The epithelial-to-mesenchymal transition induced by tumor-associated macrophages confers chemoresistance in peritoneally disseminated pancreatic cancer
The epithelial-to-mesenchymal transition induced by tumor-associated macrophages confers chemoresistance in peritoneally disseminated pancreatic cancer
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DOI：
10.1186/s13046-018-0981-2
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发表时间：
2018-12-11
影响因子：
11.3
通讯作者：
Fujiwara, Toshiyoshi
中科院分区：
文献类型：
--
作者：
Kuwada, Kazuya;Kagawa, Shunsuke;Fujiwara, Toshiyoshi
背景腹膜是胰腺癌最常见的转移部位之一，腹膜播散使胰腺癌进展迅速，化疗耐药，难以治疗。虽然肿瘤微环境在癌症发展中的作用已被公认，但腹膜环境与腹膜播散难治性之间的相关性仍不清楚。腹膜内肿瘤微环境及其在腹膜传播和化疗难治性的进展中的潜在作用，特别是侧重于巨噬细胞，investigated.Materials and MethodsPeritoneal洗涤液从胰腺癌患者，和细胞成分进行免疫荧光测定。在共培养条件下检测单核细胞THP-1细胞诱导的巨噬细胞对胰腺癌细胞的作用。结果腹腔冲洗液中，巨噬细胞沿着癌细胞一起出现，巨噬细胞的表达呈阳性。在体外共培养中，肿瘤相关巨噬细胞影响胰腺癌细胞，诱导上皮向间质转化（EMT），并使其对化疗药物更具抗性。M2巨噬细胞促进小鼠皮下肿瘤生长和腹膜播散。此外，共同接种的M2巨噬细胞赋予化疗耐药性的腹膜播散小鼠模型，这显着缩短了他们的survival.ConclusionIntraperitoneal肿瘤相关的巨噬细胞可能发挥重要作用，通过EMT诱导胰腺癌的腹膜播散和化疗耐药性的促进。
BackgroundThe peritoneum is one of the most frequent metastatic sites in pancreatic cancer patients, and peritoneal dissemination makes this disease refractory due to aggressive progression and chemoresistance. Although the role of the tumor microenvironment in cancer development is recognized, the correlation between the peritoneal environment and refractoriness of peritoneal dissemination remains unclear. The intraperitoneal tumor-microenvironment and its potential role in the progression of peritoneal dissemination and chemo-refractoriness, focusing especially on macrophages, were investigated.Materials and methodsPeritoneal washes were obtained from pancreatic cancer patients, and cellular components were subjected to immunofluorescence assays. The effects of macrophages induced from monocytic THP-1 cells on pancreatic cancer cells were examined in co-culture conditions. The in vivo effects of macrophages on tumor growth and chemo-sensitivity were investigated by subcutaneously or intraperitoneally co-injecting cancer cells with macrophages into mice.ResultsCD204-positive macrophages were present along with cancer cells in the peritoneal washes. In in vitro co-culture, tumor-associated macrophages affected pancreatic cancer cells, induced the epithelial-to-mesenchymal transition (EMT), and made them more resistant to chemotherapeutic agents. M2 macrophages promoted growth of both subcutaneous tumors and peritoneal dissemination in mice. Furthermore, co-inoculation of M2 macrophages conferred chemoresistance in the peritoneal dissemination mouse model, which significantly shortened their survival.ConclusionIntraperitoneal tumor-associated macrophages potentially play an important role in promotion of peritoneal dissemination and chemoresistance of pancreatic cancer via EMT induction.