C3a elicits unique migratory responses in immature low-density neutrophils

Hsu, Brian; Roy, Joannie; Mouhanna, Jack; Rayes, Roni F.; Ramsay, LeeAnn; Tabariès, Sébastien; Annis, Matthew G.; Watson, Ian R.; Spicer, Jonathan; Costantino, Santiago; Siegel, Peter M.

doi:10.1038/s41388-020-1169-8

Cited by 22 publications

(20 citation statements)

References 47 publications

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“…Our observations are supported by a recent study by Hsu et al, in which, compared to NDN, LDN were reported to more efficiently accumulate in the livers of mice bearing metastatic lesions [48]. However, while we noted that tumor-derived conditioned media strongly affected both NDN and LDN migration (Figure 2D and E), Hsu et al reported that media derived from liver-metastatic breast cancer cells only impacted the migration of LDN, but not of NDN [48]. We believe that our contrasting results could be due to the different methods that were used to assess neutrophil migration (i.e., Boyden chamber vs. under-agarose migration assay), as well as due to the different secretions of chemokines and soluble factors in the tumor media used in the studies (i.e., primary tumor vs. metastatic cancer cells-conditioned media).…”

Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 90%

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Tumor-Derived Factors Differentially Affect the Recruitment and Plasticity of Neutrophils

Arpinati

Kaisar-Iluz

Shaul

et al. 2021

Cancers

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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’ 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.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 90%

Tumor-Derived Factors Differentially Affect the Recruitment and Plasticity of Neutrophils

Arpinati

Kaisar-Iluz

Shaul

et al. 2021

Cancers

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“…Complement has a complex, context-dependent role in cancer, promoting or suppressing tumor growth depending on the cancer type [40]. Little is known about the crosstalk between coagulation and complement in cancer, but the local production of C3a may recruit inflammatory cells, such as PMNs [41]. In a context of complement activation, these cells might further activate coagulation [42].…”

Section: Polymorphonuclear Cells (Pmns)mentioning

confidence: 99%

Coagulome and the tumor microenvironment: an actionable interplay

et al. 2022

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HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

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“…These events were correlated with N2 neutrophil polarization and increased tumor growth (30). Interestingly, it has recently been shown that immature neutrophils preferentially respond to cancer cell derived C3a to promote their migration (31). Subsequently, it was shown that breast cancer cells that expressed high levels of G-CSF and IL-1β exhibited high neutrophil counts and tumor-associated thrombosis, which was dependent on NET formation (32).…”

Section: Neutrophil Functions That Promote Primary Tumor Growthmentioning

confidence: 98%

Neutrophils: Orchestrators of the Malignant Phenotype

2020

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Neutrophils are the first leukocytes recruited to sites of inflammation, where they execute anti-microbial functions to eliminate infectious agents. These functions include phagocytosis, release of reactive oxygen species and the formation of neutrophil extracellular traps via NETosis. Neutrophils are receiving increasing attention in the context of cancer, where these same neutrophil-associated functions are also important for modulating tumor growth and metastatic progression. Neutrophils are phenotypically heterogeneous and, depending on the context, exert anti-or pro-tumorigenic functions. Increasing evidence also suggests an important role of neutrophils and their involvement in promoting multiple steps of the metastatic cascade. The steps include: (1) local invasion and intravasation of cancer cells into circulation, (2) survival of cancer cells in the bloodstream and extravasation at a distant site, (3) early cancer cell seeding/survival, and (4) progressive growth of cancer cells to form macroscopic metastases. Although neutrophil functions designed to eliminate infectious agents can also eliminate tumor cells, their dysregulation can promote tumor growth and enable metastasis at multiple steps along the metastatic cascade. In this review, we will provide an overview of the current advances in neutrophil biology in the context of cancer. We also discuss the emerging field of immunometabolism, in which the rewiring of alternative metabolic pathways within neutrophils can impact their pro-tumorigenic/pro-metastatic functions.

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C3a elicits unique migratory responses in immature low-density neutrophils

Cited by 22 publications

References 47 publications

Tumor-Derived Factors Differentially Affect the Recruitment and Plasticity of Neutrophils

Tumor-Derived Factors Differentially Affect the Recruitment and Plasticity of Neutrophils

Coagulome and the tumor microenvironment: an actionable interplay

Neutrophils: Orchestrators of the Malignant Phenotype

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