Inflamed neutrophils sequestered at entrapped tumor cells via chemotactic confinement promote tumor cell extravasation
Open accessAbstract
Systemic inflammation occurring around the course of tumor progression and treatment are often correlated with adverse oncological outcomes. As such, it is suspected that neutrophils, the first line of defense against infection, may play important roles in linking inflammation and metastatic seeding. To decipher the dynamic roles of inflamed neutrophils during hematogenous dissemination, we employ a multiplexed microfluidic model of the human microvasculature enabling physiologically relevant transport of circulating cells combined with real-time, high spatial resolution observation of heterotypic cell-cell interactions. LPS-stimulated neutrophils (PMNs) and tumor cells (TCs) form heterotypic aggregates under flow, and arrest due to both mechanical trapping and neutrophil-endothelial adhesions. Surprisingly, PMNs are not static following aggregation, but exhibit a confined migration pattern near TC-PMN clusters. We discover that PMNs are chemotactically confined by self-secreted IL-8 and tumor-derived CXCL-1, which are immobilized by the endothelial glycocalyx. This results in significant neutrophil sequestration with arrested tumor cells, leading to the spatial localization of neutrophil-derived IL-8, which also contributes to increasing the extravasation potential of adjacent tumor cells through modulation of the endothelial barrier. Strikingly similar migration patterns and extravasation behaviors were also observed in an in vivo zebrafish model upon PMN-tumor cell coinjection into the embryo vasculature. These insights into the temporal dynamics of intravascular tumor-PMN interactions elucidate the mechanisms through which inflamed neutrophils can exert proextravasation effects at the distant metastatic site.
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Inflammatory neutrophils introduced in a microvascular network model increased tumor-cell extravasation.
“Also, inflammatory neutrophils were introduced in this model, which again increased tumor-cell extravasation [105].”
From Cancer-on-chip models for metastasis: importance of the tumor microenvironment (2024) · cites this paper as [105]
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- Authors
- Chen, M. B., Hajal, C., Benjamin, D. C., Yu, C., Azizgolshani, H., Hynes, R. O., & Kamm, R. D.
- Affiliations
- Massachusetts Institute of Technology (US)
- Koch Institute for Integrative Cancer Research At MIT (US)
- Howard Hughes Medical Institute (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2018-06-18
- Volume
- 115
- Issue
- 27
- Pages
- 7022-7027
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6142213
- OpenAlex
- W2808372201
- Cited by
- 183
- References
- 31
- Citations by year
- 2026: 13 · 2025: 21 · 2024: 23 · 2023: 20 · 2022: 30 · 2021: 31 · 2020: 30 · 2019: 11 · 2018: 3
- FWCI
- 7.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- HHS | NIH | National Cancer Institute (CA202177)
- Topics
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- tumor cell extravasation, interleukin-8, CXCL1, endothelial glycocalyx, neutrophil sequestration, tumor microenvironment, systemic inflammation, metastasis, endothelial barrier, neutrophil-endothelial adhesion
- MeSH terms
- Animals, Chemotaxis, Humans, Lipopolysaccharides, Neoplasm Proteins, Neoplasms, Neutrophils, Zebrafish, Interleukin-8, Animals, Genetically Modified, Cell Line, Tumor, Microfluidic Analytical Techniques, Chemokine CXCL1
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