Targeting Transforming Growth Factor-β (TGF-β) in Cancer and Non-Neoplastic Diseases

Abstract

Transforming growth factor-β (TGF-β) superfamily is a key player in the regulation of a wide variety of physiological processes from development to pathogenesis. Since the discovery of the prototypic member, TGF-β, almost three decades ago, there have been tremendous advances in our understanding of its complex biology. TGF-β misregulation has been implicated in the pathogenesis of a variety of diseases, including cancer with a direct role in facilitating metastasis, fibrosis and inflammation. Consequently, TGF-β is currently explored as a prognostic candidate biomarker of tumor invasiveness and metastasis; and it offers an attractive target for cancer therapy. Several anti-TGF-β approaches, such as TGF-β antibodies, antisense oligonucleotides and small molecules inhibitors of TGF-β type 1 receptor kinase, have shown great promise in the preclinical studies. Here, we consider why the TGF-βsignaling pathway is a drug target, the potential clinical applications of TGF-β inhibition, the issues arising with anti-TGF-β therapy and how these might be adopted using personalized approaches with a special care for patient selection and timing of therapy so that we may bring forward all the potentials of targeting this pathway for therapeutic uses in both cancer, preferentially in combination therapy, and non-neoplastic diseases.

Share and Cite:

Nacif, M. and Shaker, O. (2014) Targeting Transforming Growth Factor-β (TGF-β) in Cancer and Non-Neoplastic Diseases. Journal of Cancer Therapy, 5, 735-747. doi: 10.4236/jct.2014.57082.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] Calone, I. and Souchelnytskyi, S. (2012) Inhibition of TGF-β Signaling and Its Implications in Anticancer Treatments. Experimental Oncology, 34, 9-16.
[2] de Larco, J.E. and Todaro, G.J. (1978) Growth Factors from Murine Sarcoma Virus-Transformed Cells. Proceedings of the National Academy of Sciences of the United States of America, 75, 4001-4005. http://dx.doi.org/10.1073/pnas.75.8.4001
[3] Roberts, A.B., Lamb, L.C., Newton, D.L., Sporn, M.B., Larcot, J.E.D.E. and Todarot, G.J. (1980) Transforming Growth Factors: Isolation of Polypeptides from Virally and Chemically Transformed Cells by Acid/Ethanol Extraction. Proceedings of the National Academy of Sciences of the United States of America, 77, 3494-3498. http://dx.doi.org/10.1073/pnas.77.6.3494
[4] Moses, H.L., Branum, E.L., Proper, J.A. and Robinson, R.A. (1981) Transforming Growth Factor Production by Chemically Transformed Cells Transforming. Cancer Research, 41, 2842-2848.
[5] Attisano, L. and Wrana, J.L. (2002) Signal Transduction by the TGF-Beta Superfamily. Science, 296, 1646-1647. http://dx.doi.org/10.1126/science.1071809
[6] Wrana, J.L. (2013) Signaling by the TGF-β Superfamily. Cold Spring Harbor Perspectives in Biology, 5, Article ID: a011197. http://dx.doi.org/10.1101/cshperspect.a011197
[7] Derynck, R. and Akhurst, R.J. (2007) Differentiation Plasticity Regulated by TGF-Beta Family Proteins in Development and Disease. Nature Cell Biology, 9, 1000-1004. http://dx.doi.org/10.1038/ncb434
[8] Roberts, A.B. and Wakefield, L.M. (2003) The Two Faces of Transforming Growth Factor Beta in Carcinogenesis. Proceedings of the National Academy of Sciences of the United States of America, 100, 8621-8623. http://dx.doi.org/10.1073/pnas.1633291100
[9] Shi, Y. and Massagué, J. (2003) Mechanisms of TGF-Beta Signaling from Cell Membrane to the Nucleus. Cell, 113, 685-700. http://dx.doi.org/10.1016/S0092-8674(03)00432-X
[10] Akhurst, R.J. and Hata, A. (2012) Targeting the TGF-β Signalling Pathway in Disease. Nature Reviews Drug Discovery, 11, 790-811. http://dx.doi.org/10.1038/nrd3810
[11] Nagaraj, N. and Datta, P. (2010) Targeting the Transforming Growth Factor-β Signaling Pathway in Human Cancer. Expert Opinion on Investigational Drugs, 19, 77-91.
