Skip to main content

Advertisement

SpringerLink
Log in

TGF-β signalling and its role in cancer progression and metastasis

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

The transforming growth factor-β (TGF-β) system signals via protein kinase receptors and SMAD mediators to regulate a large number of biological processes. Alterations of the TGF-β signalling pathway are implicated in human cancer. Prior to tumour initiation and early during progression, TGF-β acts as a tumour suppressor; however, at later stages, it is often a tumour promoter. Knowledge about the mechanisms involved in TGF-β signal transduction has allowed a better understanding of cancer progression, invasion, metastasis and epithelial-to-mesenchymal transition. Furthermore, several molecular targets with great potential in therapeutic interventions have been identified. This review discusses the TGF-β signalling pathway, its involvement in cancer and current therapeutic approaches.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Frolik, C. A., Dart, L. L., Meyers, C. A., Smith, D. M., & Sporn, M. B. (1983). Purification and initial characterization of a type β transforming growth factor from human placenta. Proceedings of the National Academy of Sciences of the United States of America, 80(12), 3676–3680.

    PubMed  CAS  Google Scholar 

  2. Galat, A. (2011). Common structural traits for cystine knot domain of the TGF-β superfamily of proteins and three-fingered ectodomain of their cellular receptors. Cellular and Molecular Life Sciences: CMLS, 68(20), 3437–3451.

    PubMed  CAS  Google Scholar 

  3. Roberts, A. B. (1998). Molecular and cell biology of TGF-β. Mineral and Electrolyte Metabolism, 24(2–3), 111–119.

    PubMed  CAS  Google Scholar 

  4. Govinden, R., & Bhoola, K. D. (2003). Genealogy, expression, and cellular function of transforming growth factor-β. Pharmacology & Therapeutics, 98(2), 257–265.

    CAS  Google Scholar 

  5. Funkenstein, B., Olekh, E., & Jakowlew, S. B. (2010). Identification of a novel transforming growth factor-β (TGF-β6) gene in fish: regulation in skeletal muscle by nutritional state. BMC Molecular Biology, 11, 37.

    PubMed  Google Scholar 

  6. Rider, C. C., & Mulloy, B. (2010). Bone morphogenetic protein and growth differentiation factor cytokine families and their protein antagonists. The Biochemical Journal, 429(1), 1–12.

    PubMed  CAS  Google Scholar 

  7. Miyazono, K., Kamiya, Y., & Morikawa, M. (2010). Bone morphogenetic protein receptors and signal transduction. Journal of Biochemistry, 147(1), 35–51.

    PubMed  CAS  Google Scholar 

  8. Schier, A. F. (2009). Nodal morphogens. Perspectives in Biology, 1(5), a003459.

    PubMed  Google Scholar 

  9. Kumar, A., Lualdi, M., Lewandoski, M., & Kuehn, M. R. (2008). Broad mesodermal and endodermal deletion of nodal at postgastrulation stages results solely in left/right axial defects. Developmental Dynamics, 237(12), 3591–3601.

    PubMed  CAS  Google Scholar 

  10. Lee, J. D., Migeotte, I., & Anderson, K. V. (2010). Left–right patterning in the mouse requires EPB4.1l5-dependent morphogenesis of the node and midline. Developmental Biology, 346(2), 237–246.

    PubMed  CAS  Google Scholar 

  11. Lee, S. J. (1990). Identification of a novel member (GDF-1) of the transforming growth factor-β superfamily. Molecular Endocrinology, 4(7), 1034–1040.

    PubMed  CAS  Google Scholar 

  12. Moustakas, A., & Heldin, C. H. (2009). The regulation of TGF-β signal transduction. Development, 136(22), 3699–3714.

    PubMed  CAS  Google Scholar 

  13. Josso, N., Belville, C., di Clemente, N., & Picard, J. Y. (2005). AMH and AMH receptor defects in persistent Mullerian duct syndrome. Human Reproduction Update, 11(4), 351–356.

    PubMed  CAS  Google Scholar 

  14. di Clemente, N., & Belville, C. (2006). Anti-Mullerian hormone receptor defect. Clinical Endocrinology & Metabolism, 20(4), 599–610.

    Google Scholar 

  15. Rosal-Goncalves, M., Almeida, C., Barber, J., Kay, T., Limbert, C., Lopes, L., et al. (2010). Mutation of the MIF type II receptor in two brothers. Journal of Pediatric Endocrinology & Metabolism: JPEM, 23(3), 315–317.

    Google Scholar 

  16. Xia, Y., & Schneyer, A. L. (2009). The biology of activin: recent advances in structure, regulation and function. The Journal of Endocrinology, 202(1), 1–12.

    PubMed  CAS  Google Scholar 

  17. Aleman-Muench, G. R., & Soldevila, G. (2012). When versatility matters: activins/inhibins as key regulators of immunity. Immunology and Cell Biology, 90, 137–148.

    PubMed  CAS  Google Scholar 

  18. Stenvers, K. L., & Findlay, J. K. (2010). Inhibins: from reproductive hormones to tumor suppressors. Trends in Endocrinology and Metabolism, 21(3), 174–180.

    PubMed  CAS  Google Scholar 

  19. Tasaka, K., Kasahara, K., Masumoto, N., Mizuki, J., Fukami, K., Miyake, A., et al. (1994). Characterization of activin A-, activin AB- and activin B-responding cells by their responses to hypothalamic releasing hormones. Biochemical and Biophysical Research Communications, 203(3), 1739–1744.

    PubMed  CAS  Google Scholar 

  20. Shi, Y., & Massagué, J. (2003). Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell, 113(6), 685–700.

    PubMed  CAS  Google Scholar 

  21. Gatza, C. E., Oh, S. Y., & Blobe, G. C. (2010). Roles for the type III TGF-β receptor in human cancer. Cellular Signalling, 22(8), 1163–1174.

    PubMed  CAS  Google Scholar 

  22. Bernabeu, C., Lopez-Novoa, J. M., & Quintanilla, M. (2009). The emerging role of TGF-β superfamily coreceptors in cancer. Biochimica et Biophysica Acta, 1792(10), 954–973.

    PubMed  CAS  Google Scholar 

  23. Kang, J. S., Liu, C., & Derynck, R. (2009). New regulatory mechanisms of TGF-β receptor function. Trends in Cell Biology, 19(8), 385–394.

    PubMed  CAS  Google Scholar 

  24. Huminiecki, L., Goldovsky, L., Freilich, S., Moustakas, A., Ouzounis, C., & Heldin, C. H. (2009). Emergence, development and diversification of the TGF-β signalling pathway within the animal kingdom. BMC Evol Biol, 9, 28.

    PubMed  Google Scholar 

  25. Ross, S., & Hill, C. S. (2008). How the SMADs regulate transcription. The International Journal of Biochemistry & Cell Biology, 40(3), 383–408.

    CAS  Google Scholar 

  26. Tsukazaki, T., Chiang, T. A., Davison, A. F., Attisano, L., & Wrana, J. L. (1998). SARA, a Fyve domain protein that recruits SMAD2 to the TGF-β receptor. Cell, 95(6), 779–791.

