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Cellular and molecular identity of tumor-associated macrophages in glioblastoma

Item Type:Article
Title:Cellular and molecular identity of tumor-associated macrophages in glioblastoma
Creators Name:Chen, Z. and Feng, X. and Herting, C.J. and Alvarez Garcia, V. and Nie, K. and Pong, W.W. and Rasmussen, R. and Dwivedi, B. and Seby, S. and Wolf, S.A. and Gutmann, D.H. and Hambardzumyan, D.
Abstract:In glioblastoma (GBM), tumor-associated macrophages (TAM) represent up to one half of the cells of the tumor mass, including both infiltrating macrophages and resident brain microglia. In an effort to delineate the temporal and spatial dynamics of TAM composition during gliomagenesis, we employed two genetically engineered mouse models where oncogenic drivers and fluorescent reporters were expressed coordinately under the control of the monocyte/microglia-selective Cx3cr1 or Ccr2 promoters, respectively. Using this approach, we demonstrated that CX3CR1LoCCR2Hi monocytes were recruited to the glioblastoma, where they transitioned to CX3CR1HiCCR2Lo macrophages and CX3CR1HiCCR2- microglia-like cells. Infiltrating macrophages/monocytes constituted ~85% of the total TAM population, with resident microglia accounting for the ~15% remaining. Bone marrow-derived infiltrating macrophages/monocytes were recruited to the tumor early during GBM initiation, where they localized preferentially to perivascular areas. In contrast, resident microglia were localized mainly to peritumoral regions. RNA-sequencing analyses revealed differential gene expression patterns unique to infiltrating and resident cells, suggesting unique functions for each TAM population. Notably, limiting monocyte infiltration via Ccl2 genetic ablation prolonged the survival of tumor-bearing mice. Our findings illuminate the unique composition and functions of infiltrating and resident myeloid cells in GBM, establishing a rationale to target infiltrating cells in this neoplasm.
Keywords:Malignant Glioma, Microglia, Inflammatory Monocytes, CCR2, CX3CR1, Animals, Mice
Source:Cancer Research
ISSN:0008-5472
Publisher:American Association for Cancer Research (U.S.A.)
Volume:77
Number:9
Page Range:2266-2278
Date:1 May 2017
Official Publication:https://doi.org/10.1158/0008-5472.CAN-16-2310
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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