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TNF‐α enhances TGF‐β‐induced endothelial‐to‐mesenchymal transition via TGF‐β signal augmentation

The tumor microenvironment (TME) consists of various components including cancer cells, tumor vessels, cancer‐associated fibroblasts (CAFs), and inflammatory cells. These components interact with each other via various cytokines, which often induce tumor progression. Thus, a greater understanding of...

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Autores principales: Yoshimatsu, Yasuhiro, Wakabayashi, Ikumi, Kimuro, Shiori, Takahashi, Naoya, Takahashi, Kazuki, Kobayashi, Miho, Maishi, Nako, Podyma‐Inoue, Katarzyna A., Hida, Kyoko, Miyazono, Kohei, Watabe, Tetsuro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385392/
https://www.ncbi.nlm.nih.gov/pubmed/32385953
http://dx.doi.org/10.1111/cas.14455
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author Yoshimatsu, Yasuhiro
Wakabayashi, Ikumi
Kimuro, Shiori
Takahashi, Naoya
Takahashi, Kazuki
Kobayashi, Miho
Maishi, Nako
Podyma‐Inoue, Katarzyna A.
Hida, Kyoko
Miyazono, Kohei
Watabe, Tetsuro
author_facet Yoshimatsu, Yasuhiro
Wakabayashi, Ikumi
Kimuro, Shiori
Takahashi, Naoya
Takahashi, Kazuki
Kobayashi, Miho
Maishi, Nako
Podyma‐Inoue, Katarzyna A.
Hida, Kyoko
Miyazono, Kohei
Watabe, Tetsuro
author_sort Yoshimatsu, Yasuhiro
collection PubMed
description The tumor microenvironment (TME) consists of various components including cancer cells, tumor vessels, cancer‐associated fibroblasts (CAFs), and inflammatory cells. These components interact with each other via various cytokines, which often induce tumor progression. Thus, a greater understanding of TME networks is crucial for the development of novel cancer therapies. Many cancer types express high levels of TGF‐β, which induces endothelial‐to‐mesenchymal transition (EndMT), leading to formation of CAFs. Although we previously reported that CAFs derived from EndMT promoted tumor formation, the molecular mechanisms underlying these interactions remain to be elucidated. Furthermore, tumor‐infiltrating inflammatory cells secrete various cytokines, including TNF‐α. However, the role of TNF‐α in TGF‐β‐induced EndMT has not been fully elucidated. Therefore, this study examined the effect of TNF‐α on TGF‐β‐induced EndMT in human endothelial cells (ECs). Various types of human ECs underwent EndMT in response to TGF‐β and TNF‐α, which was accompanied by increased and decreased expression of mesenchymal cell and EC markers, respectively. In addition, treatment of ECs with TGF‐β and TNF‐α exhibited sustained activation of Smad2/3 signals, which was presumably induced by elevated expression of TGF‐β type I receptor, TGF‐β2, activin A, and integrin αv, suggesting that TNF‐α enhanced TGF‐β‐induced EndMT by augmenting TGF‐β family signals. Furthermore, oral squamous cell carcinoma‐derived cells underwent epithelial‐to‐mesenchymal transition (EMT) in response to humoral factors produced by TGF‐β and TNF‐α‐cultured ECs. This EndMT‐driven EMT was blocked by inhibiting the action of TGF‐βs. Collectively, our findings suggest that TNF‐α enhances TGF‐β‐dependent EndMT, which contributes to tumor progression.
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spelling pubmed-73853922020-07-30 TNF‐α enhances TGF‐β‐induced endothelial‐to‐mesenchymal transition via TGF‐β signal augmentation Yoshimatsu, Yasuhiro Wakabayashi, Ikumi Kimuro, Shiori Takahashi, Naoya Takahashi, Kazuki Kobayashi, Miho Maishi, Nako Podyma‐Inoue, Katarzyna A. Hida, Kyoko Miyazono, Kohei Watabe, Tetsuro Cancer Sci Original Articles The tumor microenvironment (TME) consists of various components including cancer cells, tumor vessels, cancer‐associated fibroblasts (CAFs), and inflammatory cells. These components interact with each other via various cytokines, which often induce tumor progression. Thus, a greater understanding of TME networks is crucial for the development of novel cancer therapies. Many cancer types express high levels of TGF‐β, which induces endothelial‐to‐mesenchymal transition (EndMT), leading to formation of CAFs. Although we previously reported that CAFs derived from EndMT promoted tumor formation, the molecular mechanisms underlying these interactions remain to be elucidated. Furthermore, tumor‐infiltrating inflammatory cells secrete various cytokines, including TNF‐α. However, the role of TNF‐α in TGF‐β‐induced EndMT has not been fully elucidated. Therefore, this study examined the effect of TNF‐α on TGF‐β‐induced EndMT in human endothelial cells (ECs). Various types of human ECs underwent EndMT in response to TGF‐β and TNF‐α, which was accompanied by increased and decreased expression of mesenchymal cell and EC markers, respectively. In addition, treatment of ECs with TGF‐β and TNF‐α exhibited sustained activation of Smad2/3 signals, which was presumably induced by elevated expression of TGF‐β type I receptor, TGF‐β2, activin A, and integrin αv, suggesting that TNF‐α enhanced TGF‐β‐induced EndMT by augmenting TGF‐β family signals. Furthermore, oral squamous cell carcinoma‐derived cells underwent epithelial‐to‐mesenchymal transition (EMT) in response to humoral factors produced by TGF‐β and TNF‐α‐cultured ECs. This EndMT‐driven EMT was blocked by inhibiting the action of TGF‐βs. Collectively, our findings suggest that TNF‐α enhances TGF‐β‐dependent EndMT, which contributes to tumor progression. John Wiley and Sons Inc. 2020-06-11 2020-07 /pmc/articles/PMC7385392/ /pubmed/32385953 http://dx.doi.org/10.1111/cas.14455 Text en © 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Articles
Yoshimatsu, Yasuhiro
Wakabayashi, Ikumi
Kimuro, Shiori
Takahashi, Naoya
Takahashi, Kazuki
Kobayashi, Miho
Maishi, Nako
Podyma‐Inoue, Katarzyna A.
Hida, Kyoko
Miyazono, Kohei
Watabe, Tetsuro
TNF‐α enhances TGF‐β‐induced endothelial‐to‐mesenchymal transition via TGF‐β signal augmentation
title TNF‐α enhances TGF‐β‐induced endothelial‐to‐mesenchymal transition via TGF‐β signal augmentation
title_full TNF‐α enhances TGF‐β‐induced endothelial‐to‐mesenchymal transition via TGF‐β signal augmentation
title_fullStr TNF‐α enhances TGF‐β‐induced endothelial‐to‐mesenchymal transition via TGF‐β signal augmentation
title_full_unstemmed TNF‐α enhances TGF‐β‐induced endothelial‐to‐mesenchymal transition via TGF‐β signal augmentation
title_short TNF‐α enhances TGF‐β‐induced endothelial‐to‐mesenchymal transition via TGF‐β signal augmentation
title_sort tnf‐α enhances tgf‐β‐induced endothelial‐to‐mesenchymal transition via tgf‐β signal augmentation
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385392/
https://www.ncbi.nlm.nih.gov/pubmed/32385953
http://dx.doi.org/10.1111/cas.14455
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