    PubMed  CAS  Google Scholar 

  27. Sflomos, G., Kostaras, E., Panopoulou, E., Pappas, N., Kyrkou, A., Politou, A. S., et al. (2011). ERBIN is a new SARA-interacting protein: competition between SARA and SMAD2 and SMAD3 for binding to ERBIN. Journal of Cell Science, 124(Pt 19), 3209–3222.

    PubMed  CAS  Google Scholar 

  28. Makkar, P., Metpally, R. P., Sangadala, S., & Reddy, B. V. (2009). Modeling and analysis of MH1 domain of SMADs and their interaction with promoter DNA sequence motif. Journal of Molecular Graphics & Modelling, 27(7), 803–812.

    CAS  Google Scholar 

  29. Itoh, S., & ten Dijke, P. (2007). Negative regulation of TGF-β receptor/SMAD signal transduction. Current Opinion in Cell Biology, 19(2), 176–184.

    PubMed  CAS  Google Scholar 

  30. Hata, A., Lagna, G., Massagué, J., & Hemmati-Brivanlou, A. (1998). SMAD6 inhibits Bmp/SMAD1 signaling by specifically competing with the SMAD4 tumor suppressor. Genes & Development, 12(2), 186–197.

    CAS  Google Scholar 

  31. Dennler, S., Huet, S., & Gauthier, J. M. (1999). A short amino-acid sequence in Mh1 domain is responsible for functional differences between SMAD2 and SMAD3. Oncogene, 18(8), 1643–1648.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  33. Rifkin, D. B. (2005). Latent transforming growth factor-β (TGF-β) binding proteins: orchestrators of TGF-β availability. The Journal of Biological Chemistry, 280(9), 7409–7412.

    PubMed  CAS  Google Scholar 

  34. Kusakabe, M., Cheong, P. L., Nikfar, R., McLennan, I. S., & Koishi, K. (2008). The structure of the TGF-β latency associated peptide region determines the ability of the proprotein convertase furin to cleave TGF-β s. Journal of Cellular Biochemistry, 103(1), 311–320.

    PubMed  CAS  Google Scholar 

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

    PubMed  Google Scholar 

  36. Santibanez, J. F., Blanco, F. J., Garrido-Martin, E. M., Sanz-Rodriguez, F., del Pozo, M. A., & Bernabeu, C. (2008). Caveolin-1 interacts and cooperates with the transforming growth factor-β type I receptor Alk1 in endothelial caveolae. Cardiovascular Research, 77(4), 791–799.

    PubMed  CAS  Google Scholar 

  37. Zhang, Y. E. (2009). Non-SMAD pathways in TGF-β signaling. Cell Research, 19(1), 128–139.

    PubMed  CAS  Google Scholar 

  38. Sanchez-Elsner, T., Botella, L. M., Velasco, B., Corbi, A., Attisano, L., & Bernabeu, C. (2001). Synergistic cooperation between hypoxia and transforming growth factor-β pathways on human vascular endothelial growth factor gene expression. The Journal of Biological Chemistry, 276(42), 38527–38535.

    PubMed  CAS  Google Scholar 

  39. Liu, F., & Matsuura, I. (2005). Inhibition of SMAD antiproliferative function by Cdk phosphorylation. Cell Cycle, 4(1), 63–66.

    PubMed  CAS  Google Scholar 

  40. Sherr, C. J., & Roberts, J. M. (1999). Cdk inhibitors: positive and negative regulators of G1-phase progression. Genes & Development, 13(12), 1501–1512.

    CAS  Google Scholar 

  41. Donovan, J., & Slingerland, J. (2000). Transforming growth factor-β and breast cancer: cell cycle arrest by transforming growth factor-β and its disruption in cancer. Breast Cancer Research, 2(2), 116–124.

    PubMed  CAS  Google Scholar 

  42. Laiho, M., DeCaprio, J. A., Ludlow, J. W., Livingston, D. M., & Massagué, J. (1990). Growth inhibition by TGF-β linked to suppression of retinoblastoma protein phosphorylation. Cell, 62(1), 175–185.

    PubMed  CAS  Google Scholar 

  43. Slingerland, J. M., Hengst, L., Pan, C. H., Alexander, D., Stampfer, M. R., & Reed, S. I. (1994). A novel inhibitor of cyclin-Cdk activity detected in transforming growth factor β-arrested epithelial cells. Molecular and Cellular Biology, 14(6), 3683–3694.

    PubMed  CAS  Google Scholar 

  44. Geng, Y., & Weinberg, R. A. (1993). Transforming growth factor β effects on expression of G1 cyclins and cyclin-dependent protein kinases. Proceedings of the National Academy of Sciences of the United States of America, 90(21), 10315–10319.

    PubMed  CAS  Google Scholar 

  45. Massagué, J., Blain, S. W., & Lo, R. S. (2000). TGF-β signaling in growth control, cancer, and heritable disorders. Cell, 103(2), 295–309.

    PubMed  Google Scholar 

  46. Pardali, K., & Moustakas, A. (2007). Actions of TGF-β as tumor suppressor and pro-metastatic factor in human cancer. Biochimica et Biophysica Acta, 1775(1), 21–62.

    PubMed  CAS  Google Scholar 

  47. Chen, C. R., Kang, Y., & Massagué, J. (2001). Defective repression of c-myc in breast cancer cells: a loss at the core of the transforming growth factor β growth arrest program. Proceedings of the National Academy of Sciences of the United States of America, 98(3), 992–999.

    PubMed  CAS  Google Scholar 

  48. Chen, C. R., Kang, Y., Siegel, P. M., & Massagué, J. (2002). E2f4/5 and P107 as SMAD cofactors linking the TGF-β receptor to c-Myc repression. Cell, 110(1), 19–32.

    PubMed  CAS  Google Scholar 

  49. Frederick, J. P., Liberati, N. T., Waddell, D. S., Shi, Y., & Wang, X. F. (2004). Transforming growth factor β-mediated transcriptional repression of c-Myc is dependent on direct binding of SMAD3 to a novel repressive SMAD binding element. Molecular and Cellular Biology, 24(6), 2546–2559.

    PubMed  CAS  Google Scholar 

  50. Yagi, K., Furuhashi, M., Aoki, H., Goto, D., Kuwano, H., Sugamura, K., et al. (2002). c-myc is a downstream target of the SMAD pathway. The Journal of Biological Chemistry, 277(1), 854–861.

    PubMed  CAS  Google Scholar 

  51. Tachibana, I., Imoto, M., Adjei, P. N., Gores, G. J., Subramaniam, M., Spelsberg, T. C., et al. (1997). Overexpression of the TGF-β -regulated zinc finger encoding gene, TIEG, induces apoptosis in pancreatic epithelial cells. The Journal of Clinical Investigation, 99(10), 2365–2374.

    PubMed  CAS  Google Scholar 

  52. Jang, C. W., Chen, C. H., Chen, C. C., Chen, J. Y., Su, Y. H., & Chen, R. H. (2002). TGF-β induces apoptosis through SMAD-mediated expression of DAP-kinase. Nature Cell Biology, 4(1), 51–58.

