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Targeting the Transforming Growth Factor-β Signaling in Cancer Therapy

  • Sheen, Yhun Yhong (College of Pharmacy, Ewha Womans University) ;
  • Kim, Min-Jin (College of Pharmacy, Ewha Womans University) ;
  • Park, Sang-A (College of Pharmacy, Ewha Womans University) ;
  • Park, So-Yeon (College of Pharmacy, Ewha Womans University) ;
  • Nam, Jeong-Seok (Laboratory of Tumor Suppressor, Lee Gil Ya Cancer and Diabetes Institute, Gachon University)
  • Received : 2013.09.12
  • Accepted : 2013.09.24
  • Published : 2013.09.30

Abstract

TGF-${\beta}$ pathway is being extensively evaluated as a potential therapeutic target. The transforming growth factor-${\beta}$ (TGF-${\beta}$) signaling pathway has the dual role in both tumor suppression and tumor promotion. To design cancer therapeutics successfully, it is important to understand TGF-${\beta}$ related functional contexts. This review discusses the molecular mechanism of the TGF-${\beta}$ pathway and describes the different ways of tumor suppression and promotion by TGF-${\beta}$. In the last part of the review, the data on targeting TGF-${\beta}$ pathway for cancer treatment is assessed. The TGF-${\beta}$ inhibitors in pre-clinical studies, and Phase I and II clinical trials are updated.

References

  1. Akiyama, Y., Iwanaga, R., Saitoh, K., Shiba, K., Ushio, K., Ikeda, E., Iwama, T., Nomizu, T. and Yuasa, Y. (1997) Transforming growth factor beta type II receptor gene mutations in adenomas from hereditary nonpolyposis colorectal cancer. Gastroenterology 112, 33-39. https://doi.org/10.1016/S0016-5085(97)70216-6
  2. Arteaga, C., Hurd, S., Winnier, A., Johnson, M., Fendly, B. and Forbes, J. (1993) Anti-transforming growth factor (TGF)-beta antibodies inhibit breast cancer cell tumorigenicity and increase mouse spleen natural killer cell activity. Implications for a possible role of tumor cell/host TGF-beta interactions in human breast cancer progression. J. Clin. Invest. 92, 2569-2576. https://doi.org/10.1172/JCI116871
  3. Bandyopadhyay, A., Agyin, J. K., Wang, L., Tang, Y., Lei, X., Story, B. M., Cornell, J. E., Pollock, B. H., Mundy, G. R. and Sun, L.-Z. (2006) Inhibition of pulmonary and skeletal metastasis by a transforming growth factor-${\beta}$ type I receptor kinase inhibitor. Cancer Res. 66, 6714-6721. https://doi.org/10.1158/0008-5472.CAN-05-3565
  4. Biswas, S., Guix, M., Rinehart, C., Dugger, T. C., Chytil, A., Moses, H. L., Freeman, M. L. and Arteaga, C. L. (2007) Inhibition of TGF-${\beta}$ with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression. J. Clin. Invest. 117, 1305-1313. https://doi.org/10.1172/JCI30740
  5. Bueno, L., de Alwis, D. P., Pitou, C., Yingling, J., Lahn, M., Glatt, S. and Troconiz, I. F. (2008) Semi-mechanistic modelling of the tumour growth inhibitory effects of LY2157299, a new type I receptor TGF-${\beta}$ kinase antagonist, in mice. Eur. J. Cancer 44, 142-150. https://doi.org/10.1016/j.ejca.2007.10.008
  6. Calone, I. and Souchelnytskyi, S. (2012) Inhibition of TGFbeta signaling and its implications in anticancer treatments. Exp. Oncol. 34, 9-16.