http://dx.doi.org/10.1517/13543780903382609
[12] Schultz-Cherry, S., Ribeiro, S., Gentry, L. and Murphy-Ullrich, J.E. (1994) Thrombospondin Binds and Activates the Small and Large Forms of Latent Transforming Growth Factor-β in a Chemically Defined System. Journal of Biological Chemistry, 269, 26775-26782.
[13] Davis-Dusenbery, B. and Hata, A. (2011) Smad-Mediated miRNA Processing: A Critical Role for a Conserved RNA Sequence. RNA Biology, 8, 71-76. http://dx.doi.org/10.4161/rna.8.1.14299
[14] Massagué, J. (2008) TGFbeta in Cancer. Cell, 134, 215-230.
http://dx.doi.org/10.1016/j.cell.2008.07.001
[15] Connolly, E.C., Freimuth, J. and Akhurst, R.J. (2012) Complexities of TGF-β Targeted Cancer Therapy. International Journal of Biological Sciences, 8, 964-978. http://dx.doi.org/10.7150/ijbs.4564
[16] Akhurst, R.J. and Derynck, R. (2001) TGF-β Signaling in Cancer—A Double-Edged Sword. Trends in Cell Biology, 11, S44-S51. http://dx.doi.org/10.1016/S0962-8924(01)02130-4
[17] Yingling, J.M., Blanchard, K.L. and Sawyer, J.S. (2004) Development of TGF-β Signalling Inhibitors for Cancer Therapy. Nature Reviews Drug Discovery, 3, 1011-1022. http://dx.doi.org/10.1038/nrd1580
[18] Ivanovic, V. (2009) Transforming Growth Factor-β: Biology and Application to Cancer Therapy. Archive of Oncology, 17, 61-64. http://dx.doi.org/10.2298/AOO0904061I
[19] Mead, A.L., Wong, T.T.L., Cordeiro, M.F., Anderson, I.K. and Khaw, P.T. (2003) Evaluation of Anti-TGF-2 Antibody as a New Postoperative Anti-Scarring Agent in Glaucoma Surgery. Investigative Ophthalmology & Visual Science, 44, 3394-3401. http://dx.doi.org/10.1167/iovs.02-0978
[20] Cordeiro, M.F., Gay, J.A. and Khaw, P.T. (1999) Human Anti-Transforming Growth Factor-β2 Antibody: A New Glaucoma Anti-Scarring Agent. Investigative Ophthalmology & Visual Science, 40, 2225-2234.
[21] Trachtman, H., Fervenza, F.C., Gipson, D.S., Heering, P., Jayne, D.R.W., Peters, H., Rota, S., Remuzzi, G., Rump, L., Sellin, L.K., Heaton, J.P.W., Streisand, J.B., Hard, M.L., Ledbetter, S.R. and Vincenti, F. (2011) A Phase 1, Single-Dose Study of Fresolimumab, an Anti-TGF-β Antibody, in Treatment-Resistant Primary Focal Segmental Glomerulosclerosis. Kidney International, 79, 1236-1243.
http://dx.doi.org/10.1038/ki.2011.33
[22] Denton, C.P., Merkel, P.A., Furst, D.E., Khanna, D., Emery, P., Hsu, V.M., Silliman, N., Streisand, J., Powell, J., Akesson, A., Coppock, J., Van Den Hoogen, F., Herrick, A., Mayes, M.D., Veale, D., Haas, J., Ledbetter, S., Korn, J.H., Black, C.M. and Seibold, J.R. (2007) Recombinant Human Anti-Transforming Growth Factor β1 Antibody Therapy in Systemic Sclerosis: A Multicenter, Randomized, Placebo-Controlled Phase I/II Trial of CAT-192. Arthritis & Rheumatism, 56, 323-333.