    PubMed  CAS  Google Scholar 

  53. Valderrama-Carvajal, H., Cocolakis, E., Lacerte, A., Lee, E. H., Krystal, G., Ali, S., et al. (2002). Activin/TGF-β induce apoptosis through SMAD-dependent expression of the lipid phosphatase ship. Nature Cell Biology, 4(12), 963–969.

    PubMed  CAS  Google Scholar 

  54. Latres, E., Malumbres, M., Sotillo, R., Martin, J., Ortega, S., Martin-Caballero, J., et al. (2000). Limited overlapping roles of P15(Ink4b) and P18(Ink4c) cell cycle inhibitors in proliferation and tumorigenesis. The EMBO Journal, 19(13), 3496–3506.

    PubMed  CAS  Google Scholar 

  55. Gomis, R. R., Alarcon, C., Nadal, C., Van Poznak, C., & Massagué, J. (2006). C/EBPβ at the core of the TGF-β cytostatic response and its evasion in metastatic breast cancer cells. Cancer Cell, 10(3), 203–214.

    PubMed  CAS  Google Scholar 

  56. Fong, S., Itahana, Y., Sumida, T., Singh, J., Coppe, J. P., Liu, Y., et al. (2003). Id-1 as a molecular target in therapy for breast cancer cell invasion and metastasis. Proceedings of the National Academy of Sciences of the United States of America, 100(23), 13543–13548.

    PubMed  CAS  Google Scholar 

  57. Adorno, M., Cordenonsi, M., Montagner, M., Dupont, S., Wong, C., Hann, B., et al. (2009). A mutant-P53/SMAD complex opposes P63 to empower TGF-β -induced metastasis. Cell, 137(1), 87–98.

    PubMed  CAS  Google Scholar 

  58. Grainger, D. J., Heathcote, K., Chiano, M., Snieder, H., Kemp, P. R., Metcalfe, J. C., et al. (1999). Genetic control of the circulating concentration of transforming growth factor type β1. Human Molecular Genetics, 8(1), 93–97.

    PubMed  CAS  Google Scholar 

  59. Yokota, M., Ichihara, S., Lin, T. L., Nakashima, N., & Yamada, Y. (2000). Association of a T29→C polymorphism of the transforming growth factor-β1 gene with genetic susceptibility to myocardial infarction in Japanese. Circulation, 101(24), 2783–2787.

    PubMed  CAS  Google Scholar 

  60. Ziv, E., Cauley, J., Morin, P. A., Saiz, R., & Browner, W. S. (2001). Association between the T29→C polymorphism in the transforming growth factor β1 gene and breast cancer among elderly white women: the study of osteoporotic fractures. Journal of the American Medical Association, 285(22), 2859–2863.

    PubMed  CAS  Google Scholar 

  61. Dunning, A. M., Ellis, P. D., McBride, S., Kirschenlohr, H. L., Healey, C. S., Kemp, P. R., et al. (2003). A transforming growth factor β1 signal peptide variant increases secretion in vitro and is associated with increased incidence of invasive breast cancer. Cancer Research, 63(10), 2610–2615.

    PubMed  CAS  Google Scholar 

  62. Hishida, A., Iwata, H., Hamajima, N., Matsuo, K., Mizutani, M., Iwase, T., et al. (2003). Transforming growth factor B1 T29c polymorphism and breast cancer risk in Japanese women. Breast Cancer, 10(1), 63–69.

    PubMed  Google Scholar 

  63. Gobbi, H., Dupont, W. D., Simpson, J. F., Plummer, W. D., Jr., Schuyler, P. A., Olson, S. J., et al. (1999). Transforming growth factor-β and breast cancer risk in women with mammary epithelial hyperplasia. Journal of the National Cancer Institute, 91(24), 2096–2101.

    PubMed  CAS  Google Scholar 

  64. de Jong, J. S., van Diest, P. J., van der Valk, P., & Baak, J. P. (1998). Expression of growth factors, growth inhibiting factors, and their receptors in invasive breast cancer. I: An inventory in search of autocrine and paracrine loops. The Journal of Pathology, 184(1), 44–52.

    PubMed  Google Scholar 

  65. de Jong, J. S., van Diest, P. J., van der Valk, P., & Baak, J. P. (1998). Expression of growth factors, growth-inhibiting factors, and their receptors in invasive breast cancer. II: Correlations with proliferation and angiogenesis. The Journal of pathology, 184(1), 53–57.

    PubMed  Google Scholar 

  66. Barlow, J., Yandell, D., Weaver, D., Casey, T., & Plaut, K. (2003). Higher stromal expression of transforming growth factor-β type II receptors is associated with poorer prognosis breast tumors. Breast Cancer Research and Treatment, 79(2), 149–159.

    PubMed  CAS  Google Scholar 

  67. Bacman, D., Merkel, S., Croner, R., Papadopoulos, T., Brueckl, W., & Dimmler, A. (2007). TGF-β receptor 2 downregulation in tumour-associated stroma worsens prognosis and high-grade tumours show more tumour-associated macrophages and lower TGF-β1 expression in colon carcinoma: a retrospective study. BMC Cancer, 7, 156.

    PubMed  Google Scholar 

  68. Tsushima, H., Kawata, S., Tamura, S., Ito, N., Shirai, Y., Kiso, S., et al. (1996). High levels of transforming growth factor β 1 in patients with colorectal cancer: association with disease progression. Gastroenterology, 110(2), 375–382.

    PubMed  CAS  Google Scholar 

  69. Friedman, E., Gold, L. I., Klimstra, D., Zeng, Z. S., Winawer, S., & Cohen, A. (1995). High levels of transforming growth factor β 1 correlate with disease progression in human colon cancer. Cancer Epidemiology, Biomarkers & Prevention, 4(5), 549–554.

    CAS  Google Scholar 

  70. Robson, H., Anderson, E., James, R. D., & Schofield, P. F. (1996). Transforming growth factor β 1 expression in human colorectal tumours: an independent prognostic marker in a subgroup of poor prognosis patients. British Journal of Cancer, 74(5), 753–758.

    PubMed  CAS  Google Scholar 

  71. Wikstrom, P., Stattin, P., Franck-Lissbrant, I., Damber, J. E., & Bergh, A. (1998). Transforming growth factor β1 is associated with angiogenesis, metastasis, and poor clinical outcome in prostate cancer. The Prostate, 37(1), 19–29.

    PubMed  CAS  Google Scholar 

  72. Diener, K. R., Need, E. F., Buchanan, G., & Hayball, J. D. (2010). TGF-β signalling and immunity in prostate tumourigenesis. Expert Opinion on Therapeutic Targets, 14(2), 179–192.

    PubMed  CAS  Google Scholar 

  73. Bierie, B., & Moses, H. L. (2006). TGF-β and cancer. Cytokine & Growth Factor Reviews, 17(1–2), 29–40.

    CAS  Google Scholar 

  74. Biswas, S., Trobridge, P., Romero-Gallo, J., Billheimer, D., Myeroff, L. L., Willson, J. K., et al. (2008). Mutational inactivation of TGFβR2 in microsatellite unstable colon cancer arises from the cooperation of genomic instability and the clonal outgrowth of transforming growth factor β resistant cells. Genes, Chromosomes & Cancer, 47(2), 95–106.

