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Author Notes:

Correspondence to: Dolores Hambardzumyan, email: hambard@ccf.org

CONTRIBUTIONS: X.F., F.S., Z.C., D.H., A.Y., Y.K., V.A.G., R.D.R., I.T. and H.Z. performed and analyzed experiments; X.L., H.K., R.R. and B.W. provided reagents; X.F. contributed to the design of the experiments; D.H. conceived, designed, and supervised the study, and wrote the manuscript.

All authors edited or commented on the manuscript.

Acknowledgments: The authors thank Drs. Jeognwu Lee and Erik Sulman for providing human GSC 827 and GSC7-11 cells, Bunny Cotleur for technical assistance with FACS analysis, Drs. Perul Kapil and Haiyan Lu for technical assistance in setting up tissue dissociation and percoll gradients, and Shannon Donnola and Paul Gambon for technical assistance with mice.

The authors also thank Dr. Cornelia Bergmann and Jennifer Powers for FACS sorting experiments. We are grateful to Dr. Bruce Lamb for active discussions.

Special thanks to Dr. Amy Nowacki for advice with appropriate statistical tests for several figures.

We also thank Drs. Bruce Trapp and Chris Nelson for critical reading of manuscript.

CONFLICTS OF INTEREST: There is no conflict of interest.

Subjects:

Research Funding:

This work was supported by National Institute of Health/National Cancer Institute (NIH/NCI grant# U01CA160882, DH, HK, FS, XF). David Heinzmann was supported by a research grant from the German Cardiac Society (DGK).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • Cell Biology
  • CX3CR1/CX3CL1 signaling
  • glioblastoma
  • microglia
  • monocyte
  • FRACTALKINE-RECEPTOR
  • STEM-CELLS
  • PERIVASCULAR NICHE
  • GLIOMA FORMATION
  • CANCER GENOMICS
  • TUMOR-GROWTH
  • GLIOBLASTOMA
  • MICROGLIA
  • MACROPHAGES
  • PROGRESSION

Loss of CX3CR1 increases accumulation of inflammatory monocytes and promotes gliomagenesis

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Journal Title:

Oncotarget

Volume:

Volume 6, Number 17

Publisher:

, Pages 15077-15094

Type of Work:

Article | Final Publisher PDF

Abstract:

The most abundant populations of non-neoplastic cells in the glioblastoma (GBM) microenvironment are resident microglia, macrophages and infiltrating monocytes from the blood circulation. The mechanisms by which monocytes infiltrate into GBM, their fate following infiltration, and their role in GBM growth are not known. Here we tested the hypothesis that loss of the fractalkine receptor CX3CR1 in microglia and monocytes would affect gliomagenesis. Deletion of Cx3cr1 from the microenvironment resulted in increased tumor incidence and shorter survival times in glioma-bearing mice. Loss of Cx3cr1 did not affect accumulation of microglia/ macrophages in peri-tumoral areas, but instead indirectly promoted the trafficking of CD11b+CD45hiCX3CR1lowLy-6ChiLy-6G-F4/80-/low circulating inflammatory monocytes into the CNS, resulting in their increased accumulation in the perivascular area. Cx3cr1- deficient microglia/macrophages and monocytes demonstrated upregulation of IL1β expression that was inversely proportional to Cx3cr1 gene dosage. The Proneural subgroup of the TCGA GBM patient dataset with high IL1β expression showed shorter survival compared to patients with low IL1β. IL1β promoted tumor growth and increased the cancer stem cell phenotype in murine and human Proneural glioma stem cells (GSCs). IL1β activated the p38 MAPK signaling pathway and expression of monocyte chemoattractant protein (MCP-1/CCL2) by tumor cells. Loss of Cx3cr1 in microglia in a monocyte-free environment had no impact on tumor growth and did not alter microglial migration. These data suggest that enhancing signaling to CX3CR1 or inhibiting IL1β signaling in intra-tumoral macrophages can be considered as potential strategies to decrease the tumor-promoting effects of monocytes in Proneural GBM.

Copyright information:

© 2015 Feng et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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