease. Nature 359, 693–699 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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 

  37. Cui, W. et al. Concerted action of TGF-β1 and its type II receptor in control of epidermal homeostasis in transgenic mice. Genes Dev. 9, 945–955 (1995).

    Article  CAS  PubMed  Google Scholar 

  38. Wang, X. J., Liefer, K. M., Tsai, S., O'Malley, B. W. & Roop, D. R. Development of gene-switch transgenic mice that inducibly express transforming growth factor β1 in the epidermis. Proc. Natl Acad. Sci. USA 96, 8483–8488 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Liu, X. et al. Conditional epidermal expression of TGFβ 1 blocks neonatal lethality but causes a reversible hyperplasia and alopecia. Proc. Natl Acad. Sci. USA 98, 9139–9144 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wang, X. J. Role of TGFβ signaling in skin carcinogenesis. Microsc. Res. Tech. 52, 420–429 (2001).

    Article  PubMed  Google Scholar 

  41. Dickson, M. C. et al. Defective haematopoiesis and vasculogenesis in transforming growth factor-β 1 knock out mice. Development 121, 1845–1854 (1995).

    CAS  PubMed  Google Scholar 

  42. Oshima, M., Oshima, H. & Taketo, M. M. TGF-β receptor type II deficiency results in defects of yolk sac hematopoiesis and vasculogenesis. Dev. Biol. 179, 297–302 (1996).

    Article  CAS  PubMed  Google Scholar 

  43. 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 

  44. Roberts, A. B. et al. Transforming growth factor type β: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc. Natl Acad. Sci. USA 83, 4167–4171 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yang, E. Y. & Moses, H. L. Transforming growth factor β 1-induced changes in cell migration, proliferation, and angiogenesis in the chicken chorioallantoic membrane. J. Cell Biol. 111, 731–741 (1990).

    Article  CAS  PubMed  Google Scholar 

  46. Oh, S. P. et al. Activin receptor-like kinase 1 modulates transforming growth factor-β1 signaling in the regulation of angiogenesis. Proc. Natl Acad. Sci. USA 97, 2626–2631 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Goumans, M. J. et al. Balancing the activation state of the endothelium via two distinct TGF-β type I receptors. EMBO J. 21, 1743–1753 (2002). Demonstrates that activation of ALK1 in endothelial cells can promote their proliferation and invasiveness, whereas ALK5 activation in the same cells reduces proliferation and invasiveness. These results might provide a basis for explaining the contradictory effects of TGF-β on endothelial cells that have been reported in the literature.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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 

  49. Letterio, J. J. et al. Autoimmunity associated with TGF-β1-deficiency in mice is dependent on MHC class II antigen expression. J. Clin. Invest. 98, 2109–2119 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kobayashi, S. et al. β2-microglobulin-deficient background ameliorates lethal phenotype of the TGF-β1 null mouse. J. Immunol. 163, 4013–4019 (1999).

    CAS  PubMed  Google Scholar 

  51. Brabletz, T. et al. Transforming growth factor β and cyclosporin A inhibit the inducible activity of the interleukin-2 gene in T cells through a noncanonical octamer-binding site. Mol. Cell Biol. 13, 1155–1162 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Sillett, H. K., Cruickshank, S. M., Southgate, J. & Trejdosiewicz, L. K. Transforming growth factor-β promotes 'death by neglect' in post-activated human T cells. Immunology 102, 310–316 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Gorelik, L. & Flavell, R. A. Transforming growth factor-β in T-cell biology. Nature Rev. Immunol. 2, 46–53 (2002).

    Article  CAS  Google Scholar 

  54. Tzachanis, D. et al. Tob is a negative regulator of activation that is expressed in anergic and quiescent T cells. Nature Immunol. 2, 1174–1182 (2001).

    Article  CAS  Google Scholar 

  55. Laiho, M., DeCaprio, J. A., Ludlow, J. W., Livingston, D. M. & Massagué, J. Growth inhibition by TGF-β linked to suppression of retinoblastoma protein phosphorylation. Cell 62, 175–185 (1990).

    Article  CAS  PubMed  Google Scholar 

  56. Blain, S. W., Montalvo, E. & Massague, J. Differential interaction of the cyclin-dependent kinase (Cdk) inhibitor p27Kip1 with cyclin A-Cdk2 and cyclin D2-Cdk4. J. Biol. Chem. 272, 25863–25872 (1997).

    Article  CAS  PubMed  Google Scholar 

  57. Datto, M. B. et al. Transforming growth factor β induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc. Natl Acad. Sci. USA 92, 5545–5549 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Reynisdottir, I., Polyak, K., Iavarone, A. & Massagué, J. Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-β. Genes Dev. 9, 1831–1845 (1995).

    Article  CAS  PubMed  Google Scholar 

  59. Hannon, G. J. & Beach, D. p15INK4B is a potential effector of TGF-β-induced cell cycle arrest. Nature 371, 257–261 (1994).

