title: Neutrophil Extracellular Traps Promote the Development and Progression of Liver Metastases after Surgical Stress.
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.
authors.affiliation: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Samer
authors.initials: S
authors.lastname: Tohme
authors.affiliation: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Hamza O
authors.initials: HO
authors.lastname: Yazdani
authors.affiliation: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Ahmed B
authors.initials: AB
authors.lastname: Al-Khafaji
authors.affiliation: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Alexis P
authors.initials: AP
authors.lastname: Chidi
authors.affiliation: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Center for Biologic Imaging, Department of Cell Biology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Patricia
authors.initials: P
authors.lastname: Loughran
authors.affiliation: Department of Pharmacology and Department of Chemical Physiology, Scripps Research Institute, La Jolla, California.
authors.forename: Kerri
authors.initials: K
authors.lastname: Mowen
authors.affiliation: Department of Biochemistry & Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania.
authors.forename: Yanming
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Simmons
authors.affiliation: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Department of Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, P.R. China.
authors.forename: Hai
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. tsunga@upmc.edu.
authors.forename: Allan
authors.initials: A
authors.lastname: Tsung
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D018450:Disease Progression; D065206:Extracellular Traps / Q000378:metabolism / Q000502:physiology*; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000473:pathology*; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology*; D051217:Toll-Like Receptor 9 / Q000378:metabolism
chemical_list: D024243:HMGB1 Protein; D051217:Toll-Like Receptor 9