  7. Capocasale, R. J., Lamb, R. J., Vonderheid, E. C., Fox, F. E., Rook, A. H., Nowell, P. C. and Moore, J. S. (1995) Reduced surface expression of transforming growth factor beta receptor type II in mitogen-activated T cells from Sezary patients. Proc. Natl. Acad. Sci. U.S.A. 92, 5501-5505. https://doi.org/10.1073/pnas.92.12.5501
  8. Chen, T., Yan, W., Wells, R. G., Rimm, D. L., McNiff, J., Leffell, D. and Reiss, M. (2001) Novel inactivating mutations of transforming growth factor-${\beta}$ type I receptor gene in head-and-neck cancer metastases. Int. J. Cancer 93, 653-661. https://doi.org/10.1002/ijc.1381
  9. Connolly, E. C., Freimuth, J. and Akhurst, R. J. (2012) Complexities of TGF-${\beta}$ targeted cancer therapy. Int. J. Biol. Sci. 8, 964-978. https://doi.org/10.7150/ijbs.4564
  10. Connolly, E. C., Saunier, E. F., Quigley, D., Luu, M. T., De Sapio, A., Hann, B., Yingling, J. M. and Akhurst, R. J. (2011) Outgrowth of drug-resistant carcinomas expressing markers of tumor aggression after long-term $T{\beta}RI/II$ kinase inhibition with LY2109761. Cancer Res. 71, 2339-2349. https://doi.org/10.1158/0008-5472.CAN-10-2941
  11. DaCosta Byfield, S. D., Major, C., Laping, N. J. and Roberts, A. B. (2004) SB-505124 is a selective inhibitor of transforming growth factor-${\beta}$ type I receptors ALK4, ALK5, and ALK7. Mol. Pharmacol. 65, 744-752. https://doi.org/10.1124/mol.65.3.744
  12. Datta, P. K. and Mann, J. R. (2008) Transforming growth factor-${\beta}$ (TGF-${\beta}$) signaling inhibitors cancer therapy in: Transforming Growth Factor-${\beta}$ in Cancer Therapy. In Cancer Treatment and therapy, Volume II, pp.573-587, Human Press.
  13. Derynck, R. and Akhurst, R. J. (2007) Differentiation plasticity regulated by TGF-${\beta}$ family proteins in development and disease. Nat. Cell Biol. 9, 1000-1004. https://doi.org/10.1038/ncb434
  14. Derynck, R., Akhurst, R. J. and Balmain, A. (2001) TGF-${\beta}$ signaling in tumor suppression and cancer progression. Nat. Genet. 29, 117-129. https://doi.org/10.1038/ng1001-117
  15. Derynck, R. and Zhang, Y. E. (2003) Smad-dependent and Smad-independent pathways in TGF-${\beta}$ family signalling. Nature 425, 577-584. https://doi.org/10.1038/nature02006
  16. Dong, M. and Blobe, G. C. (2006) Role of transforming growth factor-${\beta}$ in hematologic malignancies. Blood 107, 4589-4596. https://doi.org/10.1182/blood-2005-10-4169
  17. Ehata, S., Hanyu, A., Fujime, M., Katsuno, Y., Fukunaga, E., Goto, K., Ishikawa, Y., Nomura, K., Yokoo, H. and Shimizu, T. (2007) Ki26894, a novel transforming growth factor-${\beta}$ type I receptor kinase inhibitor, inhibits in vitro invasion and in vivo bone metastasis of a human breast cancer cell line. Cancer Sci. 98, 127-133. https://doi.org/10.1111/j.1349-7006.2006.00357.x
  18. Eppert, K., Scherer, S. W., Ozcelik, H., Pirone, R., Hoodless, P., Kim, H., Tsui, L.-C., Bapat, B., Gallinger, S. and Andrulis, I. L. (1996). MADR2 maps to 18q21 and encodes a $TGF{\beta}$-regulated MAD-related protein that is functionally mutated in colorectal carcinoma. Cell 86, 543-552. https://doi.org/10.1016/S0092-8674(00)80128-2
  19. Fernandez, T., Amoroso, S., Sharpe, S., Jones, G. M., Bliskovski, V., Kovalchuk, A., Wakefi eld, L. M., Kim, S.-J., Potter, M. and Letterio, J. J. (2002) Disruption of transforming growth factor ${\beta}$ signaling by a novel ligand-dependent mechanism. J. Exp. Med. 195, 1247-1255. https://doi.org/10.1084/jem.20011521
  20. Flavell, R. A., Sanjabi, S., Wrzesinski, S. H. and Licona-Limón, P. (2010). The polarization of immune cells in the tumour environment by $TGF{\beta}$. Nat. Rev. Immunol. 10, 554-567. https://doi.org/10.1038/nri2808
  21. Ganapathy, V., Ge, R., Grazioli, A., Xie, W., Banach-Petrosky, W., Kang, Y., Lonning, S., McPherson, J., Yingling, J. M. and Biswas, S. (2010) Targeting the transforming growth factor-${\beta}$ pathway inhibits human basal-like breast cancer metastasis. Mol. Cancer 9, 122. https://doi.org/10.1186/1476-4598-9-122
  22. Goggins, M., Shekher, M., Turnacioglu, K., Yeo, C. J., Hruban, R. H. and Kern, S. E. (1998) Genetic alterations of the transforming growth factor ${\beta}$ receptor genes in pancreatic and biliary adenocarcinomas. Cancer Res. 58, 5329-5332.