    Article  CAS  PubMed  Google Scholar 

  60. Staller, P. et al. Repression of p15INK4b expression by Myc through association with Miz-1. Nature Cell Biol. 3, 392–399 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Seoane, J. et al. TGFβ influences Myc, Miz-1 and Smad to control the CDK inhibitor p15INK4b. Nature Cell Biol. 3, 400–408 (2001). References 60 and 61 identify a role for MIZ1 and c–MYC in the repression of INK4B expression.

    Article  CAS  PubMed  Google Scholar 

  62. Seoane, J., Le, H. V. & Massagué, J. Myc suppression of the p21Cip1 Cdk inhibitor influences the outcome of the p53 response to DNA damage. Nature 419, 729–734 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. Feng, X. H., Lin, X. & Derynck, R. Smad2, Smad3 and Smad4 cooperate with Sp1 to induce p15Ink4B transcription in response to TGF-β. EMBO J. 19, 5178–5193 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Polyak, K. et al. Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78, 59–66 (1994).

    Article  CAS  PubMed  Google Scholar 

  65. Reynisdottir, I. & Massagué, J. The subcellular locations of p15Ink4b and p27Kip1 coordinate their inhibitory interactions with cdk4 and cdk2. Genes Dev. 11, 492–503 (1997).

    Article  CAS  PubMed  Google Scholar 

  66. Alexandrow, M. G. & Moses, H. L. Transforming growth factor β and cell cycle regulation. Cancer Res. 55, 1452–1457 (1995).

    CAS  PubMed  Google Scholar 

  67. Norton, J. D. ID helix–loop–helix proteins in cell growth, differentiation and tumorigenesis. J. Cell Sci. 113, 3897–3905 (2000).

    CAS  PubMed  Google Scholar 

  68. Lasorella, A., Noseda, M., Beyna, M., Yokota, Y. & Iavarone, A. Id2 is a retinoblastoma protein _target and mediates signalling by Myc oncoproteins. Nature 407, 592–598 (2000).

    Article  CAS  PubMed  Google Scholar 

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

  70. Tachibana, I. et al. Overexpression of the TGFβ-regulated zinc finger encoding gene, TIEG, induces apoptosis in pancreatic epithelial cells. J. Clin. Invest. 99, 2365–2374 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Jang, C. W. et al. TGF-β induces apoptosis through Smad-mediated expression of DAP-kinase. Nature Cell Biol. 4, 51–58 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Valderrama-Carvajal, H. et al. Activin/TGF-β induce apoptosis through Smad-dependent expression of the lipid phosphatase SHIP. Nature Cell Biol. 4, 963–969 (2002). References 70–72 are among the first to identify TGF-β-responsive genes that contribute to TGF-β-induced apoptosis.

    Article  CAS  PubMed  Google Scholar 

  73. Huang, Y. et al. Transforming growth factor-β1 suppresses serum deprivation-induced death of A549 cells through differential effects on c-Jun and JNK activities. J. Biol. Chem. 275, 18234–18242 (2000).

    Article  CAS  PubMed  Google Scholar 

  74. Shin, I., Bakin, A. V., Rodeck, U., Brunet, A. & Arteaga, C. L. Transforming growth factor β enhances epithelial cell survival via Akt-dependent regulation of FKHRL1. Mol. Biol. Cell 12, 3328–3339 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Larisch, S. et al. A novel mitochondrial septin-like protein, ARTS, mediates apoptosis dependent on its P-loop motif. Nature Cell Biol. 2, 915–921 (2000).

    Article  CAS  PubMed  Google Scholar 

  76. Perlman, R., Schiemann, W. P., Brooks, M. W., Lodish, H. F. & Weinberg, R. A. TGF-β-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation. Nature Cell Biol. 3, 708–714 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Schuster, N. & Krieglstein, K. Mechanisms of TGF-β-mediated apoptosis. Cell Tissue Res. 307, 1–14 (2002).

    Article  CAS  PubMed  Google Scholar 

  78. 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 

  79. Massagué, J., Blain, S. W. & Lo, R. S. TGFβ signaling in growth control, cancer, and heritable disorders. Cell 103, 295–309 (2000).

    Article  PubMed  Google Scholar 

  80. Wakefield, L. M. & Roberts, A. B. TGF-β signaling: positive and negative effects on tumorigenesis. Curr. Opin. Genet. Dev. 12, 22–29 (2002).

    Article  CAS  PubMed  Google Scholar 

  81. Markowitz, S. et al. Inactivation of the type II TGF-β receptor in colon cancer cells with microsatellite instability. Science 268, 1336–1338 (1995).

    Article  CAS  PubMed  Google Scholar 

  82. Lu, S. L., Zhang, W. C., Akiyama, Y., Nomizu, T. & Yuasa, Y. Genomic structure of the transforming growth factor β type II receptor gene and its mutations in hereditary nonpolyposis colorectal cancers. Cancer Res. 56, 4595–4598 (1996).

