Abstract
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 αvβ3 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.
Highlights
C Scanning and transmission electron microscopy showed extensive neutrophil extracellular trap (NET) formation in peritoneal colon cancer metastases in mice and patients
We observed that peritoneal metastasis of colon cancer cells was associated with formation of extracellular fibrillar and web-like structures in the tumors compatible with NETs (Figure 2A). It was found using transmission immunoelectron microscopy that the neutrophil-derived granule protein elastase and citrullinated histone 3 co-localized with the extracellular DNA in these extracellular fibrillar and web-like structures (Figure 2B), showing that NETs are formed in peritoneal metastases
We the ROI shared by fluorescence and electron microscopy, used a mouse model with intraperitoneal administration revealing that NETs co-localize with CT-26-green fluorescent protein (GFP) cells of colon cancer cells after laparotomy causing a midline and that DNase I reduced NETs formation in peritoneal incisional wound
Summary
Cytoreductive surgery is the only curative option for patients with peritoneal carcinomatosis, intraperitoneal recurrence rate is high making new ways to. T 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. A nodules by 88% in laparotomised animals as well as NET-induced chemokinedependent colon cancer cell migration and adhesion in vitro. 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. T strategy to antagonize intrabdominal recurrences of colon cancer after cytoreductive surgery in patients with peritoneal carcinomatosis
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