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.
Highlights
Microglia are the resident macrophages of the brain
We addressed the responses of macrophages and microglia to the earliest events of brain tumor growth
By using a combination of mutant and transgenic zebrafish lines, as well as immunohistochemistry for macrophages and microglia, we showed an immediate increase in the population of macrophage and microglia cells
Summary
Microglia are the resident macrophages of the brain (for review see [Kettenmann et al, 2011; Casano and Peri, 2015]). Recent work has highlighted the suitability of the larval zebrafish model to investigate brain tumor growth (Ju et al, 2014; Mayrhofer et al, 2017; Shin et al, 2012; Ju et al, 2015; Lal et al, 2012; Kitambi et al, 2014; Geiger et al, 2008; Lally et al, 2007); Yang et al, 2013; Jung et al, 2013; Hamilton et al (2016); Eden et al, 2015; Welker et al, 2016) We combined these advantages to study the responses of macrophages and microglia to early pre-neoplastic cells in the brain. By reducing the number of macrophages and microglia, we showed that these cells actively promote proliferation of the pre-neoplastic cells in the brain
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