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
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.
Oncol Rep. 2015 Feb;33(2):553-8. doi: 10.3892/or.2014.3636. Epub 2014 Nov 28.
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.
腹膜癌病（PC）是胃癌最常见的转移模式，其预后极差。PC的特征是纤维化严重，并伴有肠梗阻、黄疸和肾积水等阻塞性疾病。上皮-间质转化（EMT）是组织纤维化的主要原因之一，转化生长因子β（TGF-β）在EMT进展中起关键作用。蛋白结合多糖K（PSK）是一种生物反应调节剂，可在体外调节TGF-β/Smad信号通路。在本研究中，我们使用人腹膜间皮细胞（HPMC）和人胃癌细胞系建立了纤维化肿瘤模型，以评估PSK是否能减轻肿瘤纤维化。暴露于PSK的HPMC未发生通常由TGF-β处理诱导的从鹅卵石样形态向纺锤形形态的转变。免疫荧光进一步表明，PSK抑制了TGF-β诱导的HPMC中α-SMA的过表达。我们进一步通过小鼠异种移植模型表明，HPMC促进了肿瘤纤维化的增殖。此外，用PSK处理这些小鼠可显著减少可观察到的肿瘤纤维化面积。这些结果表明，接种的癌细胞通过在微环境中释放TGF-β将HPMC转化为肌成纤维细胞样细胞，促进了覆盖有HPMC的器官中纤维性肿瘤的发展。因此，我们的研究表明，PSK作为一种抗纤维化药物在治疗PC胃癌患者方面具有潜在用途。
