Neutrophil extracellular traps promote peritoneal metastasis of colon cancer cells.
Neutrophil extracellular traps promote peritoneal metastasis of colon cancer cells.
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DOI：
10.18632/oncotarget.26664
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发表时间：
2019-02-08
期刊：
影响因子：
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通讯作者：
Thorlacius, Henrik
中科院分区：
文献类型：
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作者：
Al-Haidari, Amr A;Algethami, Nader;Thorlacius, Henrik
肿瘤细胞减灭术是腹膜癌转移患者的唯一治疗选择，然而，腹膜内复发率很高，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的进展。本研究的目的是研究中性粒细胞在结肠癌细胞在腹膜腔中扩散中的作用。在外科剖腹手术后腹膜内注射鼠结肠癌细胞（CT-26）并用嗜中性粒细胞消耗抗体或DNA酶I处理的小鼠中，定量腹膜腔中转移性结节的数量。此外，从腹膜癌病患者中收集腹膜转移瘤。扫描和透射电子显微镜显示，广泛的中性粒细胞胞外陷阱（NET）形成腹膜结肠癌转移的小鼠和患者。中性粒细胞耗竭显著减少了剖腹动物的转移瘤数量。DNase I的管理减少了88%的转移性结节的数量在剖腹动物以及NET诱导的趋化因子依赖性结肠癌细胞的迁移和粘附在体外。最后，发现CT-26癌细胞表达α v β 3整联蛋白，α v整联蛋白的抑制消除了NET诱导的结肠癌细胞与玻连蛋白的粘附。总之，我们的数据表明，NET在结肠癌细胞在腹膜腔中的转移中起重要作用，并调节结肠癌细胞的迁移和粘附到细胞外基质蛋白。这些新的发现表明，靶向NET可能是一种有效的策略，以拮抗腹腔癌转移患者的细胞减灭术后结肠癌的腹腔内复发。
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 in vitro. Finally, CT-26 cancer cells were found to express the alphavbeta3 integrin and inhibition of alphav 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.