http://dx.doi.org/10.1002/art.22289
[23] Nam, J., Terabe, M., Mamura, M., Kang, M., Chae, H., Stuelten, C., Kohn, E., Tang, B., Sabzevari, H., Anver, M.R., Danielpour, D., Lonning, S., Berzofsky, J. and Wakefield, L.M. (2009) An Anti-TGF-β Antibody Suppresses Metastasis via Cooperative Effects on Multiple Cell Compartments. Cancer Research, 68, 3835-3843.
[24] Biswas, S., Nyman, J.S., Alvarez, J., Chakrabarti, A., Ayres, A., Sterling, J., Edwards, J., Rana, T., Johnson, R., Perrien, D.S., Lonning, S., Shyr, Y., Matrisian, L.M. and Mundy, G.R. (2011) Anti-Transforming Growth Factor β Antibody Treatment Rescues Bone Loss and Prevents Breast Cancer Metastasis to Bone. PLoS ONE, 6, Article ID: e27090.
http://dx.doi.org/10.1371/journal.pone.0027090
[25] Ganapathy, V., Ge, R., Grazioli, A., Xie, W., Banach-Petrosky, W., Kang, Y., Lonning, S., McPherson, J., Yingling, J.M., Biswas, S., Mundy, G.R. and Reiss, M. (2010) Targeting the Transforming Growth Factor-β Pathway Inhibits Human Basal-Like Breast Cancer Metastasis. Molecular Cancer, 9, 122.
http://dx.doi.org/10.1186/1476-4598-9-122
[26] 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-β with Neutralizing Antibodies Prevents Radiation-Induced Acceleration of Metastatic Cancer Progression. Journal of Clinical Investigation, 117, 1305-1313.
http://dx.doi.org/10.1172/JCI30740
[27] Arteaga, C.L., Hurd, S.D., Winnier, A.R., Johnson, M.D., Fendly, B.M. and Forbes, J.T. (1993) Anti-Transforming Growth Factor (TGF)-β Antibodies Inhibit Breast Cancer Cell Tumorigenicity and Increase Mouse Spleen Natural Killer Cell Activity. Journal of Clinical Investigation, 92, 2569-2576.
http://dx.doi.org/10.1172/JCI116871
[28] Zhong, Z., Carroll, K.D., Policarpio, D., Osborn, C., Gregory, M., Bassi, R., et al. (2010) Anti-Transforming Growth Factor β Receptor II Antibody Has Therapeutic Efficacy against Primary Tumor Growth and Metastasis through Multieffects on Cancer, Stroma, and Immune Cells. Clinical Cancer Research, 16, 1191-1205.
[29] 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. Journal of Biological Chemistry, 287, 18551-18561.
http://dx.doi.org/10.1074/jbc.M111.338103
[30] Van Aarsen, L.A.K., Leone, D.R., Ho, S., Dolinski, B.M., McCoon, P.E., LePage, D.J., Kelly, R., Heaney, G., Rayhorn, P., Reid, C., Simon, K.J., Horan, G.S., Tao, N., Gardner, H.A., Skelly, M.M., Gown, A.M., Thomas, G.J., Weinreb, P.H., Fawell, S.E. and Violette, S.M. (2008) Antibody-Mediated Blockade of Integrin Alpha v Beta 6 Inhibits Tumor Progression in Vivo by a Transforming Growth Factor-Beta-Regulated Mechanism. Cancer Research, 68, 561-570.
