文章：

肿瘤酸中毒：从乘客到驾驶员

Tumour acidosis: from the passenger to the driver's seat

原文发布日期：2017-09-15

DOI: 10.1038/nrc.2017.77

类型: Review Article

开放获取: 否

要点：

1. In contrast to healthy tissues, the extracellular pH of tumours is generally acidic, while the intracellular pH is slightly alkaline.
2. Exacerbated glycolysis and respiration through hydration of CO₂ contribute to the release of H⁺ ions in the tumour microenvironment, making gradients of acidosis and hypoxia non-overlapping.
3. Tumour acidosis induces a shift from HIF1α-driven glycolytic metabolism towards the metabolism of glutamine and lipids as preferred sources of energy and biosynthetic intermediates.
4. Adaptation of cancer cells to acidosis requires transcriptional (for example, HIF2α induction), post-translational (for example, changes in protein acetylation) and morphological alterations (for example, mitochondria elongation with an increase in cristae numbers).
5. Acidosis-driven tumour progression is promoted by a reduction in immunosurveillance and changes in lysosome biology that support invasiveness and autophagy.
6. Tumour acidosis can be targeted by drugs interfering with H⁺ or bicarbonate transporters, neutralized by systemic buffer administration or exploited using pH-sensitive drug-delivery systems.

要点翻译：

1. 与健康组织相比，肿瘤的细胞外pH值通常呈酸性，而细胞内pH值则呈弱碱性。
2. 糖酵解加剧和二氧化碳水合作用带来的呼吸增强，促使肿瘤微环境中H+离子释放，导致酸中毒和低氧梯度并不重叠。
3. 肿瘤酸中毒诱导细胞从HIF1α驱动的糖酵解代谢转向以谷氨酰胺和脂质作为优先能量来源及生物合成中间体的代谢模式。
4. 癌细胞对酸中毒的适应需要转录层面（如HIF2α诱导）、翻译后层面（如蛋白质乙酰化变化）和形态学层面（如线粒体伸长伴随嵴数量增加）的调整。
5. 酸中毒驱动的肿瘤进展通过免疫监视减弱和溶酶体生物学变化（促进侵袭性和自噬）得以加速。
6. 针对肿瘤酸中毒可通过以下方式干预：使用干扰H+或碳酸氢盐转运体的药物、通过全身性缓冲剂中和酸度、或利用pH敏感型药物递送系统进行靶向治疗。

英文摘要：

The high metabolic demand of cancer cells leads to an accumulation of H+ ions in the tumour microenvironment. The disorganized tumour vasculature prevents an efficient wash-out of H+ ions released into the extracellular medium but also favours the development of tumour hypoxic regions associated with a shift towards glycolytic metabolism. Under hypoxia, the final balance of glycolysis, including breakdown of generated ATP, is the production of lactate and a stoichiometric amount of H+ ions. Another major source of H+ ions results from hydration of CO2 produced in the more oxidative tumour areas. All of these events occur at high rates in tumours to fulfil bioenergetic and biosynthetic needs. This Review summarizes the current understanding of how H+-generating metabolic processes segregate within tumours according to the distance from blood vessels and inversely how ambient acidosis influences tumour metabolism, reducing glycolysis while promoting mitochondrial activity. The Review also presents novel insights supporting the participation of acidosis in cancer progression via stimulation of autophagy and immunosuppression. Finally, recent advances in the different therapeutic modalities aiming to either block pH-regulatory systems or exploit acidosis will be discussed.

摘要翻译： 

癌细胞的高代谢需求导致肿瘤微环境中H⁺离子的积聚。肿瘤血管结构紊乱，不仅阻碍了释放到细胞外介质中的H⁺离子被有效清除，还促进了肿瘤缺氧区域的形成，这些区域与向糖酵解代谢的转变相关。在缺氧条件下，糖酵解的最终产物，包括ATP的分解，是乳酸和等摩尔的H⁺离子。另一个H⁺离子的主要来源是来源于氧化性较强的肿瘤区域产生的CO₂的水合反应。所有这些事件在肿瘤中以高速率发生，以满足生物能量和生物合成的需求。本综述总结了当前关于H⁺生成代谢过程如何根据与血管的距离在肿瘤内分布的理解，以及环境酸中毒如何反过来影响肿瘤代谢，抑制糖酵解同时促进线粒体活性。综述还提出了新的见解，支持酸中毒通过刺激自噬和免疫抑制参与癌症进展。最后，将讨论在阻断pH调节系统或利用酸中毒的不同治疗方式方面的最新进展。

原文链接：

Tumour acidosis: from the passenger to the driver's seat