    CAS  Google Scholar 

  75. Grady, W. M., Myeroff, L. L., Swinler, S. E., Rajput, A., Thiagalingam, S., Lutterbaugh, J. D., et al. (1999). Mutational inactivation of transforming growth factor β receptor type Ii in microsatellite stable colon cancers. Cancer Research, 59(2), 320–324.

    PubMed  CAS  Google Scholar 

  76. Akhurst, R. J., & Derynck, R. (2001). TGF-β signaling in cancer—a double-edged sword. Trends in Cell Biology, 11(11), S44–S51.

    PubMed  CAS  Google Scholar 

  77. Parsons, R., Myeroff, L. L., Liu, B., Willson, J. K., Markowitz, S. D., Kinzler, K. W., et al. (1995). Microsatellite instability and mutations of the transforming growth factor β type II receptor gene in colorectal cancer. Cancer Research, 55(23), 5548–5550.

    PubMed  CAS  Google Scholar 

  78. Shima, K., Morikawa, T., Yamauchi, M., Kuchiba, A., Imamura, Y., Liao, X., et al. (2011). TGRβR2 and bax mononucleotide tract mutations, microsatellite instability, and prognosis in 1072 colorectal cancers. PLoS One, 6(9), e25062.

    PubMed  CAS  Google Scholar 

  79. Lucke, C. D., Philpott, A., Metcalfe, J. C., Thompson, A. M., Hughes-Davies, L., Kemp, P. R., et al. (2001). Inhibiting mutations in the transforming growth factor β type 2 receptor in recurrent human breast cancer. Cancer Research, 61(2), 482–485.

    PubMed  CAS  Google Scholar 

  80. Antony, M. L., Nair, R., Sebastian, P., & Karunagaran, D. (2010). Changes in expression, and/or mutations in TGF-β receptors (TGF-βRI and TGF-βRII) and SMAD 4 in human ovarian tumors. Journal of Cancer Research and Clinical Oncology, 136(3), 351–361.

    PubMed  CAS  Google Scholar 

  81. Scollen, S., Luccarini, C., Baynes, C., Driver, K., Humphreys, M. K., Garcia-Closas, M., et al. (2011). TGF-β signaling pathway and breast cancer susceptibility. Cancer Epidemiology, Biomarkers & Prevention, 20(6), 1112–1119.

    CAS  Google Scholar 

  82. Bellam, N., & Pasche, B. (2010). TGF-β signaling alterations and colon cancer. Cancer Treatment and Research, 155, 85–103.

    PubMed  CAS  Google Scholar 

  83. Yang, G., & Yang, X. (2010). SMAD4-mediated TGF-β signaling in tumorigenesis. International Journal of Biological Sciences, 6(1), 1–8.

    PubMed  CAS  Google Scholar 

  84. Hahn, S. A., Schutte, M., Hoque, A. T., Moskaluk, C. A., da Costa, L. T., Rozenblum, E., et al. (1996). Dpc4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science, 271(5247), 350–353.

    PubMed  CAS  Google Scholar 

  85. Kretzschmar, M. (2000). Transforming growth factor-β and breast cancer: transforming growth factor-β/SMAD signaling defects and cancer. Breast Cancer Research, 2(2), 107–115.

    PubMed  CAS  Google Scholar 

  86. Tram, E., Ibrahim-Zada, I., Briollais, L., Knight, J. A., Andrulis, I. L., & Ozcelik, H. (2011). Identification of germline alterations of the mad homology 2 domain of SMAD3 and SMAD4 from the Ontario Site of the Breast Cancer Family Registry (CFR). Breast Cancer Research, 13(4), R77.

    PubMed  CAS  Google Scholar 

  87. Ashktorab, H., Schaffer, A. A., Daremipouran, M., Smoot, D. T., Lee, E., & Brim, H. (2010). Distinct genetic alterations in colorectal cancer. PLoS One, 5(1), e8879.

    PubMed  Google Scholar 

  88. Shao, Y., Zhang, J., Zhang, R., Wan, J., Zhang, W., & Yu, B. (2012). Examination of SMAD2 and SMAD4 copy-number variations in skin cancers. Clinical & Translational Oncology, 14(2), 138–142.

    CAS  Google Scholar 

  89. Xu, G., Chakraborty, C., & Lala, P. K. (2003). Reconstitution of SMAD3 restores TGF-β response of tissue inhibitor of metalloprotease-1 upregulation in human choriocarcinoma cells. Biochemical and Biophysical Research Communications, 300(2), 383–390.

    PubMed  CAS  Google Scholar 

  90. Han, S. U., Kim, H. T., Seong, D. H., Kim, Y. S., Park, Y. S., Bang, Y. J., et al. (2004). Loss of the SMAD3 expression increases susceptibility to tumorigenicity in human gastric cancer. Oncogene, 23(7), 1333–1341.

    PubMed  CAS  Google Scholar 

  91. Walker, L. C., Fredericksen, Z. S., Wang, X., Tarrell, R., Pankratz, V. S., Lindor, N. M., et al. (2010). Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers. Breast Cancer Research: BCR, 12(6), R102.

    PubMed  CAS  Google Scholar 

  92. Arany, P. R., Flanders, K. C., DeGraff, W., Cook, J., Mitchell, J. B., & Roberts, A. B. (2007). Absence of SMAD3 confers radioprotection through modulation of Erk-Mapk in primary dermal fibroblasts. Journal of Dermatological Science, 48(1), 35–42.

    PubMed  CAS  Google Scholar 

  93. Samanta, D., Gonzalez, A. L., Nagathihalli, N., Ye, F., Carbone, D. P., & Datta, P. K. (2012). Smoking attenuates transforming growth factor-β-mediated tumor suppression function through downregulation of SMAD3 in lung cancer. Cancer Prevention Research, 5, 452–463.

    Google Scholar 

  94. Ahn, S.M., Cha, J.Y., Kim, J., Kim, D., Trang, H.T., Kim, Y.M. et al. (2012). SMAD3 regulates E-cadherin via miRNA-200 pathway. Oncogene. doi:10.1038/onc.2011.484

  95. Tian, F., Byfield, S. D., Parks, W. T., Yoo, S., Felici, A., Tang, B. W., et al. (2003). Reduction in SMAD2/3 signaling enhances tumorigenesis but suppresses metastasis of breast cancer cell lines. Cancer Research, 63(23), 8284–8292.

    PubMed  CAS  Google Scholar 

  96. Xu, J., Lamouille, S., & Derynck, R. (2009). TGF-β -induced epithelial to mesenchymal transition. Cell Research, 19(2), 156–172.

    PubMed  CAS  Google Scholar 

  97. Miyazono, K. (2009). Transforming growth factor-β signaling in epithelial–mesenchymal transition and progression of cancer. Proceedings of the Japan Academy, 85(8), 314–323.

    CAS  Google Scholar 

  98. Kimelman, D., & Kirschner, M. (1987). Synergistic induction of mesoderm by FGF and TGF-β and the identification of an mRNA coding for FGF in the early Xenopus embryo. Cell, 51(5), 869–877.