[31] Hu, Z., Zhang, Z., Guise, T. and Seth, P. (2010) Systemic Delivery of an Oncolytic Adenovirus Expressing Soluble Transforming Growth Factor-β Receptor II-Fc Fusion Protein Can Inhibit Breast Cancer Bone Metastasis in a Mouse Model. Human Gene Therapy, 21, 1623-1629.
http://dx.doi.org/10.1089/hum.2010.018
[32] Santiago, B., Gutierrez-Ca?as, I., Dotor, J., Palao, G., Lasarte, J.J., Ruiz, J., Prieto, J., Borrás-Cuesta, F. and Pablos, J.L. (2005) Topical Application of a Peptide Inhibitor of Transforming Growth Factor-β1 Ameliorates Bleomycin-Induced Skin Fibrosis. Journal of Investigative Dermatology, 125, 450-455. http://dx.doi.org/10.1111/j.0022-202X.2005.23859.x
[33] Hermida, N., López, B., González, A., Dotor, J., Lasarte, J.J., Sarobe, P., Borrás-Cuesta, F. and Díez, J. (2009) A Synthetic Peptide from Transforming Growth Factor-β1 Type III Receptor Prevents Myocardial Fibrosis in Spontaneously Hypertensive Rats. Cardiovascular Research, 81, 601-609.
http://dx.doi.org/10.1093/cvr/cvn315
[34] Llopiz, D., Dotor, J., Casares, N., Bezunartea, J., Nancy, D., Ruiz, M., Aranda, F. and Jos, J. (2009) Peptide Inhibitors of Transforming Growth Factor-β Enhance the Efficacy of Antitumor Immunotherapy. International Journal of Cancer, 125, 2614-2623.
http://dx.doi.org/10.1002/ijc.24656
[35] Lu, A., Miao, M., Schoeb, T.R., Agarwal, A. and Murphy-Ullrich, J.E. (2011) Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy. American Journal of Pathology, 178, 2573-2586.
http://dx.doi.org/10.1016/j.ajpath.2011.02.039
[36] Dy, G.K. and Adjei, A.A. (2008) Systemic Cancer Therapy: Evolution over the Last 60 Years. Cancer, 113, 1857-1887. http://dx.doi.org/10.1002/cncr.23651
[37] Strimpakos, A.S., Syrigos, K.N. and Saif, M.W. (2012) Novel Agents and New Combination Treatments on Phase I Studies on Solid Tumors and Pancreatic Cancer. JOP: Journal of the Pancreas, 13, 345-348.
[38] 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 Science, 102, 1193-1200. http://dx.doi.org/10.1111/j.1349-7006.2011.01917.x
[39] Bogdahn, U., Hau, P., Stockhammer, G., Venkataramana, N.K., Mahapatra, A.K., Suri, A., Balasubramaniam, A., Nair, S., Oliushine, V., Parfenov, V., Poverennova, I., Zaaroor, M., Jachimczak, P., Ludwig, S., Schmaus, S., Heinrichs, H. and Schlingensiepen, K.H. (2011) Targeted Therapy for High-Grade Glioma with the TGF-β2 Inhibitor Trabedersen: Results of a Randomized and Controlled Phase IIb Study. Neuro-Oncology, 13, 132-142. http://dx.doi.org/10.1093/neuonc/noq142
[40] Katz, L.H., Li, Y., Chen, J.S., Munoz, N.M., Majumdar, A., Chen, J. and Mishra, L. (2013) Targeting TGF-β Signaling in Cancer. Expert Opinion on Therapeutic Targets, 17, 743-760.
