Tumor progression stage and anatomical site regulate tumor-associated macrophage and bone marrow-derived monocyte polarization Journal Article


Authors: Redente, E. F.; Dwyer-Nield, L. D.; Merrick, D. T.; Raina, K.; Agarwal, R.; Pao, W.; Rice, P. L.; Shroyer, K. R.; Malkinson, A. M.
Article Title: Tumor progression stage and anatomical site regulate tumor-associated macrophage and bone marrow-derived monocyte polarization
Abstract: Tumor-associated macrophages (TAMs) encourage and coordinate neoplastic growth. In late stage human lung adenocarcinoma, TAMs exhibited mixed M1 (classical; argIlowiNOShigh) and M2 (alternative; argIhighiNOSlow) polarization based on arginine metabolism. In several murine cancer models including chemically and genetically-induced primary lung tumors, prostate tumors, colon xenografts, and lung metastases, TAMs expressed argIhighiNOSlow early during tumor formation; argIlowiNOShigh polarization also occurred during malignancy in some models. In a chemically-induced lung tumor model, macrophages expressed argIhighiNOSlow within one week after carcinogen treatment, followed by similar polarization of bone marrow-derived monocytes (BDMCs) a few days later. TAMs surrounding murine prostate tumors also expressed argIhighiNOSlow early during tumorigenesis, indicating that this polarization is not unique to neoplastic lungs. In a human colon cancer xenograft model, the primary tumor was surrounded by argIhighiNOSlow-expressing TAMs, and BDMCs also expressed argIhighiNOSlow, but pulmonary macrophages adopted argIhighiNOSlow polarization only after tumors metastasized to the lungs. Persistence of tumors is required to maintain TAM polarization. Indeed, in both conditional mutant Kras- and FGF10-driven models of lung cancer, mice expressing the transgene develop lung tumors that regress rapidly when the transgene is silenced. Furthermore, pulmonary macrophages expressed argIhighiNOSlow on tumor induction, but then returned to argIlow iNOSlow (no polarization) after tumors regressed. Manipulating TAM function or depleting TAMs may provide novel therapeutic strategies for preventing and treating many types of cancer. Copyright © American Society for Investigative Pathology.
Keywords: clinical article; controlled study; human tissue; nonhuman; neoplasms; tumor associated leukocyte; animal cell; mouse; phenotype; animals; mice; cancer prevention; bone marrow; animal model; lung cancer; tumor xenograft; cancer model; carcinogenesis; prostate cancer; mice, inbred strains; disease progression; colon cancer; transgene; cell polarity; interferon-gamma; oncogene k ras; monocyte; monocytes; tumor growth; disease models, animal; k ras protein; polarization; lung alveolus macrophage; macrophages, alveolar; interleukin-4; fibroblast growth factor 10; inosinate dehydrogenase; neoplasms subdivided by anatomical site; bronchoalveolar lavage fluid
Journal Title: American Journal of Pathology
Volume: 176
Issue: 6
ISSN: 0002-9440
Publisher: Elsevier Science, Inc.  
Date Published: 2010-06-01
Start Page: 2972
End Page: 2985
Language: English
DOI: 10.2353/ajpath.2010.090879
PUBMED: 20431028
PROVIDER: scopus
PMCID: PMC2877857
DOI/URL:
Notes: --- - "Cited By (since 1996): 2" - "Export Date: 20 April 2011" - "CODEN: AJPAA" - "Source: Scopus"
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  1. William Pao
    141 Pao