Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
Minimally Invasive Therapy Center, Okayama University Hospital, Okayama, Japan.
J Exp Clin Cancer Res. 2018 Dec 11;37(1):307. doi: 10.1186/s13046-018-0981-2.
The 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.
Peritoneal 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.
CD204-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.
Intraperitoneal tumor-associated macrophages potentially play an important role in promotion of peritoneal dissemination and chemoresistance of pancreatic cancer via EMT induction.
腹膜是胰腺癌患者最常见的转移部位之一，由于进展迅速且对化疗药物耐药，腹膜扩散使该疾病难以治疗。虽然肿瘤微环境在癌症发展中的作用已得到认可，但腹膜环境与腹膜扩散的耐药性之间的相关性尚不清楚。本研究聚焦于巨噬细胞，探讨了腹膜内肿瘤微环境及其在腹膜扩散和化疗耐药进展中的潜在作用。
从胰腺癌患者的腹腔冲洗液中获取细胞成分，并进行免疫荧光检测。在共培养条件下，研究了源自单核细胞 THP-1 细胞的巨噬细胞对胰腺癌细胞的影响。通过将巨噬细胞与癌细胞一起皮下或腹腔内注射到小鼠中，研究了巨噬细胞对肿瘤生长和化疗敏感性的体内影响。
在腹腔冲洗液中，CD204 阳性巨噬细胞与癌细胞共存。在体外共培养中，肿瘤相关巨噬细胞影响胰腺癌细胞，诱导上皮间质转化（EMT），并使其对化疗药物更具耐药性。M2 巨噬细胞促进了小鼠皮下肿瘤和腹膜扩散的生长。此外，M2 巨噬细胞共接种赋予了腹膜扩散小鼠模型化疗耐药性，显著缩短了它们的存活时间。
腹膜内肿瘤相关巨噬细胞通过 EMT 诱导，可能在促进胰腺癌腹膜扩散和化疗耐药性方面发挥重要作用。
