{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T20:02:45Z","timestamp":1791576165008,"version":"4.3.4"},"reference-count":61,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2021,10,11]],"date-time":"2021-10-11T00:00:00Z","timestamp":1633910400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sasson and Luisa Naor Fund","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ) and Israel\u2019s Ministry of Science and Technology (MOST)","award":["CA2656"],"award-info":[{"award-number":["CA2656"]}]},{"name":"Israel Lung Association","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["259332240\/RTG 2099"],"award-info":[{"award-number":["259332240\/RTG 2099"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Neutrophils play a key role in cancer biology. In contrast to circulating normal-density neutrophils (NDN), the amount of low-density neutrophils (LDN) significantly increases with tumor progression. The correlation between these neutrophil subpopulations and intratumoral neutrophils (TANs) is still under debate. Using 4T1 (breast) and AB12 (mesothelioma) tumor models, we aimed to elucidate the source of TANs and to assess the mechanisms driving neutrophils\u2019 plasticity in cancer. Both NDN and LDN were found to migrate in response to CXCL1 and CXCL2 exposure, and co-infiltrate the tumor site ex vivo and in vivo, although LDN migration into the tumor was higher than NDN. Tumor-derived factors and chemokines, particularly CXCL1, were found to drive neutrophil phenotypical plasticity, inducing NDN to transition towards a low-density state (LD-NDN). LD-NDN appeared to differ from NDN by displaying a phenotypical profile similar to LDN in terms of nuclear morphology, surface receptor markers, decreased phagocytic abilities, and increased ROS production. Interestingly, all three subpopulations displayed comparable cytotoxic abilities towards tumor cells. Our data suggest that TANs originate from both LDN and NDN, and that a portion of LDN derives from NDN undergoing phenotypical changes. NDN plasticity resulted in a change in surface marker expression and functional activity, gaining characteristics of LDN.<\/jats:p>","DOI":"10.3390\/cancers13205082","type":"journal-article","created":{"date-parts":[[2021,10,11]],"date-time":"2021-10-11T21:45:32Z","timestamp":1633988732000},"page":"5082","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Tumor-Derived Factors Differentially Affect the Recruitment and Plasticity of Neutrophils"],"prefix":"10.3390","volume":"13","author":[{"given":"Ludovica","family":"Arpinati","sequence":"first","affiliation":[{"name":"Hadassah Medical Center, Institute of Pulmonary Medicine, Faculty of Medicine, Hebrew University of Jerusalem, P.O. Box 12000, Jerusalem 9112001, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi","family":"Kaisar-Iluz","sequence":"additional","affiliation":[{"name":"Hadassah Medical Center, Institute of Pulmonary Medicine, Faculty of Medicine, Hebrew University of Jerusalem, P.O. Box 12000, Jerusalem 9112001, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merav E.","family":"Shaul","sequence":"additional","affiliation":[{"name":"Hadassah Medical Center, Institute of Pulmonary Medicine, Faculty of Medicine, Hebrew University of Jerusalem, P.O. Box 12000, Jerusalem 9112001, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Groth","sequence":"additional","affiliation":[{"name":"German Cancer Research Center (DKFZ), Skin Cancer Unit, 69120 Heidelberg, Germany"},{"name":"Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, 68167 Mannheim, Germany"},{"name":"Medical Faculty Mannheim, Mannheim Institute for Innate Immunoscience (MI3), University of Heidelberg, 68167 Mannheim, Germany"},{"name":"Department for Immunobiochemistry, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany"},{"name":"European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0259-1839","authenticated-orcid":false,"given":"Viktor","family":"Umansky","sequence":"additional","affiliation":[{"name":"German Cancer Research Center (DKFZ), Skin Cancer Unit, 69120 Heidelberg, Germany"},{"name":"Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, 68167 Mannheim, Germany"},{"name":"Medical Faculty Mannheim, Mannheim Institute for Innate Immunoscience (MI3), University of Heidelberg, 68167 Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zvi G.","family":"Fridlender","sequence":"additional","affiliation":[{"name":"Hadassah Medical Center, Institute of Pulmonary Medicine, Faculty of Medicine, Hebrew University of Jerusalem, P.O. Box 12000, Jerusalem 9112001, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/nri3399","article-title":"Neutrophil Recruitment and Function in Health and Inflammation","volume":"13","author":"Kolaczkowska","year":"2013","journal-title":"Nat. Rev. Immunol"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e12943","DOI":"10.1111\/eci.12943","article-title":"Neutrophil Phenotypes in Health and Disease","volume":"48","author":"Hellebrekers","year":"2018","journal-title":"Eur. J. Clin. 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