Inflamed neutrophils sequestered at entrapped tumor cells via chemotactic confinement promote tumor cell extravasation
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...
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| Format: | Article |
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Proceedings of the National Academy of Sciences
2019
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| Online Access: | http://hdl.handle.net/1721.1/120579 https://orcid.org/0000-0001-5418-5133 https://orcid.org/0000-0001-5215-6777 https://orcid.org/0000-0003-4682-9677 https://orcid.org/0000-0001-7603-8396 https://orcid.org/0000-0002-7232-304X |
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| author | Chen, Michelle B Hajal, Cynthia Benjamin, David Colin Yu, Cathy Y. Azizgolshani, Hesham Hynes, Richard O Kamm, Roger Dale |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Chen, Michelle B Hajal, Cynthia Benjamin, David Colin Yu, Cathy Y. Azizgolshani, Hesham Hynes, Richard O Kamm, Roger Dale |
| author_sort | Chen, Michelle B |
| collection | MIT |
| description | 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. Keywords: metastasis; inflammation; neutrophils; extravasation; cell migration |
| first_indexed | 2024-09-23T14:47:52Z |
| format | Article |
| id | mit-1721.1/120579 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T14:47:52Z |
| publishDate | 2019 |
| publisher | Proceedings of the National Academy of Sciences |
| record_format | dspace |
| spelling | mit-1721.1/1205792022-10-01T22:32:52Z Inflamed neutrophils sequestered at entrapped tumor cells via chemotactic confinement promote tumor cell extravasation Chen, Michelle B Hajal, Cynthia Benjamin, David Colin Yu, Cathy Y. Azizgolshani, Hesham Hynes, Richard O Kamm, Roger Dale Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Mechanical Engineering Koch Institute for Integrative Cancer Research at MIT Chen, Michelle B Hajal, Cynthia Benjamin, David Colin Yu, Cathy Y. Azizgolshani, Hesham Hynes, Richard O Kamm, Roger Dale 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. Keywords: metastasis; inflammation; neutrophils; extravasation; cell migration 2019-02-28T18:56:55Z 2019-02-28T18:56:55Z 2018-05 2017-09 2019-02-08T18:03:20Z Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/120579 Chen, Michelle B. et al. “Inflamed Neutrophils Sequestered at Entrapped Tumor Cells via Chemotactic Confinement Promote Tumor Cell Extravasation.” Proceedings of the National Academy of Sciences 115, 27 (June 2018): 7022–7027 © 2018 National Academy of Sciences https://orcid.org/0000-0001-5418-5133 https://orcid.org/0000-0001-5215-6777 https://orcid.org/0000-0003-4682-9677 https://orcid.org/0000-0001-7603-8396 https://orcid.org/0000-0002-7232-304X http://dx.doi.org/10.1073/PNAS.1715932115 Proceedings of the National Academy of Sciences Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Proceedings of the National Academy of Sciences PNAS |
| spellingShingle | Chen, Michelle B Hajal, Cynthia Benjamin, David Colin Yu, Cathy Y. Azizgolshani, Hesham Hynes, Richard O Kamm, Roger Dale Inflamed neutrophils sequestered at entrapped tumor cells via chemotactic confinement promote tumor cell extravasation |
| title | Inflamed neutrophils sequestered at entrapped tumor cells via chemotactic confinement promote tumor cell extravasation |
| title_full | Inflamed neutrophils sequestered at entrapped tumor cells via chemotactic confinement promote tumor cell extravasation |
| title_fullStr | Inflamed neutrophils sequestered at entrapped tumor cells via chemotactic confinement promote tumor cell extravasation |
| title_full_unstemmed | Inflamed neutrophils sequestered at entrapped tumor cells via chemotactic confinement promote tumor cell extravasation |
| title_short | Inflamed neutrophils sequestered at entrapped tumor cells via chemotactic confinement promote tumor cell extravasation |
| title_sort | inflamed neutrophils sequestered at entrapped tumor cells via chemotactic confinement promote tumor cell extravasation |
| url | http://hdl.handle.net/1721.1/120579 https://orcid.org/0000-0001-5418-5133 https://orcid.org/0000-0001-5215-6777 https://orcid.org/0000-0003-4682-9677 https://orcid.org/0000-0001-7603-8396 https://orcid.org/0000-0002-7232-304X |
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