Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress
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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.
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NETs have been directly associated with the initiation and induction of tumor invasion, aiding metastasis.
“recently, through increasing evidence, NETs have been directly associated with the initiation and induction of tumor invasion, aiding metastasis [20, 33–36].”
HMGB1 released during NET formation may drive proliferation and migration of cancer cells.
“HMGB1 released during NET formation may drive proliferation and migration of cancer cells (12).”
From Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps (2016) · cites this paper as [12]
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- Authors
- Tohme, S., Yazdani, H. O., Al-Khafaji, A. B., Chidi, A. P., Loughran, P., Mowen, K., Wang, Y., Simmons, R. L., Huang, H., & Tsung, A.
- Affiliations
- University of Pittsburgh Medical Center (US)
- 1Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
- Scripps Research Institute (US)
- Pennsylvania State University (US)
- Wuhan Union Hospital (CN)
- Corresponding author
- Tsung, Allan
- ORCID
- Venue
- Cancer Research
- Published
- 2016-03-14
- Volume
- 76
- Issue
- 6
- Pages
- 1367-1380
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC4794393
- OpenAlex
- W2237361742
- Cited by
- 694
- References
- 46
- Citations by year
- 2026: 52 · 2025: 72 · 2024: 79 · 2023: 90 · 2022: 89 · 2021: 109 · 2020: 65 · 2019: 47 · 2018: 38 · 2017: 33 · 2016: 18
- FWCI
- 27.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1s10od019973-01)
- National Cancer Institute (R01CA136856, T32CA113263)
- National Institute of General Medical Sciences (R01-GM95566, R01GM095566)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Cancer, Stress, Anesthesia, and Immune Response
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- neutrophil extracellular traps, liver metastasis, surgical stress, metastatic colorectal cancer, hepatectomy, tumor recurrence, HMGB1, TLR9, intratumoral hypoxia, neutrophils, DNase
- MeSH terms
- Animals, Cell Adhesion, Cell Movement, Humans, Liver, Mice, Inbred C57BL, Neoplasm Metastasis, Neoplasm Recurrence, Local, Neutrophils, Disease Progression, HMGB1 Protein, Cell Proliferation, Toll-Like Receptor 9, Mice, Extracellular Traps
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