  23. Gordon, M. S., Ilaria, R. Jr., de Alwis, D. P., Mendelson, D. S., McKane, S., Wagner, M. M., Look, K. Y. and LoRusso, P. M. (2013) A Phase I study of tasisulam sodium (LY573636 sodium), a novel anticancer compound, administered as a 24-h continuous infusion in patients with advanced solid tumors. Cancer Chemother. Pharmacol. 71, 21-27. https://doi.org/10.1007/s00280-012-1917-8
  24. Grady, W. M., Myeroff, L. L., Swinler, S. E., Rajput, A., Thiagalingam, S., Lutterbaugh, J. D., Neumann, A., Brattain, M. G., Chang, J. and Kim, S.-J. (1999) Mutational inactivation of transforming growth factor ${\beta}$ receptor type II in microsatellite stable colon cancers. Cancer Res. 59, 320-324.
  25. Grady, W. M., Rajput, A., Myeroff, L., Liu, D. F., Kwon, K., Willis, J. and Markowitz, S. (1998) Mutation of the type II transforming growth factor-${\beta}$ receptor is coincident with the transformation of human colon adenomas to malignant carcinomas. Cancer Res. 58, 3101-3104.
  26. Hagedorn, H. G., Bachmeier, B. E. and Nerlich, A. G. (2001) Synthesis and degradation of basement membranes and extracellular matrix and their regulation by TGF-${\beta}$ in invasive carcinomas (Review). Int. J. Oncol. 18, 669-681.
  27. Hau, P., Jachimczak, P., Schlingensiepen, R., Schulmeyer, F., Jauch, T., Steinbrecher, A., Brawanski, A., Proescholdt, M., Schlaier, J. and Buchroithner, J. (2007) Inhibition of TGF-${\beta}$ 2 with ap 12009 in recurrent malignant gliomas: from preclinical to phase I/II studies. Oligonucleotides 17, 201-212. https://doi.org/10.1089/oli.2006.0053
  28. Heldin, C.-H., Miyazono, K. and Ten Dijke, P. (1997) TGF-${\beta}$ signalling from cell membrane to nucleus through SMAD proteins. Nature 390, 465-471. https://doi.org/10.1038/37284
  29. Hjelmeland, M. D., Hjelmeland, A. B., Sathornsumetee, S., Reese, E. D., Herbstreith, M. H., Laping, N. J., Friedman, H. S., Bigner, D. D., Wang, X.-F. and Rich, J. N. (2004) SB-431542, a small molecule transforming growth factor-${\beta}$-receptor antagonist, inhibits human glioma cell line proliferation and motility. Mol. Cancer Ther. 3, 737-745.
  30. Kang, Y., He, W., Tulley, S., Gupta, G. P., Serganova, I., Chen, C.-R., Manova-Todorova, K., Blasberg, R., Gerald, W. L. and Massague, J. (2005) Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. Proc. Natl. Acad. Sci. U.S.A. 102, 13909-13914. https://doi.org/10.1073/pnas.0506517102
  31. Kang, Y., Siegel, P. M., Shu, W., Drobnjak, M., Kakonen, S. M., Corden- Cardo, C., Guise, T. A. and Massague, J. (2003) A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3, 537-549. https://doi.org/10.1016/S1535-6108(03)00132-6
  32. Kim, D.-K., Sheen, Y. Y., Jin, C., Park, C.-Y., Domalapally, S., Kota, S. R., Maddeboina, K. and Bala, S. V. (2011) 2-pyridyl substituted imidazoles as therapeutic ALK5 and/or ALK4 inhibitors. Google Patents. PCT/KR2011/004631.
  33. Kingsley, D. M. (1994) The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms. Genes Dev. 8, 133-146. https://doi.org/10.1101/gad.8.2.133
  34. Kingsley, L. A., Fournier, P. G., Chirgwin, J. M. and Guise, T. A. (2007) Molecular biology of bone metastasis. Mol. Cancer Ther. 6, 2609-2617. https://doi.org/10.1158/1535-7163.MCT-07-0234
  35. Korpal, M., Yan, J., Lu, X., Xu, S., Lerit, D. A. and Kang, Y. (2009) Imaging transforming growth factor-${\beta}$ signaling dynamics and therapeutic response in breast cancer bone metastasis. Nat. Med. 15, 960-966. https://doi.org/10.1038/nm.1943
  36. Lampropoulos, P., Zizi-Sermpetzoglou, A., Rizos, S., Kostakis, A., Nikiteas, N. and Papavassiliou, A. G. (2012) TGF-beta signalling in colon carcinogenesis. Cancer Lett. 314, 1-7. https://doi.org/10.1016/j.canlet.2011.09.041
  37. Lee, G. Y., Kenny, P. A., Lee, E. H. and Bissell, M. J. (2007) Three-dimensional culture models of normal and malignant breast epithelial cells. Nat. Methods 4, 359-365. https://doi.org/10.1038/nmeth1015
  38. Levy, L. and Hill, C. S. (2006) Alterations in components of the TGF-${\beta}$ superfamily signaling pathways in human cancer. Cytokine Growth Factor Rev. 17, 41-58. https://doi.org/10.1016/j.cytogfr.2005.09.009
  39. Lindley, L. E. and Briegel, K. J. (2010) Molecular characterization of $TGF{\beta}$-induced epithelial-mesenchymal transition in normal finite lifespan human mammary epithelial cells. Biochem. Biophys. Res. Commun. 399, 659-664. https://doi.org/10.1016/j.bbrc.2010.07.138
  40. Maliekal, T. T., Antony, M.-L., Nair, A., Paulmurugan, R. and Karunagaran, D. (2003) Loss of expression, and mutations of Smad 2 and Smad 4 in human cervical cancer. Oncogene 22, 4889-4897. https://doi.org/10.1038/sj.onc.1206806
  41. Mani, S. A., Guo, W., Liao, M.-J., Eaton, E. N., Ayyanan, A., Zhou, A. Y., Brooks, M., Reinhard, F., Zhang, C. C. and Shipitsin, M. (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704-715. https://doi.org/10.1016/j.cell.2008.03.027
  42. Markowitz, S., Wang, J., Myeroff, L., Parsons, R., Sun, L., Lutterbaugh, J., Fan, R. S., Zborowska, E., Kinzler, K. W. and Vogelstein, B. (1995) Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science 268, 1336-1338. https://doi.org/10.1126/science.7761852
  43. Massague, J. (2000) How cells read TGF-${\beta}$ signals. Nat. Rev. Mol. Cell Biol. 1, 169-178. https://doi.org/10.1038/35043051
  44. Massague, J. (2008) $TGF{\beta}$ in cancer. Cell 134, 215-230. https://doi.org/10.1016/j.cell.2008.07.001
  45. Massague, J. and Gomis, R. R. (2006) The logic of $TGF{\beta}$ signaling. FEBS Lett. 580, 2811-2820. https://doi.org/10.1016/j.febslet.2006.04.033
  46. Matsuyama, S., Iwadate, M., Kondo, M., Saitoh, M., Hanyu, A., Shimizu, K., Aburatani, H., Mishima, H. K., Imamura, T. and Miyazono, K. (2003) SB-431542 and Gleevec inhibit transforming growth factor-${\beta}$-induced proliferation of human osteosarcoma cells. Cancer Res. 63, 7791-7798.
  47. Melisi, D., Ishiyama, S., Sclabas, G. M., Fleming, J. B., Xia, Q., Tortora, G., Abbruzzese, J. L. and Chiao, P. J. (2008) LY2109761, a novel transforming growth factor ${\beta}$ receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. Mol. Cancer Ther. 7, 829-840. https://doi.org/10.1158/1535-7163.MCT-07-0337
  48. Meulmeester, E. and ten Dijke, P. (2011). The dynamic roles of TGF-${\beta}$ in cancer. J. Pathol. 223, 205-218.
  49. Micalizzi, D. S., Christensen, K. L., Jedlicka, P., Coletta, R. D., Barón, A. E., Harrell, J. C., Horwitz, K. B., Billheimer, D., Heichman, K. A. and Welm, A. L. (2009) The Six1 homeoprotein induces human mammary carcinoma cells to undergo epithelial-mesenchymal transition and metastasis in mice through increasing TGF-${\beta}$ signaling. J. Clin.Invest. 119, 2678-2690. https://doi.org/10.1172/JCI37815
  50. Micalizzi, D. S., Wang, C.-A., Farabaugh, S. M., Schiemann, W. P. and Ford, H. L. (2010) Homeoprotein Six1 increases TGF-${\beta}$ Type I receptor and converts TGF-${\beta}$ signaling from suppressive to supportive for tumor growth. Cancer Res. 70, 10371-10380. https://doi.org/10.1158/0008-5472.CAN-10-1354
  51. Mishra, L., Derynck, R. and Mishra, B. (2005) Transforming growth factor-${\beta}$ signaling in stem cells and cancer. Science 310, 68-71. https://doi.org/10.1126/science.1118389
  52. Mohammad, K. S., Javelaud, D., Fournier, P. G., Niewolna, M., McKenna, C. R., Peng, X. H., Duong, V., Dunn, L. K., Mauviel, A. and Guise, T. A. (2011) TGF-${\beta}$-RI kinase inhibitor SD-208 reduces the development and progression of melanoma bone metastases. Cancer Res. 71, 175-184. https://doi.org/10.1158/0008-5472.CAN-10-2651
  53. Moon, J., Kim, H., Cho, I., Sheen, Y. and Kim, D. (2006) IN-1130, a novel transforming growth factor-${\beta}$ type I receptor kinase (ALK5) inhibitor, suppresses renal fibrosis in obstructive nephropathy. Kidney Int. 70, 1234-1243. https://doi.org/10.1038/sj.ki.5001775
  54. Muraoka-Cook, R. S., Dumont, N. and Arteaga, C. L. (2005) Dual role of transforming growth factor ${\beta}$ in mammary tumorigenesis and metastatic progression. Clin. Cancer Res. 11, 937s-943s.