    CAS  PubMed  Google Scholar 

  83. Myeroff, L. L. et al. A transforming growth factor β receptor type II gene mutation common in colon and gastric but rare in endometrial cancers with microsatellite instability. Cancer Res. 55, 5545–5547 (1995).

    CAS  PubMed  Google Scholar 

  84. Izumoto, S. et al. Microsatellite instability and mutated type II transforming growth factor-β receptor gene in gliomas. Cancer Lett. 112, 251–256 (1997).

    Article  CAS  PubMed  Google Scholar 

  85. Tomita, S. et al. Analyses of microsatellite instability and the transforming growth factor-β receptor type II gene mutation in sporadic breast cancer and their correlation with clinicopathological features. Breast Cancer Res. Treat. 53, 33–39 (1999).

    Article  CAS  PubMed  Google Scholar 

  86. Furuta, K. et al. Gene mutation of transforming growth factor β1 type II receptor in hepatocellular carcinoma. Int. J. Cancer 81, 851–853 (1999).

    Article  CAS  PubMed  Google Scholar 

  87. Grady, W. M. et al. Mutational inactivation of transforming growth factor β receptor type II in microsatellite stable colon cancers. Cancer Res. 59, 320–324 (1999).

    CAS  PubMed  Google Scholar 

  88. Wang, D. et al. Analysis of specific gene mutations in the transforming growth factor-β signal transduction pathway in human ovarian cancer. Cancer Res. 60, 4507–4512 (2000).

    CAS  PubMed  Google Scholar 

  89. Chen, T., Carter, D., Garrigue-Antar, L. & Reiss, M. Transforming growth factor β type I receptor kinase mutant associated with metastatic breast cancer. Cancer Res. 58, 4805–4810 (1998).

    CAS  PubMed  Google Scholar 

  90. Goggins, M. et al. Genetic alterations of the transforming growth factor β receptor genes in pancreatic and biliary adenocarcinomas. Cancer Res. 58, 5329–5332 (1998).

    CAS  PubMed  Google Scholar 

  91. Schiemann, W. P., Pfeifer, W. M., Levi, E., Kadin, M. E. & Lodish, H. F. A deletion in the gene for transforming growth factor β type I receptor abolishes growth regulation by transforming growth factor β in a cutaneous T-cell lymphoma. Blood 94, 2854–2861 (1999).

    CAS  PubMed  Google Scholar 

  92. Pasche, B. et al. TβR-I(6A) is a candidate tumor susceptibility allele. Cancer Res. 59, 5678–5682 (1999).

    CAS  PubMed  Google Scholar 

  93. 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). One of the first demonstrations that TGF-β can exert tumour-suppressive as well as tumour-promoting effects, using a transgenic model of skin carcinogenesis.

    Article  CAS  PubMed  Google Scholar 

  94. Pierce, D. F., Jr. et al. Mammary tumor suppression by transforming growth factor β 1 transgene expression. Proc. Natl Acad. Sci. USA 92, 4254–4258 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Gorska, A. E., Joseph, H., Derynck, R., Moses, H. L. & Serra, R. Dominant-negative interference of the transforming growth factor β type II receptor in mammary gland epithelium results in alveolar hyperplasia and differentiation in virgin mice. Cell Growth Differ. 9, 229–238 (1998).

    CAS  PubMed  Google Scholar 

  96. Bottinger, E. P., Jakubczak, J. L., Haines, D. C., Bagnall, K. & Wakefield, L. M. Transgenic mice overexpressing a dominant-negative mutant type II transforming growth factor β receptor show enhanced tumorigenesis in the mammary gland and lung in response to the carcinogen 7,12-dimethylbenz-[a]-anthracene. Cancer Res. 57, 5564–5570 (1997).

    CAS  PubMed  Google Scholar 

  97. Siegel, P. M., Shu, W., Cardiff, R. D., Muller, W. J. & Massague, J. Transforming growth factor β signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc. Natl Acad. Sci. USA 100, 8430–8435 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Hahn, S. A. et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271, 350–353 (1996).

    Article  CAS  PubMed  Google Scholar 

  99. Schutte, M. et al. DPC4 gene in various tumor types. Cancer Res. 56, 2527–2530 (1996).

    CAS  PubMed  Google Scholar 

  100. Miyaki, M. et al. Higher frequency of Smad4 gene mutation in human colorectal cancer with distant metastasis. Oncogene 18, 3098–3103 (1999).

    Article  CAS  PubMed  Google Scholar 

  101. Howe, J. R. et al. Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science 280, 1086–1088 (1998).

    Article  CAS  PubMed  Google Scholar 

  102. Woodford-Richens, K. et al. Allelic loss at SMAD4 in polyps from juvenile polyposis patients and use of fluorescence in situ hybridization to demonstrate clonal origin of the epithelium. Cancer Res. 60, 2477–2482 (2000).