    PubMed  CAS  Google Scholar 

  99. Thiery, J. P. (2003). Epithelial–mesenchymal transitions in development and pathologies. Current Opinion in Cell Biology, 15(6), 740–746.

    PubMed  CAS  Google Scholar 

  100. Singh, A., & Settleman, J. (2010). EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene, 29(34), 4741–4751.

    PubMed  CAS  Google Scholar 

  101. Edme, N., Downward, J., Thiery, J. P., & Boyer, B. (2002). Ras induces NBT-II epithelial cell scattering through the coordinate activities of Rac and MAPK pathways. Journal of Cell Science, 115(Pt 12), 2591–2601.

    PubMed  CAS  Google Scholar 

  102. Horiguchi, K., Shirakihara, T., Nakano, A., Imamura, T., Miyazono, K., & Saitoh, M. (2009). Role of Ras signaling in the induction of snail by transforming growth factor-β. The Journal of Biological Chemistry, 284(1), 245–253.

    PubMed  CAS  Google Scholar 

  103. Jenndahl, L. E., Isakson, P., & Baeckstrom, D. (2005). C-Erbb2-induced epithelial–mesenchymal transition in mammary epithelial cells is suppressed by cell–cell contact and initiated prior to E-cadherin downregulation. International Journal of Oncology, 27(2), 439–448.

    PubMed  CAS  Google Scholar 

  104. Moustakas, A., & Heldin, C. H. (2007). Signaling networks guiding epithelial–mesenchymal transitions during embryogenesis and cancer progression. Cancer Science, 98(10), 1512–1520.

    PubMed  CAS  Google Scholar 

  105. Fuxe, J., Vincent, T., & Garcia de Herreros, A. (2010). Transcriptional crosstalk between TGF-β and stem cell pathways in tumor cell invasion: role of EMT promoting SMAD complexes. Cell Cycle, 9(12), 2363–2374.

    PubMed  CAS  Google Scholar 

  106. Hills, C. E., Siamantouras, E., Smith, S. W., Cockwell, P., Liu, K. K., & Squires, P. E. (2012). TGF-β modulates cell-to-cell communication in early epithelial-to-mesenchymal transition. Diabetologia, 55(3), 812–824.

    PubMed  CAS  Google Scholar 

  107. Xie, L., Law, B. K., Chytil, A. M., Brown, K. A., Aakre, M. E., & Moses, H. L. (2004). Activation of the Erk pathway is required for TGF-β1-induced EMT in vitro. Neoplasia, 6(5), 603–610.

    PubMed  CAS  Google Scholar 

  108. Bhowmick, N. A., Zent, R., Ghiassi, M., McDonnell, M., & Moses, H. L. (2001). Integrin β 1 signaling is necessary for transforming growth factor-β activation of p38MAPK and epithelial plasticity. The Journal of Biological Chemistry, 276(50), 46707–46713.

    PubMed  CAS  Google Scholar 

  109. Galliher, A. J., & Schiemann, W. P. (2006). β3 integrin and Src facilitate transforming growth factor-β mediated induction of epithelial–mesenchymal transition in mammary epithelial cells. Breast Cancer Research, 8(4), R42.

    PubMed  Google Scholar 

  110. Galliher, A. J., & Schiemann, W. P. (2007). Src phosphorylates Tyr284 in TGF-β type II receptor and regulates TGF-β stimulation of p38 MAPK during breast cancer cell proliferation and invasion. Cancer Research, 67(8), 3752–3758.

    PubMed  CAS  Google Scholar 

  111. Wendt, M. K., & Schiemann, W. P. (2009). Therapeutic targeting of the focal adhesion complex prevents oncogenic TGF-β signaling and metastasis. Breast Cancer Research, 11(5), R68.

    PubMed  Google Scholar 

  112. Wendt, M. K., Smith, J. A., & Schiemann, W. P. (2009). P130cas is required for mammary tumor growth and transforming growth factor-β-mediated metastasis through regulation of SMAD2/3 activity. The Journal of Biological Chemistry, 284(49), 34145–34156.

    PubMed  CAS  Google Scholar 

  113. Huber, M. A., Azoitei, N., Baumann, B., Grunert, S., Sommer, A., Pehamberger, H., et al. (2004). NF-κB is essential for epithelial–mesenchymal transition and metastasis in a model of breast cancer progression. The Journal of Clinical Investigation, 114(4), 569–581.

    PubMed  CAS  Google Scholar 

  114. Neil, J. R., Johnson, K. M., Nemenoff, R. A., & Schiemann, W. P. (2008). Cox-2 inactivates SMAD signaling and enhances EMT stimulated by TGF-β through a Pge2-dependent mechanisms. Carcinogenesis, 29(11), 2227–2235.

    PubMed  CAS  Google Scholar 

  115. Tian, M., & Schiemann, W. P. (2010). PGE2 receptor EP2 mediates the antagonistic effect of COX-2 on TGF-β signaling during mammary tumorigenesis. The FASEB Journal, 24(4), 1105–1116.

    CAS  Google Scholar 

  116. Bakin, A. V., Tomlinson, A. K., Bhowmick, N. A., Moses, H. L., & Arteaga, C. L. (2000). Phosphatidylinositol 3-kinase function is required for transforming growth factor β-mediated epithelial to mesenchymal transition and cell migration. The Journal of Biological Chemistry, 275(47), 36803–36810.

    PubMed  CAS  Google Scholar 

  117. Lamouille, S., & Derynck, R. (2007). Cell size and invasion in TGF-β-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway. The Journal of Cell Biology, 178(3), 437–451.

    PubMed  CAS  Google Scholar 

  118. Lamouille, S., & Derynck, R. (2011). Emergence of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin axis in transforming growth factor-β-induced epithelial–mesenchymal transition. Cells, Tissues, Organs, 193(1–2), 8–22.

    PubMed  CAS  Google Scholar 

  119. Wendt, M. K., Allington, T. M., & Schiemann, W. P. (2009). Mechanisms of the epithelial–mesenchymal transition by TGF-β. Future Oncology, 5(8), 1145–1168.

    PubMed  CAS  Google Scholar 

  120. Hurd, T. W., Gao, L., Roh, M. H., Macara, I. G., & Margolis, B. (2003). Direct interaction of two polarity complexes implicated in epithelial tight junction assembly. Nature Cell Biology, 5(2), 137–142.

    PubMed  CAS  Google Scholar 

  121. Ozdamar, B., Bose, R., Barrios-Rodiles, M., Wang, H. R., Zhang, Y., & Wrana, J. L. (2005). Regulation of the polarity protein Par6 by TGF-β receptors controls epithelial cell plasticity. Science, 307(5715), 1603–1609.

    PubMed  CAS  Google Scholar 

  122. Viloria-Petit, A. M., David, L., Jia, J. Y., Erdemir, T., Bane, A. L., Pinnaduwage, D., et al. (2009). A role for the TGF-β–Par6 polarity pathway in breast cancer progression. Proceedings of the National Academy of Sciences of the United States of America, 106(33), 14028–14033.

