Neutrophils facilitate ovarian cancer premetastatic niche formation in the omentum
Open accessAbstract
Ovarian cancer preferentially metastasizes to the omentum, a fatty tissue characterized by immune structures called milky spots, but the cellular dynamics that direct this tropism are unknown. Here, we identified that neutrophil influx into the omentum is a prerequisite premetastatic step in orthotopic ovarian cancer models. Ovarian tumor-derived inflammatory factors stimulated neutrophils to mobilize and extrude chromatin webs called neutrophil extracellular traps (NETs). NETs were detected in the omentum of ovarian tumor-bearing mice before metastasis and of women with early-stage ovarian cancer. NETs, in turn, bound ovarian cancer cells and promoted metastasis. Omental metastasis was decreased in mice with neutrophil-specific deficiency of peptidylarginine deiminase 4 (PAD4), an enzyme that is essential for NET formation. Blockade of NET formation using a PAD4 pharmacologic inhibitor also decreased omental colonization. Our findings implicate NET formation in rendering the premetastatic omental niche conducive for implantation of ovarian cancer cells and raise the possibility that blockade of NET formation prevents omental metastasis.
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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].”
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- Authors
- Lee, W., Ko, S. Y., Mohamed, M. S., Kenny, H. A., Lengyel, E., & Naora, H.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- University of Chicago (US)
- Corresponding author
- Naora, Honami
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2018-12-19
- Volume
- 216
- Issue
- 1
- Pages
- 176-194
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC6314534
- OpenAlex
- W2904189039
- Cited by
- 478
- References
- 67
- Citations by year
- 2026: 39 · 2025: 77 · 2024: 87 · 2023: 63 · 2022: 80 · 2021: 62 · 2020: 49 · 2019: 20 · 2018: 1
- FWCI
- 14.08
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- MD Anderson Cancer Center (NCI CA16672)
- National Institutes of Health (CA217931, CA207034, CA169604)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Health Sciences › Medicine › Reproductive Medicine › Ovarian cancer diagnosis and treatment
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- ovarian cancer, omental metastasis, pre-metastatic niche, neutrophils, neutrophil extracellular traps, PAD4, milky spots, tumor cell adhesion, metastasis prevention
- MeSH terms
- Protein-Arginine Deiminase Type 4, Animals, Female, Humans, Hydrolases, Mice, Nude, Neoplasm Metastasis, Neoplasms, Experimental, Neutrophils, Omentum, Ovarian Neoplasms, Peritoneal Neoplasms, Cell Line, Tumor, Mice, Extracellular Traps
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