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Frontiers of Medicine

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ISSN 2095-0225(Online)

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Front. Med.    2018, Vol. 12 Issue (4) : 387-411    https://doi.org/10.1007/s11684-018-0646-8
REVIEW
Intracellular and extracellular TGF-β signaling in cancer: some recent topics
Kohei Miyazono(), Yoko Katsuno, Daizo Koinuma, Shogo Ehata, Masato Morikawa
Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
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Abstract

Transforming growth factor (TGF)-β regulates a wide variety of cellular responses, including cell growth arrest, apoptosis, cell differentiation, motility, invasion, extracellular matrix production, tissue fibrosis, angiogenesis, and immune function. Although tumor-suppressive roles of TGF-β have been extensively studied and well-characterized in many cancers, especially at early stages, accumulating evidence has revealed the critical roles of TGF-β as a pro-tumorigenic factor in various types of cancer. This review will focus on recent findings regarding epithelial-mesenchymal transition (EMT) induced by TGF-β, in relation to crosstalk with some other signaling pathways, and the roles of TGF-β in lung and pancreatic cancers, in which TGF-β has been shown to be involved in cancer progression. Recent findings also strongly suggested that targeting TGF-β signaling using specific inhibitors may be useful for the treatment of some cancers. TGF-β plays a pivotal role in the differentiation and function of regulatory T cells (Tregs). TGF-β is produced as latent high molecular weight complexes, and the latent TGF-β complex expressed on the surface of Tregs contains glycoprotein A repetitions predominant (GARP, also known as leucine-rich repeat containing 32 or LRRC32). Inhibition of the TGF-β activities through regulation of the latent TGF-β complex activation will be discussed.
Keywords TGF-β      EMT      lung cancer      pancreatic cancer      latent form      immune function      GARP     
Corresponding Author(s): Kohei Miyazono   
Just Accepted Date: 25 June 2018   Online First Date: 25 July 2018    Issue Date: 03 September 2018
 Cite this article:   
Kohei Miyazono,Yoko Katsuno,Daizo Koinuma, et al. Intracellular and extracellular TGF-β signaling in cancer: some recent topics[J]. Front. Med., 2018, 12(4): 387-411.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-018-0646-8
https://academic.hep.com.cn/fmd/EN/Y2018/V12/I4/387
Fig.1  Intracellular signal transduction by TGF-β. Upon binding of TGF-β ligands to the receptors, the Smad pathway involving Smad2 and/or 3 (Smad2/3) and Smad4 is activated (middle). The TGF-β-Smad pathway regulates the expression of various target genes, and EMT transcription factors induced by TGF-β signaling are shown. TGF-β also activates non-Smad pathways, including the TRAF6 and/or 4 (TRAF6/4)-TAK1-JNK and/or p38 pathway, PI3K-Akt-mTOR pathway, and Ras-Erk1 and/or 2 (Erk1/2) pathway (left). In addition, the growth factor-RTK pathway modulates the TGF-β signaling pathway (right). Ub, ubiquitin; P, phosphorylation.
Fig.2  Regulation of cancer metastasis by TGF-β and analyses by whole-body tissue-clearing. TGF-β acts on epithelial cells and accelerates the invasion of cells through induction of EMT. After intravasation, TGF-β stimulates cell adhesion and survival at distant organs, and facilitates extravasation. Then, cancer cells may undergo mesenchymal-epithelial transition (MET), a reverse process of EMT, and form metastatic foci, where the cancer cells often express an epithelial cell marker E-cadherin. (A) Whole lung of mice treated with the CUBIC tissue-clearing reagents. Blue dotted line indicates the outline of the lung. (B, C) Mice were injected with A549 lung adenocarcinoma cells pretreated with TGF-β through tail vein. Cancer cells expressing mCherry (shown in red) were visualized after 1 hour (B) and 14 days (C) after injection of cells into mice. Cell nuclei were visualized by RedDot2 (shown in blue). (D) Immunostaining of lung tissue of the mouse injected with the TGF-β-treated A549 cells. Cancer cells in the metastatic foci are positively stained by anti-E-cadherin antibody. (Courtesy of Drs. Shimpei I. Kubota, Kei Takahashi, and Hiroki R. Ueda.) See Kubota et al. [113].
Fig.3  Roles of TGF-β signaling in lung adenocarcinoma and small cell lung carcinoma. (A) TGF-β signaling in lung adenocarcinoma. TGF-β signaling induces the expression of SNAI1 and SNAI2 genes, encoding Snail and Slug, respectively, and regulates the expression of other target genes involved in progression of cancer. NKX2-1/TTF-1 antagonizes the effects of TGF-β-Smad signaling. (B) TGF-β signaling in small cell lung carcinoma (SCLC). TGF-β inhibits the expression of ASCL1/ASH1 through the Smad signaling pathway. Because ASCL1 induces cell survival, TGF-β signaling attenuates the induction of cell survival by ASCL1. In SCLC cells, expression of TβRII (encoded by the TGFBR2 gene) is downregulated through an epigenetic mechanism by an increase in the EZH2 expression. Thus, TGF-β signaling is suppressed in SCLC cells, leading to enhanced cell survival in SCLC cells.
Fig.4  Roles of TGF-β signaling in pancreatic carcinoma. (A) Multistep progression of pancreatic carcinoma. Genes involved in progression of pancreatic carcinoma and the frequencies of abnormalities of these genes are shown [239]. Red, oncogene; blue, tumor-suppressive genes. (B) Tumor-suppressive and pro-tumorigenic activities of TGF-β during the development of pancreatic carcinoma.
Fig.5  Structure of pre-pro-TGF-β1 and latent forms of TGF-β. (A) Structure of pre-pro-TGF-β1. Red arrows, proteolytic processing sites; blue asterisks, cysteine residues, which form intramolecular disulfide bridges; red asterisks, cysteine residues, which form intermolecular disulfide bridges; green asterisk, cysteine residue, which forms a disulfide bridge with LTBPs or GARP; RGD, integrin recognition sequence. (B) Small latent TGF-β complex (SLC). TGF-β is produced as a latent form, consisting of the dimeric LAP proteins, which are non-covalently associated with the dimeric mature TGF-β. The RGD integrin recognition sequence is present in TGF-β1 and β3, but not in β2. Latent TGF-β is activated by various mechanisms; among those, mechanisms of activation by integrins have been best-characterized (see text). (C) Structures of the large latent TGF-β complexes (LLCs). SLCs are bound to LTBPs (LTBP-1, 3, and 4) or GARP. LTBPs are comprised of multiple EGF-like domains and 8-cysteine domains. The latent TGF-β complexes with LTBPs are released from the producer cells. LTBPs are associated with ECM proteins, which are involved in activation of the latent TGF-β. GARP is a transmembrane protein with a horseshoe-like structure. The latent TGF-β complex with GARP is thus anchored to the cell surface. The extracellular domain of GARP is comprised of multiple leucine-rich repeats.
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