RRC ID 63756
Author Yoshimatsu Y, Wakabayashi I, Kimuro S, Takahashi N, Takahashi K, Kobayashi M, Maishi N, Podyma-Inoue KA, Hida K, Miyazono K, Watabe T.
Title TNF-α enhances TGF-β-induced endothelial-to-mesenchymal transition via TGF-β signal augmentation.
Journal Cancer Sci
Abstract 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.
Volume 111(7)
Pages 2385-2399
Published 2020-7-1
DOI 10.1111/cas.14455
PMID 32385953
PMC PMC7385392
MeSH Biomarkers Cancer-Associated Fibroblasts / metabolism Carcinoma, Squamous Cell / genetics Carcinoma, Squamous Cell / metabolism Carcinoma, Squamous Cell / pathology Cell Line Cells, Cultured Endothelial Cells / metabolism Epithelial-Mesenchymal Transition* / drug effects Humans Inflammation Mediators / metabolism Mouth Neoplasms / drug therapy Mouth Neoplasms / genetics Mouth Neoplasms / metabolism Mouth Neoplasms / pathology NF-kappa B / metabolism Receptor, Transforming Growth Factor-beta Type I Signal Transduction* / drug effects Smad2 Protein / metabolism Smad3 Protein / metabolism Transforming Growth Factor beta / metabolism* Transforming Growth Factor beta / pharmacology Tumor Microenvironment / genetics Tumor Necrosis Factor-alpha / metabolism* Tumor Necrosis Factor-alpha / pharmacology
IF 4.966
Human and Animal Cells HSC-4(RCB1902)