PUBLICATION

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

Authors
Chia, K., Mazzolini, J., Mione, M., Sieger, D.
ID
ZDB-PUB-180223-52
Date
2018
Source
eLIFE   7: (Journal)
Registered Authors
Mione, Marina, Sieger, Dirk
Keywords
brain tumor, cancer biology, immunology, inflammation, live imaging, macrophages, microglia, tumor microenvironment, zebrafish
MeSH Terms
  • Neuroglia/physiology
  • Neoplastic Stem Cells/physiology*
  • Chemokine CXCL12/metabolism
  • Zebrafish Proteins/metabolism*
  • Humans
  • Receptors, CXCR4/metabolism*
  • Brain Neoplasms/pathology*
  • Proto-Oncogene Proteins c-akt/metabolism
  • Animals
  • Signal Transduction
  • Disease Models, Animal
  • Macrophages/physiology*
  • Cell Movement*
  • Animals, Genetically Modified
  • Zebrafish
(all 15)
PubMed
29465400 Full text @ Elife
Abstract
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.
Genes / Markers
Marker Marker Type Name
cxcl12aGENEchemokine (C-X-C motif) ligand 12a (stromal cell-derived factor 1)
cxcl12bGENEchemokine (C-X-C motif) ligand 12b (stromal cell-derived factor 1)
cxcr4bGENEchemokine (C-X-C motif), receptor 4b
irf8GENEinterferon regulatory factor 8
mifGENEmacrophage migration inhibitory factor
mpeg1.1GENEmacrophage expressed 1, tandem duplicate 1
p2ry12GENEpurinergic receptor P2Y12
1 - 7 of 7
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Figures
Figure Gallery (9 images)
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Expression
No data available
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
ed7TgTransgenic Insertion
    gl22TgTransgenic Insertion
      gl23TgTransgenic Insertion
        hdb3TgTransgenic Insertion
          st95
            Small Deletion
            t26035
              Point Mutation
              1 - 6 of 6
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              Human Disease / Model
              No data available
              Sequence Targeting Reagents
              No data available
              Fish
              No data available
              Antibodies
              Name Type Antigen Genes Isotypes Host Organism
              Ab1-akt1polyclonal
                IgGRabbit
                Ab2-cxcr4bpolyclonal
                  IgGRabbit
                  Ab3-sox2polyclonalIgGRabbit
                  Ab-4C4monoclonal
                    IgG1Mouse
                    Ab7-syppolyclonal
                      IgGRabbit
                      Ab9-pcnapolyclonal
                        IgGRabbit
                        1 - 6 of 6
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                        Orthology
                        No data available
                        Engineered Foreign Genes
                        Marker Marker Type Name
                        EGFPEFGEGFP
                        GFPEFGGFP
                        mCherryEFGmCherry
                        1 - 3 of 3
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                        Mapping
                        No data available