Scientific article
OA Policy
English

Origins of tumor-associated macrophages and neutrophils

Publication date2012-02-14
First online date2012-01-30
Abstract

Tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) can control cancer growth and exist in almost all solid neoplasms. The cells are known to descend from immature monocytic and granulocytic cells, respectively, which are produced in the bone marrow. However, the spleen is also a recently identified reservoir of monocytes, which can play a significant role in the inflammatory response that follows acute injury. Here, we evaluated the role of the splenic reservoir in a genetic mouse model of lung adenocarcinoma driven by activation of oncogenic Kras and inactivation of p53. We found that high numbers of TAM and TAN precursors physically relocated from the spleen to the tumor stroma, and that recruitment of tumor-promoting spleen-derived TAMs required signaling of the chemokine receptor CCR2. Also, removal of the spleen, either before or after tumor initiation, reduced TAM and TAN responses significantly and delayed tumor growth. The mechanism by which the spleen was able to maintain its reservoir capacity throughout tumor progression involved, in part, local accumulation in the splenic red pulp of typically rare extramedullary hematopoietic stem and progenitor cells, notably granulocyte and macrophage progenitors, which produced CD11b(+) Ly-6C(hi) monocytic and CD11b(+) Ly-6G(hi) granulocytic cells locally. Splenic granulocyte and macrophage progenitors and their descendants were likewise identified in clinical specimens. The present study sheds light on the origins of TAMs and TANs, and positions the spleen as an important extramedullary site, which can continuously supply growing tumors with these cells.

Keywords
  • Animals
  • Humans
  • Macrophages / immunology
  • Mice
  • Neoplasms / immunology
  • Neoplasms / pathology
  • Neutrophils / immunology
  • Spleen / immunology
  • Spleen / pathology
Affiliation entities Not a UNIGE publication
Funding
  • NIAID NIH HHS [R01 AI084880]
  • NINDS NIH HHS [R01 NS072167]
  • NHLBI NIH HHS [R01 HL095612]
  • NCI NIH HHS [U54 CA126515]
Citation (ISO format)
CORTEZ-RETAMOZO, Virna et al. Origins of tumor-associated macrophages and neutrophils. In: Proceedings of the National Academy of Sciences of the United States of America, 2012, vol. 109, n° 7, p. 2491–2496. doi: 10.1073/pnas.1113744109
Main files (1)
Article (Published version)
Identifiers
Additional URL for this publicationhttps://pnas.org/doi/full/10.1073/pnas.1113744109
Journal ISSN0027-8424
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