http://dx.doi.org/10.1517/14728222.2013.782287
[41] Nemunaitis, J., Dillman, R.O., Schwarzenberger, P.O., Senzer, N., Cunningham, C., Cutler, J., Tong, A., Kumar, P., Pappen, B., Hamilton, C., DeVol, E., Maples, P.B., Liu, L., Chamberlin, T., Shawler, D.L. and Fakhrai, H. (2006) Phase II Study of Belagenpumatucel-L, a Transforming Growth Factor Beta-2 Antisense Gene-Modified Allogeneic Tumor Cell Vaccine in Non-Small-Cell Lung Cancer. Journal of Clinical Oncology, 24, 4721-4730. http://dx.doi.org/10.1200/JCO.2005.05.5335
[42] Laping, N.J., Grygielko, E., Mathur, A., Butter, S., Bomberger, J., Tweed, C., Martin, W., Fornwald, J., Lehr, R., Harling, J., Gaster, L., Callahan, J.F. and Olson, B.A. (2002) Inhibition of Transforming Growth Factor (TGF)-Beta 1-Induced Extracellular Matrix with a Novel Inhibitor of the TGF-Beta Type I Receptor KINASE Activity: SB-431542. Molecular Pharmacology, 62, 58-64.
http://dx.doi.org/10.1124/mol.62.1.58
[43] Tanaka, H., Shinto, O., Yashiro, M., Yamazoe, S., Iwauchi, T., Muguruma, K., Kubo, N., Ohira, M. and Hirakawa, K. (2010) Transforming Growth Factor β Signaling Inhibitor, SB-431542, Induces Maturation of Dendritic Cells and Enhances Anti-Tumor Activity. Oncology Reports, 24, 1637-1643.
http://dx.doi.org/10.3892/or_00001028
[44] Byfield, S.D., Major, C., Laping, N.J. and Roberts, A.B. (2004) SB-505124 Is a Selective Inhibitor of Transforming Growth Factor-β Type I Receptors ALK4, ALK5, and ALK7. Molecular Pharmacology, 65, 744-752. http://dx.doi.org/10.1124/mol.65.3.744
[45] Ehata, S., Hanyu, A., Fujime, M., Katsuno, Y., Fukunaga, E., Goto, K., Ishikawa, Y., Nomura, K., Yokoo, H., Shimizu, T., Ogata, E., Miyazono, K., Shimizu, K. and Imamura, T. (2007) Ki26894, a Novel Transforming Growth Factor-β Type I Receptor Kinase Inhibitor, Inhibits in Vitro Invasion and in Vivo Bone Metastasis of a Human Breast Cancer Cell Line. Cancer Science, 98, 127-133.
http://dx.doi.org/10.1111/j.1349-7006.2006.00357.x
[46] 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 Research, 66, 6714-6721.
http://dx.doi.org/10.1158/0008-5472.CAN-05-3565
[47] Mohammad, K.S., Javelaud, D., Fournier, P.G.J., Niewolna, M., Mckenna, C.R., Peng, X.H., Duong, V., Dunn, L.K., Mauviel, A. and Guise, T.A. (2012) TGF-β-RI Kinase Inhibitor SD-208 Reduces the Development and Progression of Melanoma Bone Metastases. Cancer Research, 71, 175-184.
http://dx.doi.org/10.1158/0008-5472.CAN-10-2651
[48] 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 TβRI/II Kinase Inhibition with LY2109761. Cancer Research, 71, 2339-2349.
http://dx.doi.org/10.1158/0008-5472.CAN-10-2941
[49] Zhao, B.M. and Hoffmann, F.M. (2006) Inhibition of Transforming Growth Factor-β1-Induced Signaling and Epithelial-to-Mesenchymal Transition by the Smad-Binding Peptide Aptamer Trx-SARA. Molecular Biology of the Cell, 17, 3819-3831. http://dx.doi.org/10.1091/mbc.E05-10-0990
[50] Yao, E.H., Fukuda, N., Ueno, T., Matsuda, H., Nagase, H., Matsumoto, Y., Sugiyama, H. and Matsumoto, K. (2009) A Pyrrole-Imidazole Polyamide Targeting Transforming Growth Factor-β1 Inhibits Restenosis and Preserves Endothelialization in the Injured Artery. Cardiovascular Research, 81, 797-804.
