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Neutrophil Extracellular Traps Promote the Development and Progression of Liver Metastases after Surgical Stress

中性粒细胞胞外陷阱 手术应激 医学 转移 癌症 癌症研究 炎症 结直肠癌 内科学 免疫学 病理
作者
Samer Tohme,Hamza O. Yazdani,Ahmed B. Al‐Khafaji,Alexis P. Chidi,Patricia Loughran,Kerri Mowen,Yanming Wang,Richard L. Simmons,Hai Huang,Allan Tsung
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:76 (6): 1367-1380 被引量:653
标识
DOI:10.1158/0008-5472.can-15-1591
摘要

Abstract Risks of tumor recurrence after surgical resection have been known for decades, but the mechanisms underlying treatment failures remain poorly understood. Neutrophils, first-line responders after surgical stress, may play an important role in linking inflammation to cancer progression. In response to stress, neutrophils can expel their protein-studded chromatin to form local snares known as neutrophil extracellular traps (NET). In this study, we asked whether, as a result of its ability to ensnare moving cells, NET formation might promote metastasis after surgical stress. Consistent with this hypothesis, in a cohort of patients undergoing attempted curative liver resection for metastatic colorectal cancer, we observed that increased postoperative NET formation was associated with a >4-fold reduction in disease-free survival. In like manner, in a murine model of surgical stress employing liver ischemia-reperfusion, we observed an increase in NET formation that correlated with an accelerated development and progression of metastatic disease. These effects were abrogated by inhibiting NET formation in mice through either local treatment with DNAse or inhibition of the enzyme peptidylarginine deaminase, which is essential for NET formation. In growing metastatic tumors, we found that intratumoral hypoxia accentuated NET formation. Mechanistic investigations in vitro indicated that mouse neutrophil–derived NET triggered HMGB1 release and activated TLR9-dependent pathways in cancer cells to promote their adhesion, proliferation, migration, and invasion. Taken together, our findings implicate NET in the development of liver metastases after surgical stress, suggesting that their elimination may reduce risks of tumor relapse. Cancer Res; 76(6); 1367–80. ©2016 AACR.
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