    CAS  PubMed  Google Scholar 

  103. Takaku, K. et al. Gastric and duodenal polyps in Smad4 (Dpc4) knockout mice. Cancer Res. 59, 6113–6117 (1999).

    CAS  PubMed  Google Scholar 

  104. Xu, X. et al. Haploid loss of the tumor suppressor Smad4/Dpc4 initiates gastric polyposis and cancer in mice. Oncogene 19, 1868–1874 (2000).

    Article  CAS  PubMed  Google Scholar 

  105. Takaku, K. et al. Intestinal tumorigenesis in compound mutant mice of both Dpc4 (Smad4) and Apc genes. Cell 92, 645–656 (1998).

    Article  CAS  PubMed  Google Scholar 

  106. Hohenstein, P. et al. Serrated adenomas and mixed polyposis caused by a splice acceptor deletion in the mouse Smad4 gene. Genes Chromosom. Cancer 36, 273–282 (2003).

    Article  CAS  PubMed  Google Scholar 

  107. Uchida, K. et al. Somatic in vivo alterations of the JV18-1 gene at 18q21 in human lung cancers. Cancer Res. 56, 5583–5585 (1996).

    CAS  PubMed  Google Scholar 

  108. Eppert, K. et al. MADR2 maps to 18q21 and encodes a TGFβ-regulated MAD-related protein that is functionally mutated in colorectal carcinoma. Cell 86, 543–552 (1996).

    Article  CAS  PubMed  Google Scholar 

  109. Hamamoto, T. et al. Compound disruption of smad2 accelerates malignant progression of intestinal tumors in apc knockout mice. Cancer Res. 62, 5955–5961 (2002).

    CAS  PubMed  Google Scholar 

  110. Zhu, Y., Richardson, J. A., Parada, L. F. & Graff, J. M. Smad3 mutant mice develop metastatic colorectal cancer. Cell 94, 703–714 (1998).

    Article  CAS  PubMed  Google Scholar 

  111. Yang, X. et al. _targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-β. EMBO J. 18, 1280–1291 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Datto, M. B. et al. _targeted disruption of Smad3 reveals an essential role in transforming growth factor β-mediated signal transduction. Mol. Cell Biol. 19, 2495–2504 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Factor, V. M. et al. Constitutive expression of mature transforming growth factor β1 in the liver accelerates hepatocarcinogenesis in transgenic mice. Cancer Res. 57, 2089–2095 (1997).

    CAS  PubMed  Google Scholar 

  114. Bandyopadhyay, A. et al. A soluble transforming growth factor β type III receptor suppresses tumorigenicity and metastasis of human breast cancer MDA-MB-231 cells. Cancer Res. 59, 5041–5046 (1999).

    CAS  PubMed  Google Scholar 

  115. Muraoka, R. S. et al. Blockade of TGF-β inhibits mammary tumor cell viability, migration, and metastases. J. Clin. Invest. 109, 1551–1559 (2002). Describes the use of a soluble inhibitor that binds and neutralizes TGF-β to impair mammary tumour metastasis without accelerating mammary tumorigenesis in transgenic mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. 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). An inhibitor similar to that used in reference 115 was expressed as a transgene in the mammary glands of transgenic mice. Mammary tumorigenesis was not affected by expression of the inhibitor in an ErbB2 transgenic tumour model, but the ability of tumour cells to metastasize to the lungs was reduced. Interestingly, no evidence of inflammatory side effects was observed from the systemic distribution of the Tgf-β inhibitor.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Oft, M., Heider, K. H. & Beug, H. TGFβ signaling is necessary for carcinoma cell invasiveness and metastasis. Curr. Biol. 8, 1243–1252 (1998).

    Article  CAS  PubMed  Google Scholar 

  118. 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 

  119. Torre-Amione, G. et al. A highly immunogenic tumor transfected with a murine transforming growth factor type β 1 cDNA escapes immune surveillance. Proc. Natl Acad. Sci. USA 87, 1486–1490 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. 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). Demonstrates that activation of the TGF-β pathway in T cells by tumour-derived TGF-β compromises T-cell-mediated antitumour immunity. A dominant-negative TGF-β type II receptor, when expressed in T cells, allowed for the rapid and complete clearance of injected tumour cells.

    Article  CAS  PubMed  Google Scholar 

  121. Geissmann, F. et al. TGF-β1 prevents the noncognate maturation of human dendritic Langerhans cells. J. Immunol. 162, 4567–4575 (1999).

