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肿瘤起始细胞诱导 Cxcr4 介导的促肿瘤巨噬细胞浸润大脑。

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

机构信息

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.

Centre for Integrative Biology (CIBIO), University of Trento, Trento, Italy.

出版信息

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

DOI:10.7554/eLife.31918
PMID:29465400
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5821457/
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 () 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.

摘要

现在已经清楚的是，小胶质细胞和巨噬细胞存在于脑肿瘤中，但它们是否以及如何影响肿瘤的发生和发展尚不清楚。利用斑马鱼（）模型的优势，我们发现巨噬细胞和小胶质细胞在大脑中的癌基因激活后立即作出反应。在幼鱼斑马鱼的神经细胞中过表达人 AKT1，会导致巨噬细胞和小胶质细胞群体显著增加。通过使用转基因和突变斑马鱼系的组合，我们表明这种增加是由 Sdf1b-Cxcr4b 信号介导的外周巨噬细胞浸润到大脑中引起的。有趣的是，共聚焦活细胞成像揭示了巨噬细胞/小胶质细胞与前瘤细胞之间高度动态的相互作用，但不会导致前瘤细胞的吞噬。最后，耗尽巨噬细胞和小胶质细胞会导致致癌细胞增殖的显著减少。因此，巨噬细胞和小胶质细胞在肿瘤微环境发育的最早阶段就表现出促进肿瘤的功能。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7997/5821457/47027b3e7be9/elife-31918-fig8.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7997/5821457/93aa03408b4e/elife-31918-fig6.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7997/5821457/47027b3e7be9/elife-31918-fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7997/5821457/ee787ef3c497/elife-31918-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7997/5821457/ee7a9360bd9b/elife-31918-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7997/5821457/2991ffc99322/elife-31918-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7997/5821457/52345a7bdf4c/elife-31918-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7997/5821457/eff23c52f96d/elife-31918-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7997/5821457/209bdf616570/elife-31918-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7997/5821457/19fe01ac4509/elife-31918-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7997/5821457/f9074f707e20/elife-31918-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7997/5821457/93aa03408b4e/elife-31918-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7997/5821457/8f29a503a332/elife-31918-fig7.jpg
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