  55. Muraoka, R. S., Dumont, N., Ritter, C. A., Dugger, T. C., Brantley, D. M., Chen, J., Easterly, E., Roebuck, L. R., Ryan, S. and Gotwals, P. J. (2002) Blockade of TGF-${\beta}$ inhibits mammary tumor cell viability, migration, and metastases. J. Clin. Invest. 109, 1551-1559. https://doi.org/10.1172/JCI0215234
  56. Nam, J.-S., Terabe, M., Mamura, M., Kang, M.-J., Chae, H., Stuelten, C., Kohn, E., Tang, B., Sabzevari, H. and Anver, M. R. (2008) An anti-transforming growth factor ${\beta}$ antibody suppresses metastasis via cooperative effects on multiple cell compartments. Cancer Res. 68, 3835-3843. https://doi.org/10.1158/0008-5472.CAN-08-0215
  57. Padua, D. and Massague, J. (2009) Roles of $TGF{\beta}$ in metastasis. Cell Res. 19, 89-102. https://doi.org/10.1038/cr.2008.316
  58. Padua, D., Zhang, X. H.-F., Wang, Q., Nadal, C., Gerald, W. L., Gomis, R. R. and Massague, J. (2008) $TGF{\beta}$ primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133, 66-77. https://doi.org/10.1016/j.cell.2008.01.046
  59. Park, C.-Y., Son, J.-Y., Jin, C. H., Nam, J.-S., Kim, D.-K. and Sheen, Y. Y. (2011a) EW-7195, a novel inhibitor of ALK5 kinase inhibits EMT and breast cancer metastasis to lung. Eur. J. Cancer 47, 2642-2653. https://doi.org/10.1016/j.ejca.2011.07.007
  60. Park, C. Y., Kim, D. K. and Sheen, Y. Y. (2011b) EW-7203, a novel small molecule inhibitor of transforming growth factor-${\beta}$ (TGF-${\beta}$) type I receptor/activin receptor/like kinase-5, blocks TGF-${\beta}1$- mediated epithelial-to-mesenchymal transition in mammary epithelial cells. Cancer Sci. 102, 1889-1896. https://doi.org/10.1111/j.1349-7006.2011.02014.x
  61. Parsons, R., Myeroff, L. L., Liu, B., Willson, J. K., Markowitz, S. D., Kinzler, K. W. and Vogelstein, B. (1995) Microsatellite instability and mutations of the transforming growth factor ${\beta}$ type II receptor gene in colorectal cancer. Cancer Res. 55, 5548-5550.
  62. Peng, H., Carretero, O. A., Vuljaj, N., Liao, T.-D., Motivala, A., Peterson, E. L. and Rhaleb, N.-E. (2005) Angiotensin-converting enzyme inhibitors a new mechanism of action. Circulation 112, 2436-2445. https://doi.org/10.1161/CIRCULATIONAHA.104.528695
  63. Porter, P. L. (2009) Global trends in breast cancer incidence and mortality. Salud Publica Mex. 51, s141-s146. https://doi.org/10.1590/S0036-36342009000800003
  64. Roberts, A. B. and Wakefield, L. M. (2003) The two faces of transforming growth factor ${\beta}$ in carcinogenesis. Proc. Natl. Acad. Sci. U.S.A. 100, 8621-8623. https://doi.org/10.1073/pnas.1633291100
  65. Rowland-Goldsmith, M. A., Maruyama, H., Matsuda, K., Idezawa, T., Ralli, M., Ralli, S. and Korc, M. (2002) Soluble type II transforming growth factor-${\beta}$ receptor attenuates expression of metastasis-associated genes and suppresses pancreatic cancer cell metastasis1. Mol. Cancer Ther. 1, 161-167. https://doi.org/10.4161/cbt.62
  66. Sanchez-Elsner, T., Botella, L. M., Velasco, B., Corbi, A., Attisano, L. and Bernabeu, C. (2001) Synergistic cooperation between hypoxia and transforming growth factor-${\beta}$ pathways on human vascular endothelial growth factor gene expression. J. Biol. Chem. 276, 38527-38535. https://doi.org/10.1074/jbc.M104536200
  67. Sanchez-Zamorano, L. M., Flores-Luna, L., Angeles-Llerenas, A., Romieu, I., Lazcano-Ponce, E., Miranda-Hernandez, H., Mainero-Ratchelous, F. and Torres-Mejía, G. (2011) Healthy lifestyle on the risk of breast cancer. Cancer Epidemiol. Biomarkers Prev. 20, 912-922. https://doi.org/10.1158/1055-9965.EPI-10-1036