    CAS  PubMed  Google Scholar 

  122. Geiser, A. G. et al. Transforming growth factor β 1 (TGF-β 1) controls expression of major histocompatibility genes in the postnatal mouse: aberrant histocompatibility antigen expression in the pathogenesis of the TGF-β 1 null mouse phenotype. Proc. Natl Acad. Sci. USA 90, 9944–9948 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Dong, Y., Tang, L., Letterio, J. J. & Benveniste, E. N. The Smad3 protein is involved in TGF-β inhibition of class II transactivator and class II MHC expression. J. Immunol. 167, 311–319 (2001).

    Article  CAS  PubMed  Google Scholar 

  124. Wallick, S. C., Figari, I. S., Morris, R. E., Levinson, A. D. & Palladino, M. A. Immunoregulatory role of transforming growth factor β (TGF-β) in development of killer cells: comparison of active and latent TGF-β 1. J. Exp. Med. 172, 1777–1784 (1990).

    Article  CAS  PubMed  Google Scholar 

  125. Arteaga, C. L. et al. Anti-transforming growth factor (TGF)-β antibodies inhibit breast cancer cell tumorigenicity and increase mouse spleen natural killer cell activity. Implications for a possible role of tumor cell/host TGF-β interactions in human breast cancer progression. J. Clin. Invest. 92, 2569–2576 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Chen, J. J., Sun, Y. & Nabel, G. J. Regulation of the proinflammatory effects of Fas ligand (CD95L). Science 282, 1714–1717 (1998).

    Article  CAS  PubMed  Google Scholar 

  127. de Jong, J. S., van Diest, P. J., van der Valk, P. & Baak, J. P. Expression of growth factors, growth-inhibiting factors, and their receptors in invasive breast cancer II: correlations with proliferation and angiogenesis. J. Pathol. 184, 53–57 (1998).

    Article  CAS  PubMed  Google Scholar 

  128. Hasegawa, Y. et al. Transforming growth factor-β1 level correlates with angiogenesis, tumor progression, and prognosis in patients with nonsmall cell lung carcinoma. Cancer 91, 964–971 (2001).

    Article  CAS  PubMed  Google Scholar 

  129. Stearns, M. E., Garcia, F. U., Fudge, K., Rhim, J. & Wang, M. Role of interleukin 10 and transforming growth factor β1 in the angiogenesis and metastasis of human prostate primary tumor lines from orthotopic implants in severe combined immunodeficiency mice. Clin. Cancer Res. 5, 711–720 (1999).

    CAS  PubMed  Google Scholar 

  130. Tuxhorn, J. A., McAlhany, S. J., Yang, F., Dang, T. D. & Rowley, D. R. Inhibition of transforming growth factor-β activity decreases angiogenesis in a human prostate cancer-reactive stroma xenograft model. Cancer Res. 62, 6021–6025 (2002).

    CAS  PubMed  Google Scholar 

  131. Bandyopadhyay, A. et al. Extracellular domain of TGFβ type III receptor inhibits angiogenesis and tumor growth in human cancer cells. Oncogene 21, 3541–3551 (2002).

    Article  CAS  PubMed  Google Scholar 

  132. Pertovaara, L. et al. Vascular endothelial growth factor is induced in response to transforming growth factor-β in fibroblastic and epithelial cells. J. Biol. Chem. 269, 6271–6274 (1994).

    CAS  PubMed  Google Scholar 

  133. Shimo, T. et al. Involvement of CTGF, a hypertrophic chondrocyte-specific gene product, in tumor angiogenesis. Oncology 61, 315–322 (2001).

    Article  CAS  PubMed  Google Scholar 

  134. Kang, Y. et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3, 537–549 (2003). Shows that TGF-β further activates expression of two genes that promote breast cancer metastasis to the bone.

    Article  CAS  PubMed  Google Scholar 

  135. Enholm, B. et al. Comparison of VEGF, VEGF-B, VEGF-C and Ang-1 mRNA regulation by serum, growth factors, oncoproteins and hypoxia. Oncogene 14, 2475–2483 (1997).

    Article  CAS  PubMed  Google Scholar 

  136. Boyer, A. S. et al. TGFβ2 and TGFβ3 have separate and sequential activities during epithelial-mesenchymal cell transformation in the embryonic heart. Dev. Biol. 208, 530–545 (1999).

    Article  CAS  PubMed  Google Scholar 

  137. Kaartinen, V. et al. Abnormal lung development and cleft palate in mice lacking TGF-β 3 indicates defects of epithelial-mesenchymal interaction. Nature Genet. 11, 415–421 (1995).

    Article  CAS  PubMed  Google Scholar 

  138. Proetzel, G. et al. Transforming growth factor-β 3 is required for secondary palate fusion. Nature Genet. 11, 409–414 (1995).

    Article  CAS  PubMed  Google Scholar 

  139. 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). One of the first demonstrations that TGF-β can cooperate with an activated RAS pathway in mammary tumour cells to induce an epithelial–mesenchymal transition, and enhance tumour-cell invasiveness.

