title: Protein-bound polysaccharide K suppresses tumor fibrosis in gastric cancer by inhibiting the TGF-β signaling pathway.
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.
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Shinbo
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Sachio
authors.initials: S
authors.lastname: Fushida
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Tsukada
authors.affiliation: Center for Biomedical Research and Education, School of Medicine, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Harada
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Kinoshita
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Katsunobu
authors.initials: K
authors.lastname: Oyama
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Okamoto
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Itasu
authors.initials: I
authors.lastname: Ninomiya
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takamura
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Kitagawa
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fujimura
authors.affiliation: Department of Surgical Oncology, Osaka City University, Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yashiro
authors.affiliation: Department of Surgical Oncology, Osaka City University, Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Kousei
authors.initials: K
authors.lastname: Hirakawa
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ohta
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D005656:Fungal Proteins / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011134:Polysaccharides / Q000008:administration & dosage* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000199:Actins; D005656:Fungal Proteins; D011134:Polysaccharides; D016212:Transforming Growth Factor beta; C494124:protein-bound polysaccharide K, Basidiomycetes