CD90+ mesothelial-like cells in peritoneal fluid promote peritoneal metastasis by forming a tumor permissive microenvironment.
CD90+ mesothelial-like cells in peritoneal fluid promote peritoneal metastasis by forming a tumor permissive microenvironment.
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DOI：
10.1371/journal.pone.0086516
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Watanabe T
中科院分区：
文献类型：
--
作者：
Kitayama J;Emoto S;Yamaguchi H;Ishigami H;Watanabe T
腹膜腔是胃肠道和卵巢癌细胞转移的共同靶点，但导致腹膜转移的机制尚未完全阐明。在这项研究中，我们研究了腹膜液中的细胞在腹膜转移发展中的作用。我们发现，一小部分具有CD 90（+）/CD 45（-）表型的人腹膜内细胞在培养物中生长旺盛，具有间皮样外观。间皮样细胞（mesothelial-like cells，MLC）具有间充质干细胞的特性，如可分化为脂肪细胞、骨细胞和软骨细胞，并能抑制T细胞增殖。这些细胞在TGF-β刺激下高表达I型胶原、波形蛋白、α-平滑肌肌动蛋白和成纤维细胞活化蛋白-α，这是活化的肌成纤维细胞的特征。腹腔内共注射MLCs与人胃癌细胞系MKN 45，显着增加裸鼠腹膜转移形成率。组织学检查发现，许多MLCs植入转移结节，主要位于纤维区。达沙替尼，一种有效的酪氨酸激酶抑制剂，在体外强烈抑制MLCs的增殖，但不抑制MKN 45。然而，口服达沙替尼显著抑制了MKN 45腹膜转移的发展，并导致转移性结节的纤维形成减少。这些结果表明，漂浮在腹腔液中的MLCs支持腹膜转移的发展，可能通过生产的许可的微环境，因此MLCs的功能封锁是一个合理的策略来治疗复发性腹部恶性肿瘤。
The peritoneal cavity is a common target of metastatic gastrointestinal and ovarian cancer cells, but the mechanisms leading to peritoneal metastasis have not been fully elucidated. In this study, we examined the roles of cells in peritoneal fluids on the development of peritoneal metastasis. We found that a minor subset of human intraperitoneal cells with CD90(+)/CD45(−) phenotype vigorously grew in culture with mesothelial-like appearance. The mesothelial-like cells (MLC) displayed the characteristics of mesenchymal stem cell, such as differentiating into adipocytes, osteocytes, and chondrocytes, and suppressing T cell proliferation. These cells highly expressed type I collagen, vimentin, α-smooth muscle actin and fibroblast activated protein-α by the stimulation with TGF-β, which is characteristic of activated myofibroblasts. Intraperitoneal co-injection of MLCs with the human gastric cancer cell line, MKN45, significantly enhanced the rate of metastatic formation in the peritoneum of nude mice. Histological examination revealed that many MLCs were engrafted in metastatic nodules and were mainly located at the fibrous area. Dasatinib, a potent tyrosine kinase inhibitor, strongly inhibited the proliferation of MLCs but not MKN45 in vitro. Nevertheless, oral administration of Dasatinib significantly inhibited the development of peritoneal metastasis of MKN45, and resulted in reduced fibrillar formation of metastatic nodules. These results suggest floating MLCs in the peritoneal fluids support the development of peritoneal metastasis possibly through the production of the permissive microenvironment, and thus the functional blockade of MLCs is a reasonable strategy to treat recurrent abdominal malignancies.
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