Mesothelial Cells Create a Novel Tissue Niche That Facilitates Gastric Cancer Invasion
Mesothelial Cells Create a Novel Tissue Niche That Facilitates Gastric Cancer Invasion
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DOI：
10.1158/0008-5472.can-16-0964
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发表时间：
2017-02-01
期刊：
影响因子：
11.2
通讯作者：
Aiba, Namiko
中科院分区：
文献类型：
--
作者：
Tanaka, Masamitsu;Kuriyama, Sei;Aiba, Namiko
腹膜间皮细胞（PMC）覆盖在腹腔器官表面。在这项研究中，谱系追踪显示PMCs引导癌细胞侵袭胃壁和腹膜转移病变。覆盖胃表面的浆膜pmc进入胃壁，创造了一个有利于胃癌细胞侵袭的新生态位。PMC浸润是由癌细胞衍生的含有wnt3a的细胞外囊泡的掺入诱导的。浸润的pmc反过来促进了癌细胞的浆膜下浸润。癌细胞与pmc的相互吸引加速了肿瘤向胃壁的侵袭，pmc引导的癌细胞向腹壁和膈内播散性肿瘤的侵袭。Dickkopf-1的羧基末端的添加在体外和体内胃壁减弱了pmc对癌细胞的定向侵袭。pmc对醛脱氢酶（ALDH）抑制剂双硫仑（DSF）敏感，ALDH活性在pmc中升高。Wnt3a上调ALDH，添加DSF可抑制PMCs的侵袭特性，而DSF预处理可抑制PMCs的胃浸润和癌细胞的浆膜下侵袭。我们的研究结果表明，稳定pmc可能成为预防胃癌局部侵袭和转移的有效治疗方法。(c) 2016年aacr。
Peritoneal mesothelial cells (PMC) cover organ surfaces in the abdominal cavity. In this study, lineage tracing revealed that the PMCs guide cancer cell invasion in the gastric wall and in peritoneal metastatic lesions. Serosal PMCs covering the stomach surface entered the gastric wall to create a novel niche that favored gastric cancer cell invasion. PMC infiltration was induced by incorporation of cancer cell-derived, Wnt3a-containing extracellular vesicles. Infiltrated PMCs in turn promoted subserosal invasion of cancer cells. Mutual attraction between cancer cells and PMCs accelerated tumor invasion in the gastric wall, and PMC-led cancer cell invasion in disseminated tumors within the abdominal wall and diaphragm. Addition of the carboxyl terminus of Dickkopf-1 attenuated directional invasion of PMCs toward cancer cells both in vitro and in the gastric wall in vivo. PMCs were sensitive to the aldehyde dehydrogenase (ALDH) inhibitor disulfiram (DSF), as ALDH activity is elevated in PMCs. Wnt3a upregulated ALDH, and addition of DSF inhibited the invasive properties of PMCs, whereas DSF pretreatment suppressed gastric infiltration of PMCs and subserosal invasion by cancer cells. Our results suggest that stabilization of PMCs may become an effective therapy for the prevention of local invasion and metastasis of gastric cancer. (C) 2016 AACR.