    Article  CAS  PubMed  Google Scholar 

  140. Miettinen, P. J., Ebner, R., Lopez, A. R. & Derynck, R. TGF-β induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors. J. Cell Biol. 127, 2021–2036 (1994).

    Article  CAS  PubMed  Google Scholar 

  141. Portella, G. et al. Transforming growth factor β is essential for spindle cell conversion of mouse skin carcinoma in vivo: implications for tumor invasion. Cell Growth Differ. 9, 393–404 (1998).

    CAS  PubMed  Google Scholar 

  142. Oft, M., Akhurst, R. J. & Balmain, A. Metastasis is driven by sequential elevation of H-ras and Smad2 levels. Nature Cell Biol. 4, 487–494 (2002). Using experimental metastasis assays, this study indicates that SMAD signalling, in concert with activated RAS, induces an epithelial–mesenchymal transition in squamous carcinoma cells that facilitates their extravastion into the lungs.

    Article  CAS  PubMed  Google Scholar 

  143. Thiery, J. P. Epithelial–mesenchymal transitions in tumour progression. Nature Rev. Cancer 2, 442–454 (2002).

    Article  CAS  Google Scholar 

  144. Comijn, J. et al. The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol. Cell 7, 1267–1278 (2001).

    Article  CAS  PubMed  Google Scholar 

  145. Peinado, H., Quintanilla, M. & Cano, A. Transforming growth factor β 1 induces snail transcription factor in epithelial cell lines. Mechanisms for Epithelial–Mesenchymal transitions. J. Biol. Chem. 278, 21113–21123 (2003).

    Article  CAS  PubMed  Google Scholar 

  146. Savagner, P., Yamada, K. M. & Thiery, J. P. The zinc-finger protein slug causes desmosome dissociation, an initial and necessary step for growth factor-induced epithelial-mesenchymal transition. J. Cell Biol. 137, 1403–1419 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Hajra, K. M., Chen, D. Y. & Fearon, E. R. The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res. 62, 1613–1618 (2002).

    CAS  PubMed  Google Scholar 

  148. Romano, L. A. & Runyan, R. B. Slug is an essential _target of TGFβ2 signaling in the developing chicken heart. Dev. Biol. 223, 91–102 (2000).

    Article  CAS  PubMed  Google Scholar 

  149. Chen, C. R., Kang, Y. & Massagué, J. Defective repression of c-myc in breast cancer cells: a loss at the core of the transforming growth factor β growth arrest program. Proc. Natl Acad. Sci. USA 98, 992–999 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Dumont, N. & Arteaga, C. L. _targeting the TGFβ signaling network in human neoplasia. Cancer Cell 3, 531–536 (2003).

    Article  CAS  PubMed  Google Scholar 

  151. Laping, N. J. et al. Inhibition of transforming growth factor (TGF)-β1-induced extracellular matrix with a novel inhibitor of the TGF-β type I receptor kinase activity: SB-431542. Mol. Pharmacol. 62, 58–64 (2002).

    Article  CAS  PubMed  Google Scholar 

  152. 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 

  153. Pierce, D. F., Jr. et al. Inhibition of mammary duct development but not alveolar outgrowth during pregnancy in transgenic mice expressing active TGF-β 1. Genes Dev. 7, 2308–2317 (1993).

    Article  CAS  PubMed  Google Scholar 

  154. Jhappan, C. et al. _targeting expression of a transforming growth factor β 1 transgene to the pregnant mammary gland inhibits alveolar development and lactation. EMBO J. 12, 1835–1845 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Nguyen, A. V. & Pollard, J. W. Transforming growth factor β3 induces cell death during the first stage of mammary gland involution. Development 127, 3107–3118 (2000).

    CAS  PubMed  Google Scholar 

  156. Joseph, H., Gorska, A. E., Sohn, P., Moses, H. L. & Serra, R. Overexpression of a kinase-deficient transforming growth factor-β type II receptor in mouse mammary stroma results in increased epithelial branching. Mol. Biol. Cell 10, 1221–1234 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Wang, X. J. et al. Expression of a dominant-negative type II transforming growth factor β (TGF-β) receptor in the epidermis of transgenic mice blocks TGF-β-mediated growth inhibition. Proc. Natl Acad. Sci. USA 94, 2386–2391 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Ashcroft, G. S. et al. Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nature Cell Biol. 1, 260–266 (1999). Demonstrates that SMAD3 functions as a central mediator of TGF-β-induced growth-inhibitory signals in keratinocytes, and that loss of SMAD3 results in greater keratinocyte proliferation and faster healing of incisional wounds.

    Article  CAS  PubMed  Google Scholar 

  159. Ko, T. C. et al. TGF-β1 effects on proliferation of rat intestinal epithelial cells are due to inhibition of cyclin D1 expression. Oncogene 16, 3445–3454 (1998).

