Al-Haidari Amr A, Algethami Nader, Lepsenyi Mattias, Rahman Milladur, Syk Ingvar, Thorlacius Henrik
Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, 20502 Malmö, Sweden.
Oncotarget. 2019 Feb 8;10(12):1238-1249. doi: 10.18632/oncotarget.26664.
Cytoreductive surgery is the only curative option for patients with peritoneal carcinomatosis, however, intraperitoneal recurrence rate is high making new ways to prevent cancer recurrence an urgent need. Recent evidence suggests that neutrophils are involved in cancer progression. The purpose of our study was to examine the role of neutrophils in the spread of colon cancer cells in the peritoneal cavity. The number of metastatic noduli in the peritoneal cavity was quantified in mice injected with murine colon cancer cells (CT-26) intraperitoneally after surgical laparotomy and treated with a neutrophil depleting antibody or DNase I. In addition, peritoneal metastases were harvested from patients with peritoneal carcinomatosis. Scanning and transmission electron microscopy showed extensive neutrophil extracellular trap (NET) formation in peritoneal colon cancer metastases in mice and patients. Neutrophil depletion markedly reduced the number of metastases in laparotomised animals. Administration of DNase I decreased the number of metastatic nodules by 88% in laparotomised animals as well as NET-induced chemokine-dependent colon cancer cell migration and adhesion . Finally, CT-26 cancer cells were found to express the αβ integrin and inhibition of αv integrin abolished NET-induced adhesion of colon cancer cells to vitronectin. Taken together, our data show that NETs play an important role in colon cancer cell metastasis in the peritoneal cavity and regulate colon cancer cell migration and adhesion to extracellular matrix proteins. These novel findings suggest that targeting NETs might be an effective strategy to antagonize intrabdominal recurrences of colon cancer after cytoreductive surgery in patients with peritoneal carcinomatosis.
细胞减灭术是腹膜癌患者唯一的治愈选择，然而，腹腔内复发率很高，因此迫切需要新的方法来预防癌症复发。最近的证据表明，中性粒细胞参与癌症进展。我们研究的目的是探讨中性粒细胞在结肠癌细胞腹腔播散中的作用。在手术剖腹术后向小鼠腹腔注射鼠结肠癌细胞（CT-26），并用中性粒细胞清除抗体或脱氧核糖核酸酶I处理，然后对腹腔内转移结节的数量进行定量。此外，从腹膜癌患者中获取腹膜转移灶。扫描电子显微镜和透射电子显微镜显示，在小鼠和患者的腹膜结肠癌转移灶中存在广泛的中性粒细胞胞外陷阱（NET）形成。中性粒细胞清除显著减少了剖腹动物的转移灶数量。在剖腹动物中，给予脱氧核糖核酸酶I可使转移结节数量减少88%，同时也减少了NET诱导的趋化因子依赖性结肠癌细胞迁移和黏附。最后，发现CT-26癌细胞表达αβ整合素，抑制αv整合素可消除NET诱导的结肠癌细胞与玻连蛋白的黏附。综上所述，我们的数据表明，NETs在结肠癌细胞腹腔转移中起重要作用，并调节结肠癌细胞向细胞外基质蛋白的迁移和黏附。这些新发现表明，针对NETs可能是一种有效的策略，可对抗腹膜癌患者细胞减灭术后结肠癌的腹腔内复发。
