Abstract
Transforming growth factor-beta 1-3 (TGFβ) are members of a large multifunctional regulatory polypeptide family that controls cellular functions including proliferation, differentiation, migration, apoptosis, adhesion, angiogenesis, immune surveillance, and survival in many cell types. In intact canonical TGFβ signaling, the binding of a TGFβ to the TGFβ type II receptor enables the formation of a heteromeric complex between TGFβ type I and type II receptors. The type I receptor is phosphorylated by the type II receptor serine/threonine kinase. The activated type I receptor phosphorylates receptor-activated Smads that complex with Smad 4. The Smad complexes translocate into the nucleus and regulate target gene transcription through direct or indirect interaction with DNA-binding transcription factors or coactivators. Tumors are resistant to growth inhibition by TGFβ due to inactivation of the TGFβ signaling pathway or aberrant regulation of the cell cycle, in fact, many tumors secrete high levels of TGFβ. TGFβ knockout mice suffer from lethal multifocal inflammatory disease indicating the importance of TGFβ in maintaining immune system homeostasis. TGFβ pathway-directed therapy could reverse the immunosuppressive effects of this cytokine on the host as well as decrease extracellular matrix formation, angiogenesis, and osteolytic activity; and increase the sensitivity of the malignant cells to cytotoxic therapies and immunotherapies.
References
Calvo-Aller E, Baselga J, Glatt S, Cleverly A, Lahn M, Arteaga CL, Rothenberg ML, Carducci MA. First human dose escalation study in patients with metastatic malignancies to determine safety and pharmacokinetics of LY2157299, a small molecule inhibitor of the transforming growth factor-beta receptor I kinase. J Clin Oncol 2008;26 (suppl):Abstr# 14554.
Derynck R, Miyazono K. TGF-β and the TGF-β family. In: Derynck R, Miyazono K, editors. The TGF-β family. New York: Cold Spring Harbor Laboratories Press/Cold Spring Harbor; 2008. p. 29–44.
Goff LW, De Braud FG, Cohen RB, Berlin J, Noberasco C, Borghaei H, Wang E, Hu Lowe D, Levin WJ, Gallo-Stampino C. Phase I study of PF-03446962, a fully human mab against ALK1, a TGFβ receptor involved in tumor angiogenesis. J Clin Oncol 2010;28 (suppl):Abstr# 3034.
Hsu FJ, Teicher BA, McPherson JM. Rationale for anti-TGF-b antibody therapy in oncology. In: Jakowlew SB, editor. Transforming growth factor –β in cancer therapy, vol. II. Totowa: Humana Press Inc; 2008. p. 757–74. ISBN 978-1-59745-293-9
Jakowlew SB. Component hardware for ttransforming growth factor-β signal transduction: TGF-β ligands, TGF-β receptors and Smads. In: Jakowlew SB, editor. Transforming growth factor –β in cancer therapy, vol. I. Totowa: Humana Press Inc; 2008. p. 3–22.
Morris JC, Shapiro GI, Tan AR, Lawrence DP, Olencki TE, Dezube BJ, Hsu FJ, Reiss M, Berzofsky JA. Phase I/II study of GC1008: a human anti-transforming growth factor-beta (TGFβ) monoclonal antibody (MAb) in patients with advanced malignant melanoma (MM) or renal cell carcinoma (RCC). J Clin Oncol 2008;26 (suppl):Abstr# 9028.
Oettle H, Hilbig A, Seufferlein T, Luger T, Schmid RM, von Wichert G, Schmaus S, Heinrichs H, Schlingensiepen K. Trabedersen (AP12009) in the treatment of patients with advanced tumors: completion of dose-escalation and first efficacy data. J Clin Oncol 2010;28 (suppl):Abstr# 2611.
Pinkas J, Teicher BA. TGF-β in cancer and as a therapeutic target. Biochem Pharmacol. 2006;72:523–9.
Roberts AB, Anzano MA, Meyers CA, Wideman J, Blacher R, Pan YC, Stein S, Lehrman SR, Smith JM, Lamb LC, et al. Purification and properties of a type β transforming growth factor from bovine kidney. Biochem. 1983;22:5692–8.
Teicher BA. Transforming growth factor-β and the immune response to malignant disease. Clin Cancer Res. 2007;13:6247–51.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Section Editor information
Rights and permissions
Copyright information
© 2016 Springer Science+Business Media New York
About this entry
Cite this entry
Teicher, B. (2016). TGF Beta Receptors. In: Marshall, J.L. (eds) Cancer Therapeutic Targets. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6613-0_75-2
Download citation
DOI: https://doi.org/10.1007/978-1-4614-6613-0_75-2
Received:
Accepted:
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4614-6613-0
Online ISBN: 978-1-4614-6613-0
eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences