Okazaki Mitsuyoshi, Fushida Sachio, Harada Shinichi, Tsukada Tomoya, Kinoshita Jun, Oyama Katsunobu, Miyashita Tomoharu, Ninomiya Itasu, Ohta Tetsuo
Department of Gastroenterological Surgery, Division of Cancer medicine, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8641, Ishikawa, Japan.
Center for Biomedical Research and Education, School of Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8641, Ishikawa, Japan.
BMC Cancer. 2017 Jan 5;17(1):23. doi: 10.1186/s12885-016-2991-9.
The clinical prognosis of gastric cancer with peritoneal dissemination is poor because of its chemoresistance and rich fibrosis. While several gastric cancer cell lines have been used to establish models of peritoneal dissemination by intraperitoneal injection, most peritoneal tumors that form adopt a medullary pattern in microscopic appearance. This histological finding for the model differs from that in the clinical situation. This study was performed to demonstrate the contribution of human peritoneal mesothelial cells (HPMCs) to fibrotic tumor formation and to establish a new xenograft model with high potential for peritoneal dissemination with organ invasion and extensive fibrosis.
We established four types of xenograft model: i) intraperitoneal injection of MKN45-P cells alone (control group), ii) injection of MKN45-P cells co-cultured with HPMCs (co-cultured group), iii) scratching the parietal peritoneum (parietal group), and iv) scratching the visceral peritoneum (visceral group) with a cotton swab before injection of co-cultured cells. Fibrosis, α-smooth muscle actin expression, and organ invasion by tumor cells were all assessed by immunohistochemical examination.
All mice developed abdominal swelling with peritoneal tumors and bloody ascites. Tumors of the control and co-cultured groups were not invasive or fibrotic. Contrastingly, tumors of the scratch groups exhibited rich stromal fibrosis and possessed increased α-smooth muscle actin (α-SMA) expression. In particular, the visceral group showed edematous and spreading tumors invading the intestinal wall.
We established a model of peritoneal dissemination with organ invasion and stromal fibrosis. Formation of peritoneal dissemination required a favorable environment for cell adhesion, invasion, and growth. This model may be useful for analyzing the pathogenesis and treatment of peritoneal dissemination of gastric cancer.
伴有腹膜播散的胃癌临床预后较差，因其具有化学抗性且纤维化严重。虽然已有几种胃癌细胞系通过腹腔注射用于建立腹膜播散模型，但大多数形成的腹膜肿瘤在显微镜下呈现髓样模式。该模型的这一组织学发现与临床情况不同。本研究旨在证明人腹膜间皮细胞（HPMC）对纤维化肿瘤形成的作用，并建立一种具有高腹膜播散潜能、伴有器官侵犯和广泛纤维化的新型异种移植模型。
我们建立了四种类型的异种移植模型：i）单独腹腔注射MKN45-P细胞（对照组），ii）注射与HPMC共培养的MKN45-P细胞（共培养组），iii）刮擦壁腹膜（壁腹膜组），以及iv）在注射共培养细胞前用棉签刮擦脏腹膜（脏腹膜组）。通过免疫组织化学检查评估纤维化、α-平滑肌肌动蛋白表达以及肿瘤细胞的器官侵犯情况。
所有小鼠均出现腹部肿胀、腹膜肿瘤和血性腹水。对照组和共培养组的肿瘤无侵袭性或纤维化。相反，刮擦组的肿瘤表现出丰富的间质纤维化且α-平滑肌肌动蛋白（α-SMA）表达增加。特别是，脏腹膜组显示出水肿性且蔓延的肿瘤侵犯肠壁。
我们建立了一种伴有器官侵犯和间质纤维化的腹膜播散模型。腹膜播散的形成需要有利于细胞黏附、侵袭和生长的环境。该模型可能有助于分析胃癌腹膜播散的发病机制和治疗方法。
