BGI Education Center, University of Chinese Academy of Sciences, Shenzhen, 518083, China.
Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, 2100, Copenhagen, Denmark; Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, DK-2200, Copenhagen, Denmark.
Int J Biochem Cell Biol. 2020 Aug;125:105796. doi: 10.1016/j.biocel.2020.105796. Epub 2020 Jun 25.
pH gradient reversal refers to intracellular alkalization and extracellular acidification commonly seen in malignant tumors. To meet their high anabolic demand, cancer cells rewire their glucose metabolism from oxidative phosphorylation to lactate fermentation, which results in the excessive generation of protons. To avoid lethal cytosolic acidification, lactate-fermenting cancer cells activate multiple acid removal pathways leading to the acidification of the extracellular space. This acidification is often further intensified by the defective capacity of the disorganized tumor vasculature to dilute protons away from the cancer tissue. The cancer-specific proton equilibrium with highly alkaline cytosol and acidic extracellular space is emerging as a fundamental driving force for cancer growth. Here, we discuss how cancer cells establish and maintain reversed pH gradient, how pH gradient reversal fuels cancer progression, and how these mechanisms can be targeted in cancer therapy.
pH 梯度逆转是指恶性肿瘤中常见的细胞内碱化和细胞外酸化。为了满足其高合成代谢的需求，癌细胞将葡萄糖代谢从氧化磷酸化重编为乳酸发酵，这导致质子的过度产生。为了避免致命的细胞质酸化，进行乳酸发酵的癌细胞激活多种酸清除途径，导致细胞外空间酸化。这种酸化通常进一步加剧，原因是组织紊乱的肿瘤血管系统无法将质子从癌组织中稀释。具有高度碱性细胞质和酸性细胞外空间的癌症特异性质子平衡正成为癌症生长的基本驱动力。在这里，我们讨论癌细胞如何建立和维持 pH 梯度逆转，以及 pH 梯度逆转如何促进癌症进展，以及如何在癌症治疗中靶向这些机制。