http://dx.doi.org/10.1093/cvr/cvn355
[51] Chen, M., Matsuda, H., Wang, L., Watanabe, T., Kimura, M.T., Igarashi, J., Wang, X., Sakimoto, T., Fukuda, N., Sawa, M. and Nagase, H. (2010) Pretranscriptional Regulation of Tgf-β1 by PI Polyamide Prevents Scarring and Accelerates Wound Healing of the Cornea after Exposure to Alkali. Molecular Therapy, 18, 519-527. http://dx.doi.org/10.1038/mt.2009.263
[52] Washio, H., Fukuda, N., Matsuda, H., Nagase, H., Watanabe, T., Matsumoto, Y. and Terui, T. (2011) Transcriptional Inhibition of Hypertrophic Scars by a Gene Silencer, Pyrrole-Imidazole Polyamide, Targeting the TGF-β1 Promoter. Journal of Investigative Dermatology, 131, 1987-1995.
http://dx.doi.org/10.1038/jid.2011.150
[53] Chen, H.Y., Huang, X.R., Wang, W., Li, J.H., Heuchel, R.L., Chung, A.C.K. and Lan, H.Y. (2011) The Protective Role of Smad7 in Diabetic Kidney Disease: Mechanism and Therapeutic Potential Objective. Diabetes, 60, 590-601. http://dx.doi.org/10.2337/db10-0403
[54] Larriba, M.J., Valle, N., Pálmer, H.G., Ordó?ez-Morán, P., Alvarez-Díaz, S., Becker, K.F., Gamallo, C., de Herreros, A.G., González-Sancho, J.M. and Mu?oz, A. (2007) The Inhibition of Wnt/β-Catenin Signalling by 1α, 25-Dihydroxyvitamin D3 Is Abrogated by Snail1 in Human Colon Cancer Cells. Endocrine Related Cancer, 14, 141-151. http://dx.doi.org/10.1677/ERC-06-0028
[55] Walia, B., Wang, L., Merlin, D. and Sitaraman, S.V. (2003) TGF-Beta Down-Regulates IL-6 Signaling in Intestinal Epithelial Cells: Critical Role of SMAD-2. FASEB Journal, 17, 2130-2132.
[56] Lin, L., Amin, R., Gallicano, G.I., Glasgow, E., Jogunoori, W., Jessup, J.M., Zasloff, M., Marshall, J.L., Shetty, K., Johnson, L., Mishra, L. and He, A.R. (2009) The STAT3 Inhibitor NSC 74859 Is Effective in Hepatocellular Cancers with Disrupted TGF-β Signaling. Oncogene, 28, 961-972.
http://dx.doi.org/10.1038/onc.2008.448
[57] Gomis, R.R., Alarcón, C., Nadal, C., Van Poznak, C. and Massagué, J. (2006) C/EBPβ at the Core of the TGFβ Cytostatic Response and Its Evasion in Metastatic Breast Cancer Cells. Cancer Cell, 10, 203-214.
http://dx.doi.org/10.1016/j.ccr.2006.07.019
[58] Bierie, B. and Moses, H.L. (2009) Gain or Loss of TGFβ Signaling in Mammary Carcinoma Cells Can Promote Metastasis. Cell Cycle, 8, 3319-3327. http://dx.doi.org/10.4161/cc.8.20.9727
[59] Bierie, B., Chung, C.H., Parker, J.S., Stover, D.G., Cheng, N., Chytil, A., Aakre, M., Shyr, Y. and Moses, H.L. (2009) Abrogation of TGF-β Signaling Enhances Chemokine Production and Correlates with Prognosis in Human Breast Cancer. Journal of Clinical Investigation, 119, 1571-1582.
http://dx.doi.org/10.1172/JCI37480
[60] Bandyopadhyay, A., Wang, L., Agyin, J., Tang, Y., Lin, S., Yeh, I.T., De, K. and Sun, L.Z. (2010) Doxorubicin in Combination with a Small TGFβ Inhibitor: A Potential Novel Therapy for Metastatic Breast Cancer in Mouse Models. PLoS ONE, 5, Article ID: e10365.
