Tumor initiating cells induce Cxcr4-mediated infiltration of pro-tumoral macrophages into the brain.
Tumor initiating cells induce Cxcr4-mediated infiltration of pro-tumoral macrophages into the brain.
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DOI：
10.7554/elife.31918
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发表时间：
2018-02-21
期刊：
影响因子：
7.7
通讯作者：
Sieger D
中科院分区：
文献类型：
--
作者：
Chia K;Mazzolini J;Mione M;Sieger D
现在已经清楚，小胶质细胞和巨噬细胞存在于脑肿瘤中，但它们是否或如何影响肿瘤的发生和发展尚不清楚。利用斑马鱼（Danio rerio）模型的优势，我们发现巨噬细胞和小胶质细胞对大脑中的癌基因激活立即做出反应。人类 AKT1 在斑马鱼幼虫神经细胞内的过度表达导致巨噬细胞和小胶质细胞数量显着增加。通过使用转基因和突变斑马鱼系的组合，我们发现这种增加是由 Sdf1b-Cxcr4b 信号传导介导的外周巨噬细胞浸润到大脑中引起的。有趣的是，共焦实时成像揭示了巨噬细胞/小胶质细胞和肿瘤前细胞之间高度动态的相互作用，这不会导致肿瘤前细胞的吞噬作用。最后，巨噬细胞和小胶质细胞的消耗导致致癌细胞增殖显着减少。因此，巨噬细胞和小胶质细胞在肿瘤微环境发展的最早阶段就已经显示出肿瘤促进功能。脑肿瘤可能具有侵袭性、难以治疗并且通常无法治愈。通过手术切除脑肿瘤可能具有挑战性，因为肿瘤细胞会渗入健康组织。脑肿瘤在与其他细胞（例如免疫系统细胞）密切接触的情况下生长。这包括巨噬细胞和小胶质细胞，它们通常可以保护我们免受伤害和感染。然而，巨噬细胞和小胶质细胞实际上并没有像人们想象的那样对抗肿瘤，而是支持脑肿瘤的生长。目前尚不清楚在脑肿瘤的发展过程中巨噬细胞和小胶质细胞如何以及何时开始帮助肿瘤细胞生长。该领域之前的研究主要集中在脑肿瘤中预先发现的这些细胞类型。奇亚等人。现在研究了肿瘤发展的最早阶段，监测巨噬细胞和小胶质细胞对癌细胞的反应。为了模仿人类脑肿瘤，Chia 等人。在斑马鱼幼虫的神经细胞中表达了一种促进癌症的人类蛋白质。这些细胞开始表现得像早期肿瘤细胞。活体显微镜显示肿瘤细胞吸引巨噬细胞和小胶质细胞进入其区域，并且它们还激活免疫细胞。生化实验表明，早期肿瘤细胞会产生并释放一种名为 Sdf1 的蛋白质。巨噬细胞和小胶质细胞通过细胞表面一种名为 Cxcr4 的蛋白质来感知环境中的 Sdf1。当斑马鱼中的 Cxcr4 基因被删除时，巨噬细胞和小胶质细胞就不会被招募到正在发育的肿瘤中。当斑马鱼幼虫中的巨噬细胞和小胶质细胞被耗尽时，带有突变蛋白的神经细胞生长得不太好，这支持了免疫细胞促进早期肿瘤发展的观点。更好地了解肿瘤细胞和免疫细胞在大脑中如何相互作用可能有助于寻找新的抗癌药物。此外，当肿瘤在治疗后复发时，巨噬细胞和小胶质细胞被招募到肿瘤细胞的方式可能是相似的。未来的研究将检验这一假设，如果它被证明是正确的，干扰巨噬细胞和小胶质细胞的反应可能会延缓肿瘤的复发。
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. Brain tumors can be aggressive, difficult to treat and are often incurable. Removing brain tumors by surgery can be challenging because the tumor cells infiltrate into the healthy tissue. Brain tumors grow in close physical contact with other cells, such as cells of the immune system. This includes cells called macrophages and microglia, which normally defend us against injuries and infections. However, instead of acting against the tumor as one might expect, macrophages and microglia actually support the growth of brain tumors. It is not clear how and when during the development of a brain tumor the macrophages and microglia start helping the tumor cells to grow. Previous studies in this area have focused on these cell types found in advance brain tumors. Chia et al. have now looked at the earliest stages of tumor development, monitoring how macrophages and microglia respond to cancer cells. To mimic human brain tumors, Chia et al. expressed a cancer-promoting version of a human protein in nerve cells of zebrafish larvae. These cells started behaving like early tumor cells. Live microscopy revealed that the tumor cells attract macrophages and microglia into their area, and that they also activate the immune cells. Biochemical experiments showed that the early tumor cells make and release a protein called Sdf1. Macrophages and microglia sense Sdf1 in the environment with a protein called Cxcr4 on their cell surfaces. When the gene for Cxcr4 was deleted in the zebrafish, the macrophages and microglia were not recruited into the developing tumors. When macrophages and microglia were depleted from the zebrafish larvae, the nerve cells with the mutant protein grew less well, supporting the idea that the immune cells enhance the development of early tumors. A better understanding of how tumor cells and immune cells interact in the brain may help in the search for new anti-cancer drugs. Furthermore, the way in which macrophages and microglia are recruited to the tumor cells could be similar when tumors return after treatment. Future studies will test this hypothesis and, if it proves true, interfering with the macrophage and microglia response might delay the relapse of tumors.