  68. Sawyer, T. K. (2004) Novel oncogenic protein kinase inhibitors for cancer therapy. Curr. Med. Chem. Anticancer Agents 4, 449-455. https://doi.org/10.2174/1568011043352830
  69. Schlingensiepen, K. H., Jaschinski, F., Lang, S. A., Moser, C., Geissler, E. K., Schlitt, H. J., Kielmanowicz, M. and Schneider, A. (2011) Transforming growth factor-beta 2 gene silencing with trabedersen (AP 12009) in pancreatic cancer. Cancer Sci. 102, 1193-1200. https://doi.org/10.1111/j.1349-7006.2011.01917.x
  70. Shi, Y. and Massague, J. (2003) Mechanisms of TGF-${\beta}$ signaling from cell membrane to the nucleus. Cell 113, 685-700. https://doi.org/10.1016/S0092-8674(03)00432-X
  71. Shinto, O., Yashiro, M., Kawajiri, H., Shimizu, K., Shimizu, T., Miwa, A. and Hirakawa, K. (2010) Inhibitory effect of a $TGF\beta$ receptor type-I inhibitor, Ki26894, on invasiveness of scirrhous gastric cancer cells. Br. J. Cancer 102, 844-851. https://doi.org/10.1038/sj.bjc.6605561
  72. Shirakihara, T., Horiguchi, K., Miyazawa, K., Ehata, S., Shibata, T., Morita, I., Miyazono, K. and Saitoh, M. (2011) TGF-${\beta}$ regulates isoform switching of FGF receptors and epithelial-mesenchymal transition. EMBO J. 30, 783-795. https://doi.org/10.1038/emboj.2010.351
  73. Subramanian, G., Schwarz, R. E., Higgins, L., McEnroe, G., Chakravarty, S., Dugar, S. and Reiss, M. (2004) Targeting endogenous transforming growth factor ${\beta}$ receptor signaling in SMAD4-deficient human pancreatic carcinoma cells inhibits their invasive phenotype 1. Cancer Res. 64, 5200-5211. https://doi.org/10.1158/0008-5472.CAN-04-0018
  74. Takenoshita, S., Tani, M., Nagashima, M., Hagiwara, K., Bennett, W. P., Yokota, J. and Harris, C. C. (1997) Mutation analysis of coding sequences of the entire transforming growth factor beta type II receptor gene in sporadic human colon cancer using genomic DNA and intron primers. Oncogene 14, 1255-1258. https://doi.org/10.1038/sj.onc.1200938
  75. Takeuchi, K., Abe, M., Hiasa, M., Oda, A., Amou, H., Kido, S., Harada, T., Tanaka, O., Miki, H. and Nakamura, S. (2010) TGF-${\beta}$ inhibition restores terminal osteoblast differentiation to suppress myeloma growth. PLoS One 5, e9870. https://doi.org/10.1371/journal.pone.0009870
  76. Tanaka, H., Shinto, O., Yashiro, M., Yamazoe, S., Iwauchi, T., Muguruma, K., Kubo, N., Ohira, M. and Hirakawa, K. (2010) Transforming growth factor ${\beta}$ signaling inhibitor, SB-431542, induces maturation of dendritic cells and enhances anti-tumor activity. Oncol. Rep. 24, 1637-1643.
  77. Thiery, J. P., Acloque, H., Huang, R. Y. and Nieto, M. A. (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139, 871-890. https://doi.org/10.1016/j.cell.2009.11.007
  78. Thomas, D. A. and Massagué, J. (2005) TGF-${\beta}$ directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 8, 369-380. https://doi.org/10.1016/j.ccr.2005.10.012
  79. Thuault, S., Valcourt, U., Petersen, M., Manfioletti, G., Heldin, C.-H. and Moustakas, A. (2006) Transforming growth factor-${\beta}$ employs HMGA2 to elicit epithelial-mesenchymal transition. J. Cell Biol. 174, 175-183. https://doi.org/10.1083/jcb.200512110
  80. Travis, R. C., Reeves, G. K., Green, J., Bull, D., Tipper, S. J., Baker, K., Beral, V., Peto, R., Bell, J. and Zelenika, D. (2010) Gene-environment interactions in 7610 women with breast cancer: prospective evidence from the Million Women Study. Lancet 375, 2143-2151. https://doi.org/10.1016/S0140-6736(10)60636-8