http://dx.doi.org/10.1371/journal.pone.0010365
[61] Quante, M., Tu, S.P., Tomita, H., Gonda, T., Wang, S.S.W., Takashi, S., Baik, G.H., Shibata, W., Diprete, B., Betz, K.S., Friedman, R., Varro, A., Tycko, B. and Wang, T.C. (2011) Bone Marrow-Derived Myofibroblasts Contribute to the Mesenchymal Stem Cell Niche and Promote Tumor Growth. Cancer Cell, 19, 257-272. http://dx.doi.org/10.1016/j.ccr.2011.01.020
[62] Hayashi, T., Hideshima, T., Nguyen, A.N., Munoz, O., Podar, K., Hamasaki, M., Ishitsuka, K., Yasui, H., Richardson, P., Chakravarty, S., Murphy, A., Chauhan, D., Higgins, L.S. and Anderson, K.C. (2004) Transforming Growth Factor β Receptor I Kinase Inhibitor Down-Regulates Cytokine Secretion and Multiple Myeloma Cell Growth in the Bone Marrow Microenvironment. Clinical Cancer Research, 10, 7540-7546. http://dx.doi.org/10.1158/1078-0432.CCR-04-0632
[63] Gadir, N., Jackson, D.N., Lee, E. and Foster, D.A. (2008) Defective TGF-β Signaling Sensitizes Human Cancer Cells to Rapamycin. Oncogene, 27, 1055-1062. http://dx.doi.org/10.1038/sj.onc.1210721
[64] Filyak, Y., Filyak, O. and Stoika, R. (2007) Transforming Growth Factor β-1 Enhances Cytotoxic Effect of Doxorubicin in Human Lung Adenocarcinoma Cells of A549 Line. Cell Biology International, 31, 851-855. http://dx.doi.org/10.1016/j.cellbi.2007.02.008
[65] Shinto, O., Yashiro, M., Kawajiri, H., Shimizu, K., Shimizu, T., Miwa, A. and Hirakawa, K. (2010) Combination Effect of a TGF-β Receptor Kinase Inhibitor with 5-FU Analog S1 on Lymph Node Metastasis of Scirrhous Gastric Cancer in Mice. Cancer Science, 101, 1846-1852.
http://dx.doi.org/10.1111/j.1349-7006.2010.01606.x
[66] Wallace, A., Kapoor, V., Sun, J., Mrass, P., Weninger, W., Daniel, F., June, C., Kaiser, L.R., Ling, L.E. and Albelda, S.M. (2009) TGF-β Receptor Blockade Augments the Effectiveness of Adoptive T-Cell Therapy of Established Solid Cancers. Clinical Cancer Research, 14, 3966-3974.
http://dx.doi.org/10.1158/1078-0432.CCR-08-0356
[67] Zhang, Q., Yang, X.J., Kundu, S.D., Pins, M., Javonovic, B., Meyer, R., Kim, S.J., Greenberg, N.M., Kuzel, T., Meagher, R., Guo, Y. and Lee, C. (2006) Blockade of Transforming Growth Factor-β Signaling in Tumor-Reactive CD8(+) T Cells Activates the Antitumor Immune Response Cycle. Molecular Cancer Therapeutics, 5, 1733-1743. http://dx.doi.org/10.1158/1535-7163.MCT-06-0109
[68] Kirshner, J., Jobling, M.F., Pajares, M.J., Ravani, S.A., Glick, A.B., Lavin, M.J., Koslov, S., Shiloh, Y. and Barcellos-Hoff, M.H. (2006) Inhibition of Transforming Growth Factor-β 1 Signaling Attenuates Ataxia Telangiectasia Mutated Activity in Response to Genotoxic Stress. Cancer Research, 66, 10861-10869. http://dx.doi.org/10.1158/0008-5472.CAN-06-2565
[69] Bouquet, F., Pal, A., Pilones, K.A., Demaria, S. and Hann, B. (2011) TGFβ1 Inhibition Increases the Radiosensitivity of Breast Cancer Cells in Vitro and Promotes Tumor Control by Radiation in Vivo. Clinical Cancer Research, 17, 6754-6765. http://dx.doi.org/10.1158/1078-0432.CCR-11-0544
[70] Zhang, M., Kleber, S., Rohrich, M., Timke, C., Han, N. and Tuettenberg, J. (2011) Blockade of TGF-β Signaling by the TGFβ R-I Kinase Inhibitor LY2109761 Enhances Radiation Response and Prolongs Survival in Glioblastoma. Cancer Research, 71, 7155-7167.
