Acidity promotes tumour progression by altering macrophage phenotype in prostate cancer
Acidity promotes tumour progression by altering macrophage phenotype in prostate cancer
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DOI：
10.1038/s41416-019-0542-2
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发表时间：
2019-10-01
影响因子：
8.8
通讯作者：
Gillies, Robert
中科院分区：
文献类型：
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作者：
El-Kenawi, Asmaa;Gatenbee, Chandler;Gillies, Robert
背景：即使在氧气存在的情况下，肿瘤也能迅速将葡萄糖发酵成乳酸，并且高糖酵解与低灌注的耦合导致细胞外酸化。我们假设酸度，独立于乳酸，可以增加巨噬细胞的原肿瘤表型。方法：我们分析了人类前列腺癌的公开数据，以寻找巨噬细胞标志物和糖酵解基因之间的线性相关性。在一系列的体外实验中，我们使用两性离子缓冲液来调节pH。然后，我们利用在C57BL/6小鼠中建立的皮下和转基因肿瘤模型以及计算机模拟来将肿瘤进展与巨噬细胞浸润联系起来，并描述酸度的作用。结果：通过基因表达、细胞因子谱分析和功能分析，在pH 6.8下激活巨噬细胞可增强il -4驱动的表型。这些结果在体内得到了概括，在前列腺癌的TRAMP模型中，中和瘤内酸度降低了巨噬细胞的原肿瘤表型，同时也降低了肿瘤的发病率和侵袭。这些结果使用模拟巨噬细胞对环境信号反应的计算机数学模型进行了概括。通过关闭酸诱导的细胞反应，我们的计算机数学模型显示耐酸巨噬细胞可以限制肿瘤的进展。结论：本研究提示肿瘤酸性通过改变巨噬细胞激活状态促进前列腺癌的发生。
BACKGROUND: Tumours rapidly ferment glucose to lactic acid even in the presence of oxygen, and coupling high glycolysis with poor perfusion leads to extracellular acidification. We hypothesise that acidity, independent from lactate, can augment the protumour phenotype of macrophages.METHODS: We analysed publicly available data of human prostate cancer for linear correlation between macrophage markers and glycolysis genes. We used zwitterionic buffers to adjust the pH in series of in vitro experiments. We then utilised subcutaneous and transgenic tumour models developed in C57BL/6 mice as well as computer simulations to correlate tumour progression with macrophage infiltration and to delineate role of acidity.RESULTS: Activating macrophages at pH 6.8 in vitro enhanced an IL-4-driven phenotype as measured by gene expression, cytokine profiling, and functional assays. These results were recapitulated in vivo wherein neutralising intratumoural acidity reduced the protumour phenotype of macrophages, while also decreasing tumour incidence and invasion in the TRAMP model of prostate cancer. These results were recapitulated using an in silico mathematical model that simulate macrophage responses to environmental signals. By turning off acid-induced cellular responses, our in silico mathematical modelling shows that acid-resistant macrophages can limit tumour progression.CONCLUSIONS: This study suggests that tumour acidity contributes to prostate carcinogenesis by altering the state of macrophage activation.