    Article  CAS  PubMed  Google Scholar 

  160. Beck, P. L. et al. Transforming growth factor-β mediates intestinal healing and susceptibility to injury in vitro and in vivo through epithelial cells. Am. J. Pathol. 162, 597–608 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Lee, M. S. et al. Accumulation of extracellular matrix and developmental dysregulation in the pancreas by transgenic production of transforming growth factor-β 1. Am. J. Pathol. 147, 42–52 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Bottinger, E. P. et al. Expression of a dominant-negative mutant TGF-β type II receptor in transgenic mice reveals essential roles for TGF-β in regulation of growth and differentiation in the exocrine pancreas. EMBO J. 16, 2621–2633 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Sanderson, N. et al. Hepatic expression of mature transforming growth factor β 1 in transgenic mice results in multiple tissue lesions. Proc. Natl Acad. Sci. USA 92, 2572–2576 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Bottinger, E. P. et al. The recombinant proregion of transforming growth factor β1 (latency-associated peptide) inhibits active transforming growth factor β1 in transgenic mice. Proc. Natl Acad. Sci. USA 93, 5877–5882 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Martikainen, P., Kyprianou, N. & Isaacs, J. T. Effect of transforming growth factor-β 1 on proliferation and death of rat prostatic cells. Endocrinology 127, 2963–2968 (1990).

    Article  CAS  PubMed  Google Scholar 

  166. Kundu, S. D. et al. Absence of proximal duct apoptosis in the ventral prostate of transgenic mice carrying the C3(1)-TGF-β type II dominant negative receptor. Prostate 43, 118–124 (2000).

    Article  CAS  PubMed  Google Scholar 

  167. Choi, M. E. & Ballermann, B. J. Inhibition of capillary morphogenesis and associated apoptosis by dominant negative mutant transforming growth factor-β receptors. J. Biol. Chem. 270, 21144–21150 (1995).

    Article  CAS  PubMed  Google Scholar 

  168. Hyman, K. M. et al. Transforming growth factor-β1 induces apoptosis in vascular endothelial cells by activation of mitogen-activated protein kinase. Surgery 132, 173–179 (2002).

    Article  PubMed  Google Scholar 

  169. Leveen, P. et al. Induced disruption of the transforming growth factor β type II receptor gene in mice causes a lethal inflammatory disorder that is transplantable. Blood 100, 560–568 (2002).

    Article  CAS  PubMed  Google Scholar 

  170. Gorelik, L. & Flavell, R. A. Abrogation of TGFβ signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 12, 171–181 (2000). Indicates that the inflammatory phenotype previously observed in Tgf-β1−/− mice can be accounted for, in large measure, by loss of Tgf-β responsiveness in T cells.

    Article  CAS  PubMed  Google Scholar 

  171. Lucas, P. J., Kim, S. J., Melby, S. J. & Gress, R. E. Disruption of T cell homeostasis in mice expressing a T cell-specific dominant negative transforming growth factor β II receptor. J. Exp. Med. 191, 1187–1196 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Nakao, A. et al. Blockade of transforming growth factor β/Smad signaling in T cells by overexpression of Smad7 enhances antigen-induced airway inflammation and airway reactivity. J. Exp. Med. 192, 151–158 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Rich, J. N., Zhang, M., Datto, M. B., Bigner, D. D. & Wang, X. F. Transforming growth factor-β-mediated p15INK4B induction and growth inhibition in astrocytes is SMAD3-dependent and a pathway prominently altered in human glioma cell lines. J. Biol. Chem. 274, 35053–35058 (1999).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We apologize to those colleagues whose publications could not be cited because of space limitations. Work from the authors' laboratory is supported by grants from the National Institutes of Health and the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

  1. Cancer Biology and Genetics Program, Howard Hughes Medical Institute, Memorial Sloan–Kettering Cancer Center, New York, 10021, NY, USA

    Peter M. Siegel & Joan Massagué

Authors
  1. Peter M. Siegel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joan Massagué
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joan Massagué.

Related links

Related links

DATABASES

Cancer.gov

breast cancer

colon cancers

endometrial cancer

liver cancer

lung cancer

ovarian cancer

pancreatic cancer

LocusLink

ANG1

Arts

ATF3

CDK2

CDK4

CDK6

CDKN1A

CDKN2B

c-MYC

CTGF

DAPK

DAXX

E-cadherin

ID1

ID2

ID3

Il11

KIP1

KIP2

MIZ1

PTHRP

SARA

SHIP

SMAD2

SMAD3

SMAD4

SMAD7

SMURF1

TβRI

TβRII

TGF-β

TIEG1

VEGF

FURTHER INFORMATION

Joan Massagué's lab

Glossary

NUCLEOPORINS

Proteins that form pores in the nuclear envelope that facilitate the movement of molecules into and out of the nucleus.