  81. Uhl, M., Aulwurm, S., Wischhusen, J., Weiler, M., Ma, J. Y., Almirez, R., Mangadu, R., Liu, Y.-W., Platten, M. and Herrlinger, U. (2004) SD-208, a novel transforming growth factor ${\beta}$ receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitro and in vivo. Cancer Res. 64, 7954-7961. https://doi.org/10.1158/0008-5472.CAN-04-1013
  82. van Meeteren, L. A., Thorikay, M., Bergqvist, S., Pardali, E., Stampino, C. G., Hu-Lowe, D., Goumans, M.-J. and ten Dijke, P. (2012) Anti-human activin receptor-like kinase 1 (ALK1) antibody attenuates bone morphogenetic protein 9 (BMP9)-induced ALK1 signaling and interferes with endothelial cell sprouting. J. Biol. Chem. 287, 18551-18561. https://doi.org/10.1074/jbc.M111.338103
  83. Viloria-Petit, A. M., David, L., Jia, J. Y., Erdemir, T., Bane, A. L., Pinnaduwage, D., Roncari, L., Narimatsu, M., Bose, R. and Moffat, J. (2009) A role for the $TGF{\beta}$-Par6 polarity pathway in breast cancer progression. Proc. Natl. Acad. Sci. U.S.A. 106, 14028-14033. https://doi.org/10.1073/pnas.0906796106
  84. Wakefield, L. M. and Roberts, A. B. (2002) TGF-${\beta}$ signaling: positive and negative effects on tumorigenesis. Curr. Opin. Genet. Dev. 12, 22-29. https://doi.org/10.1016/S0959-437X(01)00259-3
  85. Wang, D., Kanuma, T., Mizunuma, H., Takama, F., Ibuki, Y., Wake, N., Mogi, A., Shitara, Y. and Takenoshita, S. (2000) Analysis of specific gene mutations in the transforming growth factor-${\beta}$ signal transduction pathway in human ovarian cancer. Cancer Res. 60, 4507-4512.
  86. Wendt, M. K., Smith, J. A. and Schiemann, W. P. (2010) Transforming growth factor-${\beta}$-induced epithelial-mesenchymal transition facilitates epidermal growth factor-dependent breast cancer progression. Oncogene 29, 6485-6498. https://doi.org/10.1038/onc.2010.377
  87. Wiercinska, E., Naber, H. P., Pardali, E., van der Pluijm, G., van Dam, H. and ten Dijke, P. (2011) The TGF-${\beta}$/Smad pathway induces breast cancer cell invasion through the up-regulation of matrix metalloproteinase 2 and 9 in a spheroid invasion model system. Breast Cancer Res. Treat. 128, 657-666. https://doi.org/10.1007/s10549-010-1147-x
  88. Yakicier, M., Irmak, M., Romano, A., Kew, M. and Ozturk, M. (1999) Smad2 and Smad4 gene mutations in hepatocellular carcinoma. Oncogene 18, 4879-4883. https://doi.org/10.1038/sj.onc.1202866
  89. Yang, Y.-A., Dukhanina, O., Tang, B., Mamura, M., Letterio, J. J., Mac-Gregor, J., Patel, S. C., Khozin, S., Liu, Z.-y. and Green, J. (2002) Lifetime exposure to a soluble TGF-${\beta}$ antagonist protects mice against metastasis without adverse side effects. J. Clin. Invest. 109, 1607-1615. https://doi.org/10.1172/JCI200215333
  90. Yingling, J. M., Blanchard, K. L. and Sawyer, J. S. (2004) Development of TGF-${\beta}$ signalling inhibitors for cancer therapy. Nat. Rev. Drug Discov. 3, 1011-1022. https://doi.org/10.1038/nrd1580
  91. Zhang, B., Halder, S. K., Zhang, S. and Datta, P. K. (2009) Targeting transforming growth factor-${\beta}$ signaling in liver metastasis of colon cancer. Cancer Lett. 277, 114-120. https://doi.org/10.1016/j.canlet.2008.11.035
  92. Zhang, Y. and Derynck, R. (1999) Regulation of Smad signalling by protein associations and signalling crosstalk. Trends Cell Biol. 9, 274-279. https://doi.org/10.1016/S0962-8924(99)01579-2

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