Protein-bound polysaccharide K suppresses tumor fibrosis in gastric cancer by inhibiting the TGF-β signaling pathway

Shinbo,Toshifumi; Fushida,Sachio; Tsukada,Tomoya; Harada,Shinichi; Kinoshita,Jun; Oyama,Katsunobu; Okamoto,Koichi; Ninomiya,Itasu; Takamura,Hiroyuki; Kitagawa,Hirohisa; Fujimura,Takeshi; Yashiro,Masakazu; Hirakawa,Kousei; Ohta,Tetsuo

doi:10.3892/or.2014.3636

Protein-bound polysaccharide K suppresses tumor fibrosis in gastric cancer by inhibiting the TGF-β signaling pathway

Authors:
- Toshifumi Shinbo
- Sachio Fushida
- Tomoya Tsukada
- Shinichi Harada
- Jun Kinoshita
- Katsunobu Oyama
- Koichi Okamoto
- Itasu Ninomiya
- Hiroyuki Takamura
- Hirohisa Kitagawa
- Takeshi Fujimura
- Masakazu Yashiro
- Kousei Hirakawa
- Tetsuo Ohta
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Affiliations: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan, Center for Biomedical Research and Education, School of Medicine, Kanazawa University, Kanazawa 920-8641, Japan, Department of Surgical Oncology, Osaka City University, Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan
Published online on: November 28, 2014 https://doi.org/10.3892/or.2014.3636
Pages: 553-558
Copyright: © Shinbo 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 carcinomatosis (PC) is the most frequent metastatic pattern of gastric cancer and its prognosis is extremely poor. PC is characterized by rich fibrosis and the development of obstructive disorders such as ileus, jaundice and hydronephrosis. Epithelial-mesenchymal transition (EMT) is one of the major causes of tissue fibrosis and transforming growth factor β (TGF-β) has a pivotal function in the progression of EMT. Protein-bound polysaccharide K (PSK) is a biological response modifier that can modulate the TGF-β/Smad signaling pathway in vitro. In the present study, we established a fibrotic tumor model using human peritoneal mesothelial cells (HPMCs) and a human gastric cancer cell line to evaluate whether PSK attenuates tumor fibrosis. HPMCs exposed to PSK did not undergo the morphological change from a cobblestone-like pattern to a spindle-shape pattern normally induced by treatment with TGF-β. Immunofluorescence further demonstrated that PSK suppressed TGF-β-induced overexpression of α-SMA in the HPMCs. We further showed that HPMCs contributed to the proliferation of tumor fibrosis by using a mouse xenograft model. Additionally, PSK treatment of these mice significantly reduced the area of observable tumor fibrosis. These results suggest that seeded cancer cells transformed HPMCs into myofibroblast-like cells through their release of TGF-β in the microenvironment, facilitating the development of fibrous tumors in organs covered with HPMCs. Therefore, our study indicates that PSK has potential utility as an anti-fibrotic agent in the treatment of gastric cancer patients with PC.

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