E3 UBIQUITIN LIGASE

The third enzyme in a series — the first two are designated E1 and E2 — that are responsible for ubiquitylation of _target proteins. E3 enzymes provide platforms for the binding of E2 enzymes and their specific substrates, thereby coordinating ubiquitylation of the selected substrates.

CAVEOLIN-RICH VESICLES

Invaginations in the plasma membrane or closed vesicles that are enriched for proteins called caveolins. These vesicles are believed to participate in endocytic processes.

ERK1/2

Extracellular-signal-regulated kinases are constituents in a kinase cascade that lie downstream of RAS.

p38

A member of the mitogen-activated protein kinase family that is activated by inflammatory cytokines and cellular responses to environmental stress.

JNK

(c-JUN amino-terminal kinase). A stress-induced protein kinase that has been implicated in cell death or cell viability — depending on the cellular context — and that is activated by XIAP.

LOBULO-ALVEOLAR

Differentiation of the mammary epithelium into functional secretory units during pregnancy that can produce milk proteins during lactation.

EXTRACELLULAR MATRIX

(ECM). A complex, three-dimensional network of very large macromolecules that provides contextual information and an architectural scaffold for cellular adhesion and migration.

IL-2

A cytokine that belongs to the interleukin family that is produced by leukocytes and is important for inducing T-cell proliferation.

CTLs

T lymphocytes that exert a cytolytic function following engagement of their T-cell antigen receptor on _target cells.

TH1

A T-helper-1-cell-mediated immune response is mediated by pro-inflammatory cytokines such as interferon-γ, interleukin-1β and tumour necrosis factor-α. It promotes cellular immune responses against intracellular infections and malignancy.

TH2

A T-helper-2 response involves production of cytokines, such as interleukin-4, which stimulate antibody production. TH2 cytokines promote secretory immune responses of mucosal surfaces to extracellular pathogens and allergic reactions.

RESTRICTION POINT

The point at which cells become committed to enter into S phase of the cell cycle.

BASIC HELIX–LOOP–HELIX TRANSCRIPTION FACTORS

A diverse family of general transcriptional regulators that dimerize through the basic helix–loop–helix motif and that bind DNA via the basic domain.

BCL2 FAMILY

A family of proteins that inhibit or activate apoptosis through modification of mitochondrial function.

CASPASES

A family of cysteine-containing aspartic-acid-specific proteases that are involved in the initiation/execution phases of apoptosis.

MICROSATELLITE INSTABILITY

(MSI). Describes diploid tumours in which genetic instability is due to a high mutation rate, primarily in short nucleotide repeats. Cancers with the MSI phenotype are associated with defects in DNA mismatch-repair genes.

DOMINANT-NEGATIVE

A defective protein that inhibits wild-type function by retaining interaction capabilities that result in distortion or competition with normal proteins.

FAMILIAL JUVENILE POLYPOSIS

An inherited disease that is characterized by the development of benign polyps, usually in the colon.

ORTHOTOPIC

Occurring in the normal or usual position (for example, the orthotopic site for breast cancer cells is in the mammary gland).

CD8+

T cell bearing the CD8 cell-surface glycoprotein, which recognizes major histocompatibility complex class I molecules on _target cells. CD8+ T cells are usually cytotoxic T cells.

CD4+

Helper T lymphocytes that express the co-receptor CD4, which recognizes antigenic peptides (or helper epitopes) that are presented by human leukocyte antigen class II molecules. They exert regulatory and helper functions for B cells, cytotoxic T lymphocytes and other immune effector cells.

T-CELL ANERGY

A state of T-cell unresponsiveness to various stimuli, including antigen presentation.

MAJOR HISTOCOMPATIBILITY COMPLEX

(MHC). Locus of genes that encode products essential to immune function. Class I and class II MHC genes encode proteins that are involved in antigen presentation to T cells.

NEUTROPHILS

Leukocytes of the polymorphonuclear leukocyte subgroup that form the primary defence against bacterial function.

MATRIX METALLOPROTEINASES

A family of proteolytic enzymes that degrade the extracellular matrix and that have important roles in tissue remodelling and tumour metastasis.

DESMOSOMES

An adhesive junction that anchors intermediate filaments between adjoining cells.

BIGENIC MICE

Transgenic mice that have been engineered to simultaneously express two different transgenes in the same _target organ.

EXTRAVASATION

Passage from the blood or lymph vessel into tissue.

OSTEOLYSIS

Destruction of bone that is mediated by bone-resorbing cells, usually osteoclasts.

AUTOIMMUNE INFLAMMATORY DISEASE

A condition that is characterized by infiltration of inflammatory cells into several organ systems accompanied by the production of circulating autoimmune antibodies.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Siegel, P., Massagué, J. Cytostatic and apoptotic actions of TGF-β in homeostasis and cancer. Nat Rev Cancer 3, 807–820 (2003). https://doi.org/10.1038/nrc1208

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc1208

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing
  NODES
Association 1
INTERN 2
twitter 1