http://dx.doi.org/10.1158/0008-5472.CAN-11-1212
[71] Zhou, L., Mcmahon, C., Bhagat, T., Alencar, C., Yu, Y., Fazzari, M., Sohal, D., Heuck, C., Ng, C., Mo, Y., Shen, W., Wickrema, A., Kong, G., Friedman, E., Sokol, L., Lahn, M.M., List, A., Bitzer, M. and Verma, A. (2011) Reduced SMAD7 Leads to Overactivation of TGF-β Signaling in MDS That Can Be Reversed by a Specific Inhibitor of TGF-β Receptor I Kinase. Cancer Research, 71, 955-963.
http://dx.doi.org/10.1158/0008-5472.CAN-10-2933
[72] Heany, M.L. and Golde, D.W. (1999) Myelodysplasia. New England Journal of Medicine, 340, 1649-1660. http://dx.doi.org/10.1056/NEJM199905273402107
[73] Liu, Y. (2006) Renal Fibrosis: New Insights into the Pathogenesis and Therapeutics. Kidney International, 69, 213-217. http://dx.doi.org/10.1038/sj.ki.5000054
[74] Lan, H.Y. (2011) Diverse Roles of TGF-β/Smads in Renal Fibrosis and Inflammation. International Journal of Biological Sciences, 7, 1056-1067. http://dx.doi.org/10.7150/ijbs.7.1056
[75] Fragiadaki, M. and Mason, R.M. (2011) Epithelial-Mesenchymal Transition in Renal Fibrosis-Evidence for and against. International Journal of Experimental Pathology, 92, 143-150.
http://dx.doi.org/10.1111/j.1365-2613.2011.00775.x
[76] Pardali, E. and ten Dijke, P. (2012) TGFβ Signaling and Cardiovascular Diseases. International Journal of Biological Sciences, 8, 195-213. http://dx.doi.org/10.7150/ijbs.8.195
[77] Merkel, P.A., Silliman, N.P., Denton, C.P., Furst, D.E., Khanna, D., Emery, P., Hsu, V.M., Streisand, J.B., Polisson, R.P., Akesson, A., Coppock, J., van den Hoogen, F., Herrick, A., Mayes, M.D., Veale, D., Seibold, J.R., Black, C.M. and Korn, J.H. (2008) Validity, Reliability, and Feasibility of Durometer Measurements of Scleroderma Skin Disease in a Multicenter Treatment Trial. Arthritis and Rheumatism, 59, 699-705.
[78] Yadav, H., Quijano, C., Kamaraju, A.K., Gavrilova, O., Malek, R., Chen, W., Zerfas, P., Zhigang, D., Wright, E.C., Stuelten, C., Sun, P., Lonning, S., Skarulis, M., Sumner, A.E., Finkel, T. and Rane, S.G. (2011) Protection from Obesity and Diabetes by Blockade of TGF-β/Smad3 Signaling. Cell Metabolism, 14, 67-79. http://dx.doi.org/10.1016/j.cmet.2011.04.013

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.