    PubMed  CAS  Google Scholar 

  123. Araki, S., Eitel, J. A., Batuello, C. N., Bijangi-Vishehsaraei, K., Xie, X. J., Danielpour, D., et al. (2010). TGF-β1-induced expression of human Mdm2 correlates with late-stage metastatic breast cancer. The Journal of Clinical Investigation, 120(1), 290–302.

    PubMed  CAS  Google Scholar 

  124. Pandey, J., Umphress, S. M., Kang, Y., Angdisen, J., Naumova, A., Mercer, K. L., et al. (2007). Modulation of tumor induction and progression of oncogenic K-Ras-positive tumors in the presence of TGF-β 1 haploinsufficiency. Carcinogenesis, 28(12), 2589–2596.

    PubMed  CAS  Google Scholar 

  125. Padua, D., Zhang, X. H., Wang, Q., Nadal, C., Gerald, W. L., Gomis, R. R., et al. (2008). TGF-β primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell, 133(1), 66–77.

    PubMed  CAS  Google Scholar 

  126. Greco, C., Forte, L., Erba, P., & Mariani, G. (2011). Bone metastases, general and clinical issues. The Quarterly Journal of Nuclear Medicine and Molecular Imaging, 55(4), 337–352.

    PubMed  CAS  Google Scholar 

  127. Yin, J. J., Pollock, C. B., & Kelly, K. (2005). Mechanisms of cancer metastasis to the bone. Cell Research, 15(1), 57–62.

    PubMed  CAS  Google Scholar 

  128. Yin, J. J., Selander, K., Chirgwin, J. M., Dallas, M., Grubbs, B. G., Wieser, R., et al. (1999). TGF-β signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. The Journal of Clinical Investigation, 103(2), 197–206.

    PubMed  CAS  Google Scholar 

  129. Guise, T. A., Yin, J. J., Taylor, S. D., Kumagai, Y., Dallas, M., Boyce, B. F., et al. (1996). Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. The Journal of Clinical Investigation, 98(7), 1544–1549.

    PubMed  CAS  Google Scholar 

  130. Kingsley, L. A., Fournier, P. G., Chirgwin, J. M., & Guise, T. A. (2007). Molecular biology of bone metastasis. Molecular Cancer Therapeutics, 6(10), 2609–2617.

    PubMed  CAS  Google Scholar 

  131. Muller, A., Homey, B., Soto, H., Ge, N., Catron, D., Buchanan, M. E., et al. (2001). Involvement of chemokine receptors in breast cancer metastasis. Nature, 410(6824), 50–56.

    PubMed  CAS  Google Scholar 

  132. Kang, Y., Siegel, P. M., Shu, W., Drobnjak, M., Kakonen, S. M., Cordon-Cardo, C., et al. (2003). A multigenic program mediating breast cancer metastasis to bone. Cancer Cell, 3(6), 537–549.

    PubMed  CAS  Google Scholar 

  133. Thiery, J. P., Acloque, H., Huang, R. Y., & Nieto, M. A. (2009). Epithelial–mesenchymal transitions in development and disease. Cell, 139(5), 871–890.

    PubMed  CAS  Google Scholar 

  134. Soto, A. M., & Sonnenschein, C. (2011). The tissue organization field theory of cancer: a testable replacement for the somatic mutation theory. BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology, 33(5), 332–340.

    Google Scholar 

  135. Leight, J. L., Wozniak, M. A., Chen, S., Lynch, M. L., & Chen, C. S. (2012). Matrix rigidity regulates a switch between TGF-β 1-induced apoptosis and epithelial–mesenchymal transition. Molecular Biology of the Cell, 23, 781–791.

    PubMed  CAS  Google Scholar 

  136. Copple, B. L. (2010). Hypoxia stimulates hepatocyte epithelial to mesenchymal transition by hypoxia-inducible factor and transforming growth factor-β-dependent mechanisms. Liver International, 30(5), 669–682.

    PubMed  CAS  Google Scholar 

  137. Guan, F., Schaffer, L., Handa, K., & Hakomori, S. I. (2010). Functional role of gangliotetraosylceramide in epithelial-to-mesenchymal transition process induced by hypoxia and by TGF-β. The FASEB Journal, 24(12), 4889–4903.

    CAS  Google Scholar 

  138. Mak, P., Leav, I., Pursell, B., Bae, D., Yang, X., Taglienti, C. A., et al. (2010). ERbβ impedes prostate cancer EMT by destabilizing HIF-1α and inhibiting VEGF-mediated snail nuclear localization: implications for Gleason grading. Cancer Cell, 17(4), 319–332.

    PubMed  CAS  Google Scholar 

  139. Kuperwasser, C., Chavarria, T., Wu, M., Magrane, G., Gray, J. W., Carey, L., et al. (2004). Reconstruction of functionally normal and malignant human breast tissues in mice. Proceedings of the National Academy of Sciences of the United States of America, 101(14), 4966–4971.

    PubMed  CAS  Google Scholar 

  140. Bhowmick, N. A., Chytil, A., Plieth, D., Gorska, A. E., Dumont, N., Shappell, S., et al. (2004). TGF-β signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science, 303(5659), 848–851.

    PubMed  CAS  Google Scholar 

  141. Maffini, M. V., Soto, A. M., Calabro, J. M., Ucci, A. A., & Sonnenschein, C. (2004). The stroma as a crucial target in rat mammary gland carcinogenesis. Journal of Cell Science, 117(Pt 8), 1495–1502.

    PubMed  CAS  Google Scholar 

  142. de Visser, K. E., Eichten, A., & Coussens, L. M. (2006). Paradoxical roles of the immune system during cancer development. Nature Reviews. Cancer, 6(1), 24–37.

    PubMed  Google Scholar 

  143. Shull, M. M., Ormsby, I., Kier, A. B., Pawlowski, S., Diebold, R. J., Yin, M., et al. (1992). Targeted disruption of the mouse transforming growth factor-β 1 gene results in multifocal inflammatory disease. Nature, 359(6397), 693–699.

    PubMed  CAS  Google Scholar 

  144. Engle, S. J., Ormsby, I., Pawlowski, S., Boivin, G. P., Croft, J., Balish, E., et al. (2002). Elimination of colon cancer in germ-free transforming growth factor β 1-deficient mice. Cancer Research, 62(22), 6362–6366.

    PubMed  CAS  Google Scholar 

  145. Ewan, K. B., Oketch-Rabah, H. A., Ravani, S. A., Shyamala, G., Moses, H. L., & Barcellos-Hoff, M. H. (2005). Proliferation of estrogen receptor-α-positive mammary epithelial cells is restrained by transforming growth factor-β1 in adult mice. The American Journal of Pathology, 167(2), 409–417.

    PubMed  CAS  Google Scholar 

  146. Barcellos-Hoff, M. H., & Akhurst, R. J. (2009). Transforming growth factor-β in breast cancer: too much, too late. Breast Cancer Research, 11(1), 202.

    PubMed  Google Scholar 

  147. Saunier, E. F., & Akhurst, R. J. (2006). TGF-β inhibition for cancer therapy. Current Cancer Drug Targets, 6(7), 565–578.

