Tumor initiating cells induce Cxcr4-mediated infiltration of pro-tumoral macrophages into the brain

Elife. 2018 Feb 21:7:e31918. doi: 10.7554/eLife.31918.


It is now clear that microglia and macrophages are present in brain tumors, but whether or how they affect initiation and development of tumors is not known. Exploiting the advantages of the zebrafish (Danio rerio) model, we showed that macrophages and microglia respond immediately upon oncogene activation in the brain. Overexpression of human AKT1 within neural cells of larval zebrafish led to a significant increase in the macrophage and microglia populations. By using a combination of transgenic and mutant zebrafish lines, we showed that this increase was caused by the infiltration of peripheral macrophages into the brain mediated via Sdf1b-Cxcr4b signaling. Intriguingly, confocal live imaging reveals highly dynamic interactions between macrophages/microglia and pre-neoplastic cells, which do not result in phagocytosis of pre-neoplastic cells. Finally, depletion of macrophages and microglia resulted in a significant reduction of oncogenic cell proliferation. Thus, macrophages and microglia show tumor promoting functions already during the earliest stages of the developing tumor microenvironment.

Keywords: brain tumor; cancer biology; immunology; inflammation; live imaging; macrophages; microglia; tumor microenvironment; zebrafish.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Brain Neoplasms / pathology*
  • Cell Movement*
  • Chemokine CXCL12 / metabolism
  • Disease Models, Animal
  • Humans
  • Macrophages / physiology*
  • Neoplastic Stem Cells / physiology*
  • Neuroglia / physiology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, CXCR4 / metabolism*
  • Signal Transduction
  • Zebrafish
  • Zebrafish Proteins / metabolism*


  • CXCR4b protein, zebrafish
  • Chemokine CXCL12
  • Receptors, CXCR4
  • Zebrafish Proteins
  • cxcl12a protein, zebrafish
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt