The role of human peritoneal mesothelial cells in the fibrosis and progression of gastric cancer

Tsukada,Tomoya; Fushida,Sachio; Harada,Shinichi; Yagi,Yasumichi; Kinoshita,Jun; Oyama,Katsunobu; Tajima,Hidehiro; Fujita,Hideto; Ninomiya,Itasu; Fujimura,Takashi; Ohta,Tetsuo

doi:10.3892/ijo.2012.1490

The role of human peritoneal mesothelial cells in the fibrosis and progression of gastric cancer

Authors:
- Tomoya Tsukada
- Sachio Fushida
- Shinichi Harada
- Yasumichi Yagi
- Jun Kinoshita
- Katsunobu Oyama
- Hidehiro Tajima
- Hideto Fujita
- Itasu Ninomiya
- Takashi Fujimura
- Tetsuo Ohta
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Affiliations: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan, Center for Biomedical Research and Education, School of Medicine, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
Published online on: May 18, 2012 https://doi.org/10.3892/ijo.2012.1490
Pages: 476-482
Copyright: © Tsukada et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Peritoneal dissemination is the most frequent metastatic pattern of scirrhous gastric cancer. However, despite extensive research effort, disease outcomes have not improved sufficiently. Tumor progression and metastasis result from interactions between cancer and various cells in the stroma, including endothelial cells, immune cells and fibroblasts. Fibroblasts have been particularly well studied; they are known to change into carcinoma-associated fibroblasts (CAFs) and produce transforming growth factor β (TGF-β), which mediates cancer-stroma interactions. Here, we investigated whether TGF-β derived from cancer cells in the peritoneal microenvironment activates human peritoneal mesothelial cells (HPMCs), leading to the progression and fibrosis of gastric cancer. We found that activated HPMCs (a-HPMCs) took on a spindle shape formation, decreased the expression of E-cadherin and increased that of α-SMA. Furthermore, a-HPMCs became more invasive and upregulated proliferation of human gastric cancer-derived MKN45 cells following direct cell-cell contact. Notably, MKN45 cells co-cultured with a-HPMCs also acquired anchorage-independent cell growth and decreased expression of E-cadherin in vitro. To measure the effects of the co-culture in vivo, we developed a mouse xenograft model into which different culture products were subcutaneously injected. The largest tumors were observed in mice that had been given MKN45 cells co-cultured with a-HPMCs. Furthermore, these tumors contained HPMC-derived fibrous tissue. Thus, the epithelial-mesenchymal transition (EMT) of HPMCs appears to drive peritoneal dissemination and tumor fibrosis.

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