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      Targeting the TGF-β1 Pathway to Prevent Normal Tissue Injury After Cancer Therapy

      research-article
      The Oncologist
      AlphaMed Press
      Transforming growth factor β, Complications, Fibrosis, Lung Cancer

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          Abstract

          Evidence supporting the critical role of transforming growth factor β1 in the development of normal tissue injury after cancer therapy is reviewed and the results of recent research aimed at preventing normal tissue injury by targeting the transforming growth factor β1 pathway are presented.

          Abstract

          With >10,000,000 cancer survivors in the U.S. alone, the late effects of cancer treatment are a significant public health issue. Over the past 15 years, much work has been done that has led to an improvement in our understanding of the molecular mechanisms underlying the development of normal tissue injury after cancer therapy. In many cases, these injuries are characterized at the histologic level by loss of parenchymal cells, excessive fibrosis, and tissue atrophy. Among the many cytokines involved in this process, transforming growth factor (TGF)-β1 is thought to play a pivotal role. TGF-β1 has a multitude of functions, including both promoting the formation and inhibiting the breakdown of connective tissue. It also inhibits epithelial cell proliferation. TGF-β1 is overexpressed at sites of injury after radiation and chemotherapy. Thus, TGF-β1 represents a logical target for molecular therapies designed to prevent or reduce normal tissue injury after cancer therapy. Herein, the evidence supporting the critical role of TGF-ß1 in the development of normal tissue injury after cancer therapy is reviewed and the results of recent research aimed at preventing normal tissue injury by targeting the TGF-ß1 pathway are presented.

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          Most cited references108

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          Making sense of latent TGFbeta activation.

          TGFbeta is secreted as part of a latent complex that is targeted to the extracellular matrix. A variety of molecules, 'TGFbeta activators,' release TGFbeta from its latent state. The unusual temporal discontinuity of TGFbeta synthesis and action and the panoply of TGFbeta effects contribute to the interest in TGF-beta. However, the logical connections between TGFbeta synthesis, storage and action are obscure. We consider the latent TGFbeta complex as an extracellular sensor in which the TGFbeta propeptide functions as the detector, latent-TGFbeta-binding protein (LTBP) functions as the localizer, and TGF-beta functions as the effector. Such a view provides a logical continuity for various aspects of TGFbeta biology and allows us to appreciate TGFbeta biology from a new perspective.
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            Cell size and invasion in TGF-β–induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway

            Epithelial to mesenchymal transition (EMT) occurs during development and cancer progression to metastasis and results in enhanced cell motility and invasion. Transforming growth factor-β (TGF-β) induces EMT through Smads, leading to transcriptional regulation, and through non-Smad pathways. We observe that TGF-β induces increased cell size and protein content during EMT. This translational regulation results from activation by TGF-β of mammalian target of rapamycin (mTOR) through phosphatidylinositol 3-kinase and Akt, leading to the phosphorylation of S6 kinase 1 and eukaryotic initiation factor 4E–binding protein 1, which are direct regulators of translation initiation. Rapamycin, a specific inhibitor of mTOR complex 1, inhibits the TGF-β–induced translation pathway and increase in cell size without affecting the EMT phenotype. Additionally, rapamycin decreases the migratory and invasive behavior of cells that accompany TGF-β–induced EMT. The TGF-β–induced translation pathway through mTOR complements the transcription pathway through Smads. Activation of mTOR by TGF-β, which leads to increased cell size and invasion, adds to the role of TGF-β–induced EMT in cancer progression and may represent a therapeutic opportunity for rapamycin analogues in cancer.
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              TGF beta signals through a heteromeric protein kinase receptor complex.

              Transforming growth factor beta (TGF beta) binds with high affinity to the type II receptor, a transmembrane protein with a cytoplasmic serine/threonine kinase domain. We show that the type II receptor requires both its kinase activity and association with another TGF beta-binding protein, the type I receptor, to signal growth inhibition and early gene responses. Receptors I and II associate as interdependent components of a heteromeric complex: receptor I requires receptor II to bind TGF beta, and receptor II requires receptor I to signal. This mode of operation points to fundamental differences between this receptor and the protein-tyrosine kinase cytokine receptors.
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                Author and article information

                Journal
                Oncologist
                Oncologist
                oncologist
                theoncologist
                The Oncologist
                The Oncologist
                AlphaMed Press (Durham, NC, USA )
                1083-7159
                1549-490X
                April 2010
                : 15
                : 4
                : 350-359
                Affiliations
                [1]Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia, USA
                Author notes
                Correspondence: Mitchell S. Anscher, M.D., VCU Medical Center, 401 College Street, P.O. Box 980058, Richmond, Virginia 23298-0058, USA. Telephone: 804-828-7238; Fax: 804-828-7232; E-mail: manscher@ 123456mcvh-vcu.edu

                Disclosures: Mitchell S. Anscher: Consultant/advisory role: Civa Tech.

                The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers.

                Article
                3505244
                10.1634/theoncologist.2009-S101
                3227962
                20413640
                17f74af7-d36a-45a5-aab8-775e1323cfcc
                ©AlphaMed Press

                available online without subscription through the open access option.

                History
                : 28 October 2008
                : 29 April 2009
                Categories
                New Translational Research in Radiation Oncology: A Tribute to Eli Glatstein

                Oncology & Radiotherapy
                complications,transforming growth factor β,fibrosis,lung cancer
                Oncology & Radiotherapy
                complications, transforming growth factor β, fibrosis, lung cancer

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