    PubMed  CAS  Google Scholar 

  148. Yang, L. (2010). TGF-β and cancer metastasis: an inflammation link. Cancer Metastasis Reviews, 29(2), 263–271.

    PubMed  Google Scholar 

  149. Nam, J. S., Terabe, M., Mamura, M., Kang, M. J., Chae, H., Stuelten, C., et al. (2008). An anti-transforming growth factor β antibody suppresses metastasis via cooperative effects on multiple cell compartments. Cancer Research, 68(10), 3835–3843.

    PubMed  CAS  Google Scholar 

  150. Ohmori, T., Yang, J. L., Price, J. O., & Arteaga, C. L. (1998). Blockade of tumor cell transforming growth factor-βs enhances cell cycle progression and sensitizes human breast carcinoma cells to cytotoxic chemotherapy. Experimental Cell Research, 245(2), 350–359.

    PubMed  CAS  Google Scholar 

  151. Liu, P., Menon, K., Alvarez, E., Lu, K., & Teicher, B. A. (2000). Transforming growth factor-β and response to anticancer therapies in human liver and gastric tumors in vitro and in vivo. International Journal of Oncology, 16(3), 599–610.

    PubMed  CAS  Google Scholar 

  152. Teicher, B. A. (2001). Malignant cells, directors of the malignant process: role of transforming growth factor-β. Cancer Metastasis Reviews, 20(1–2), 133–143.

    PubMed  CAS  Google Scholar 

  153. Teicher, B. A., Ikebe, M., Ara, G., Keyes, S. R., & Herbst, R. S. (1997). Transforming growth factor-β 1 overexpression produces drug resistance in vivo: reversal by decorin. In Vivo, 11(6), 463–472.

    PubMed  CAS  Google Scholar 

  154. Kirshner, J., Jobling, M. F., Pajares, M. J., Ravani, S. A., Glick, A. B., Lavin, M. J., et al. (2006). Inhibition of transforming growth factor-β1 signaling attenuates ataxia telangiectasia mutated activity in response to genotoxic stress. Cancer Research, 66(22), 10861–10869.

    PubMed  CAS  Google Scholar 

  155. Ewan, K. B., Henshall-Powell, R. L., Ravani, S. A., Pajares, M. J., Arteaga, C., Warters, R., et al. (2002). Transforming growth factor-β1 mediates cellular response to DNA damage in situ. Cancer Research, 62(20), 5627–5631.

    PubMed  CAS  Google Scholar 

  156. Zhang, M., Kleber, S., Rohrich, M., Timke, C., Han, N., Tuettenberg, J., et al. (2011). Blockade of TGF-β signaling by the TGF-β R-I kinase inhibitor Ly2109761 enhances radiation response and prolongs survival in glioblastoma. Cancer Research, 71(23), 7155–7167.

    PubMed  CAS  Google Scholar 

  157. Liu, Y., Kudo, K., Abe, Y., Hu, D. L., Kijima, H., Nakane, A., et al. (2009). Inhibition of transforming growth factor-β, hypoxia-inducible factor-α and vascular endothelial growth factor reduced late rectal injury induced by irradiation. Journal of Radiation Research, 50(3), 233–239.

    PubMed  CAS  Google Scholar 

  158. Kakeji, Y., Maehara, Y., Ikebe, M., & Teicher, B. A. (1997). Dynamics of tumor oxygenation, CD31 staining and transforming growth factor-β levels after treatment with radiation or cyclophosphamide in the rat 13762 mammary carcinoma. International Journal of Radiation Oncology, Biology, Physics, 37(5), 1115–1123.

    PubMed  CAS  Google Scholar 

  159. Vujaskovic, Z., Marks, L. B., & Anscher, M. S. (2000). The physical parameters and molecular events associated with radiation-induced lung toxicity. Seminars in Radiation Oncology, 10(4), 296–307.

    PubMed  CAS  Google Scholar 

  160. Hofer, S. O., Molema, G., Hermens, R. A., Wanebo, H. J., Reichner, J. S., & Hoekstra, H. J. (1999). The effect of surgical wounding on tumour development. European Journal of Surgical Oncology, 25(3), 231–243.

    PubMed  CAS  Google Scholar 

  161. Teicher, B. A., Maehara, Y., Kakeji, Y., Ara, G., Keyes, S. R., Wong, J., et al. (1997). Reversal of in vivo drug resistance by the transforming growth factor-β inhibitor decorin. International Journal of Cancer, 71(1), 49–58.

    CAS  Google Scholar 

  162. Yamaguchi, K., Takagi, Y., Aoki, S., Futamura, M., & Saji, S. (2000). Significant detection of circulating cancer cells in the blood by reverse transcriptase-polymerase chain reaction during colorectal cancer resection. Annals of Surgery, 232(1), 58–65.

    PubMed  CAS  Google Scholar 

  163. Tsushima, H., Ito, N., Tamura, S., Matsuda, Y., Inada, M., Yabuuchi, I., et al. (2001). Circulating transforming growth factor β 1 as a predictor of liver metastasis after resection in colorectal cancer. Clinical Cancer Research, 7(5), 1258–1262.

    PubMed  CAS  Google Scholar 

  164. Shim, K. S., Kim, K. H., Han, W. S., & Park, E. B. (1999). Elevated serum levels of transforming growth factor-β1 in patients with colorectal carcinoma: its association with tumor progression and its significant decrease after curative surgical resection. Cancer, 85(3), 554–561.

    PubMed  CAS  Google Scholar 

  165. Feltl, D., Zavadova, E., Pala, M., & Hozak, P. (2005). The dynamics of plasma transforming growth factor β 1 (TGF-β1) level during radiotherapy with or without simultaneous chemotherapy in advanced head and neck cancer. Oral Oncology, 41(2), 208–213.

    PubMed  CAS  Google Scholar 

  166. Robert, F., Busby, E., Marques, M. B., Reynolds, R. E., & Carey, D. E. (2003). Phase II study of docetaxel plus enoxaparin in chemotherapy-naive patients with metastatic non-small cell lung cancer: preliminary results. Lung Cancer, 42(2), 237–245.

    PubMed  Google Scholar 

  167. Dave, H., Shah, M., Trivedi, S., & Shukla, S. (2011). Prognostic utility of circulating transforming growth factor β 1 in breast cancer patients. The International Journal of Biological Markers, 27, 53–59.

    Google Scholar 

  168. Hirohashi, S., & Kanai, Y. (2003). Cell adhesion system and human cancer morphogenesis. Cancer Science, 94(7), 575–581.

    PubMed  CAS  Google Scholar 

  169. Teicher, B. A., Holden, S. A., Ara, G., & Chen, G. (1996). Transforming growth factor-β in in vivo resistance. Cancer Chemotherapy and Pharmacology, 37(6), 601–609.

    PubMed  CAS  Google Scholar 

  170. Andarawewa, K. L., Erickson, A. C., Chou, W. S., Costes, S. V., Gascard, P., Mott, J. D., et al. (2007). Ionizing radiation predisposes nonmalignant human mammary epithelial cells to undergo transforming growth factor β induced epithelial to mesenchymal transition. Cancer Research, 67(18), 8662–8670.

    PubMed  CAS  Google Scholar 

  171. Begg, A. C., Stewart, F. A., & Vens, C. (2011). Strategies to improve radiotherapy with targeted drugs. Nature Reviews. Cancer, 11(4), 239–253.

    PubMed  CAS  Google Scholar 

  172. Burdak-Rothkamm, S., & Prise, K. M. (2009). New molecular targets in radiotherapy: DNA damage signalling and repair in targeted and non-targeted cells. European Journal of Pharmacology, 625(1–3), 151–155.

    PubMed  CAS  Google Scholar 

  173. Wiegman, E. M., Blaese, M. A., Loeffler, H., Coppes, R. P., & Rodemann, H. P. (2007). TGF-β-1 dependent fast stimulation of ATM and P53 phosphorylation following exposure to ionizing radiation does not involve TGF-β-receptor I signalling. Radiotherapy and Oncology, 83(3), 289–295.

    PubMed  CAS  Google Scholar 

  174. Bouquet, F., Pal, A., Pilones, K. A., Demaria, S., Hann, B., Akhurst, R. J., et al. (2011). TGF-β 1 inhibition increases the radiosensitivity of breast cancer cells in vitro and promotes tumor control by radiation in vivo. Clinical Cancer Research, 17(21), 6754–6765.

    PubMed  CAS  Google Scholar 

  175. Martin, M., Lefaix, J., & Delanian, S. (2000). TGF-β 1 and radiation fibrosis: a master switch and a specific therapeutic target? International Journal of Radiation Oncology, Biology, Physics, 47(2), 277–290.

    PubMed  CAS  Google Scholar 

  176. Anscher, M. S., Thrasher, B., Rabbani, Z., Teicher, B., & Vujaskovic, Z. (2006). Antitransforming growth factor-β antibody 1d11 ameliorates normal tissue damage caused by high-dose radiation. International Journal of Radiation Oncology, Biology, Physics, 65(3), 876–881.

    PubMed  CAS  Google Scholar 

  177. Lan, H. Y. (2011). Diverse roles of TGF-β/SMADs in renal fibrosis and inflammation. International Journal of Biological Sciences, 7(7), 1056–1067.

    PubMed  CAS  Google Scholar 

  178. Kalluri, R., & Neilson, E. G. (2003). Epithelial–mesenchymal transition and its implications for fibrosis. The Journal of Clinical Investigation, 112(12), 1776–1784.

    PubMed  CAS  Google Scholar 

  179. Anido, J., Saez-Borderias, A., Gonzalez-Junca, A., Rodon, L., Folch, G., Carmona, M. A., et al. (2010). TGF-β receptor inhibitors target the CD44(High)/Id1(High) glioma-initiating cell population in human glioblastoma. Cancer Cell, 18(6), 655–668.

    PubMed  CAS  Google Scholar 

  180. Fransvea, E., Angelotti, U., Antonaci, S., & Giannelli, G. (2008). Blocking transforming growth factor-β up-regulates E-cadherin and reduces migration and invasion of hepatocellular carcinoma cells. Hepatology, 47(5), 1557–1566.

    PubMed  CAS  Google Scholar 

  181. Fu, K., Corbley, M. J., Sun, L., Friedman, J. E., Shan, F., Papadatos, J. L., et al. (2008). Sm16, an orally active TGF-β type I receptor inhibitor prevents myofibroblast induction and vascular fibrosis in the rat carotid injury model. Arteriosclerosis, Thrombosis, and Vascular Biology, 28(4), 665–671.

    PubMed  CAS  Google Scholar 

  182. Wallace, A., Kapoor, V., Sun, J., Mrass, P., Weninger, W., Heitjan, D. F., et al. (2008). Transforming growth factor-β receptor blockade augments the effectiveness of adoptive T-cell therapy of established solid cancers. Clinical Cancer Research, 14(12), 3966–3974.

    PubMed  CAS  Google Scholar 

  183. Fakhrai, H., Dorigo, O., Shawler, D. L., Lin, H., Mercola, D., Black, K. L., et al. (1996). Eradication of established intracranial rat gliomas by transforming growth factor β antisense gene therapy. Proceedings of the National Academy of Sciences of the United States of America, 93(7), 2909–2914.

    PubMed  CAS  Google Scholar 

  184. Maggard, M., Meng, L., Ke, B., Allen, R., Devgan, L., & Imagawa, D. K. (2001). Antisense TGF-β2 immunotherapy for hepatocellular carcinoma: treatment in a rat tumor model. Annals of Surgical Oncology, 8(1), 32–37.

    PubMed  CAS  Google Scholar 

  185. Olivares, J., Kumar, P., Yu, Y., Maples, P. B., Senzer, N., Bedell, C., et al. (2011). Phase I trial of TGF-β 2 antisense GM-SCF gene-modified autologous tumor cell (Tag) vaccine. Clinical Cancer Research, 17(1), 183–192.

    PubMed  CAS  Google Scholar 

  186. Lampropoulos, P., Zizi-Sermpetzoglou, A., Rizos, S., Kostakis, A., Nikiteas, N., Papavassiliou, A.G. (2012). Prognostic significance of transforming growth factor β (TGF-β) signaling axis molecules and E-cadherin in colorectal cancer. Tumour Biology. doi:10.1007/s13277-012-0333-3.

  187. Matsumura, N., Huang, Z., Mori, S., Baba, T., Fujii, S., Konishi, I., et al. (2011). Epigenetic suppression of the TGF-β pathway revealed by transcriptome profiling in ovarian cancer. Genome Research, 21(1), 74–82.

    PubMed  CAS  Google Scholar 

  188. Wang, Z., Chen, C., Finger, S. N., Kwajah, S., Jung, M., Schwarz, H., et al. (2009). Suberoylanilide hydroxamic acid: a potential epigenetic therapeutic agent for lung fibrosis? The European Respiratory Journal, 34(1), 145–155.

    PubMed  CAS  Google Scholar 

  189. Duenas-Gonzalez, A., Candelaria, M., Perez-Plascencia, C., Perez-Cardenas, E., de la Cruz-Hernandez, E., & Herrera, L. A. (2008). Valproic acid as epigenetic cancer drug: preclinical, clinical and transcriptional effects on solid tumors. Cancer Treatment Reviews, 34(3), 206–222.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Special thanks are for our colleagues for valuable discussions and Hans van Dam for critical reading of the manuscript. Our research on TGF-β in cancer is supported by Netherlands Organization for Scientific Research and Centre for Biomedical Genetics. We apologize to those authors whose works are not cited here.

Author information

Authors and Affiliations

  1. Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Center, Postbus 9600, 2300 RC, Leiden, the Netherlands

    Yvette Drabsch & Peter ten Dijke

  2. Uppsala University and Ludwig Institute for Cancer Research, Box 595, 75124, Uppsala, Sweden

    Peter ten Dijke

Authors
  1. Yvette Drabsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter ten Dijke
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yvette Drabsch.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Drabsch, Y., ten Dijke, P. TGF-β signalling and its role in cancer progression and metastasis. Cancer Metastasis Rev 31, 553–568 (2012). https://doi.org/10.1007/s10555-012-9375-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-012-9375-7

Keywords

Search

Navigation