Intravital 2-photon imaging reveals distinct morphology and infiltrative properties of glioblastoma-associated macrophages

Zhihong Chen, James L. Ross, Dolores Hambardzumyan

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

Characterized by a dismal survival rate and limited response to therapy, glioblastoma (GBM) remains one of the most aggressive human malignancies. Recent studies of the role of tumor-associated macrophages (TAMs) in the progression of GBMs have demonstrated that TAMs are significant contributors to tumor growth, invasion, and therapeutic resistance. TAMs, which include brain-resident microglia and circulating bone marrow derived-monocytes (BMDMs), are typically grouped together in histopathological and molecular analyses due to the lack of reliable markers of distinction. To develop more effective therapies aimed at specific TAM populations, we must first understand how these cells differ both morphologically and behaviorally. Furthermore, we must develop a deeper understanding of the mechanisms encouraging their infiltration and how these mechanisms can be therapeutically exploited. In this study, we combined immunocompetent lineage tracing mouse models of GBM with high-resolution open-skull 2-photon microscopy to investigate the phenotypical and functional characteristics of TAMs. We demonstrate that TAMs are composed of 2 morphologically distinct cell types that have differential migratory propensities. We show that BMDMs are smaller, minimally branched cells that are highly migratory compared with microglia, which are larger, highly branched stationary cells. In addition, 2 populations of monocytic macrophages were observed that differed in terms of CX3CR1 expression and migratory capacity. Finally, we demonstrate the efficacy of anti-vascular endothelial growth factor A blockade for prohibiting TAM infiltration, especially against BMDMs. Taken together, our data clearly define characteristics of individual TAM populations and suggest that combination therapy with antivas-cular and antichemotaxis therapy may be an attractive option for treating these tumors.

Original languageEnglish
Pages (from-to)14254-14259
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number28
DOIs
StatePublished - 2019
Externally publishedYes

Keywords

  • Glioblastoma
  • Macrophage
  • Microglia
  • Monocyte
  • Two-photon

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