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Gastric Cancer
Published in: Gastric Cancer 1/2018

Open Access 01-01-2018 | Original Article

Importance of human peritoneal mesothelial cells in the progression, fibrosis, and control of gastric cancer: inhibition of growth and fibrosis by tranilast

Authors: Hiroto Saito, Sachio Fushida, Shinichi Harada, Tomoharu Miyashita, Katsunobu Oyama, Takahisa Yamaguchi, Tomoya Tsukada, Jun Kinoshita, Hidehiro Tajima, Itasu Ninomiya, Tetsuo Ohta

Published in: Gastric Cancer | Issue 1/2018

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Abstract

Background

Scirrhous gastric cancer is an intractable disease with a high incidence of peritoneal dissemination and obstructive symptoms (e.g., ileus, jaundice, and hydronephrosis) arising from accompanying marked fibrosis. Microenvironmental interactions between cancer cells and cancer-associated fibroblasts are the suggested cause of the disease. We elucidated the mechanisms of tumor growth and fibrosis using human peritoneal mesothelial cells (HPMCs) and investigated the effects of tranilast treatment on cells and a xenograft mouse model of fibrosis.

Methods

HPMCs were isolated from surgically excised omentum and their interaction with MKN-45 gastric cancer cells was investigated using co-culture. Furthermore, a fibrosis tumor model was developed based on subcutaneous transplantation of co-cultured cells into the dorsal side of nude mice to form large fibrotic tumors. Mice were subsequently treated with or without tranilast.

Results

The morphology of HPMCs treated with transforming growth factor (TGF)-β1 changed from cobblestone to spindle-type. Moreover, E-cadherin was weakly expressed whereas high levels of α-smooth muscle actin expression were observed. TGF-β-mediated epithelial–mesenchymal transition-like changes in HPMCs were inhibited in a dose-dependent manner following tranilast treatment through inhibition of Smad2 phosphorylation. In the mouse model, tumor size decreased significantly and fibrosis was inhibited in the tranilast treatment group compared with that in the control group.

Conclusions

Tranilast acts on the TGF-β/Smad pathway to inhibit interactions between cancer cells and cancer-associated fibroblasts, thereby inhibiting tumor growth and fibrosis. This study supports the hypothesis that tranilast represents a novel strategy to prevent fibrous tumor establishment represented by peritoneal dissemination.
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Metadata
Title
Importance of human peritoneal mesothelial cells in the progression, fibrosis, and control of gastric cancer: inhibition of growth and fibrosis by tranilast
Authors
Hiroto Saito
Sachio Fushida
Shinichi Harada
Tomoharu Miyashita
Katsunobu Oyama
Takahisa Yamaguchi
Tomoya Tsukada
Jun Kinoshita
Hidehiro Tajima
Itasu Ninomiya
Tetsuo Ohta
Publication date
01-01-2018
Publisher
Springer Japan
Published in
Gastric Cancer / Issue 1/2018
Print ISSN: 1436-3291
Electronic ISSN: 1436-3305
DOI
https://doi.org/10.1007/s10120-017-0726-5

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