Intracellular and extracellular TGF-β signaling in cancer: some recent topics

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

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Acknowledgements

We thank all the members of the Molecular Pathology Laboratory at The University of Tokyo, especially Drs. Kei Takahashi, Shimpei I. Kubota, and Akihiro Katsura, for discussion. We also thank Prof. Hiroki R. Ueda (Department of Systems Pharmacology, The University of Tokyo) for collaboration. This research is supported by KAKENHI, grants-in-aid for scientific research on Innovative Area on Integrated Analysis and Regulation of Cellular Diversity (No. 17H06326, KM), from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT) and Scientific Research (S) (No. 15H05774, KM) from the Japan Society for the Promotion of Science (JSPS). This work is also supported by Project for Cancer Research and Therapeutic Evolution (P-CREATE; No. 17cm0106313h0002, SE) from the Japan Agency for Medical Research and Development (AMED). KM was supported by Yasuda Medical Foundation.

Compliance with ethics guidelines

Kohei Miyazono, Yoko Katsuno, Daizo Koinuma, Shogo Ehata, and Masato Morikawa declare no competing or financial interests. This manuscript does not involve any research protocols requiring approval by the relevant ethical committee or institutional review board.

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