Department of Cancer Physiology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., Tampa, FL, 33602, USA.
Research Institute for Clinical Physiology, Kyoto, 604-8472, Japan.
Cancer Metastasis Rev. 2019 Jun;38(1-2):205-222. doi: 10.1007/s10555-019-09792-7.
While cancer is commonly described as "a disease of the genes," it is also associated with massive metabolic reprogramming that is now accepted as a disease "Hallmark." This programming is complex and often involves metabolic cooperativity between cancer cells and their surrounding stroma. Indeed, there is emerging clinical evidence that interrupting a cancer's metabolic program can improve patients' outcomes. The most commonly observed and well-studied metabolic adaptation in cancers is the fermentation of glucose to lactic acid, even in the presence of oxygen, also known as "aerobic glycolysis" or the "Warburg Effect." Much has been written about the mechanisms of the Warburg effect, and this remains a topic of great debate. However, herein, we will focus on an important sequela of this metabolic program: the acidification of the tumor microenvironment. Rather than being an epiphenomenon, it is now appreciated that this acidosis is a key player in cancer somatic evolution and progression to malignancy. Adaptation to acidosis induces and selects for malignant behaviors, such as increased invasion and metastasis, chemoresistance, and inhibition of immune surveillance. However, the metabolic reprogramming that occurs during adaptation to acidosis also introduces therapeutic vulnerabilities. Thus, tumor acidosis is a relevant therapeutic target, and we describe herein four approaches to accomplish this: (1) neutralizing acid directly with buffers, (2) targeting metabolic vulnerabilities revealed by acidosis, (3) developing acid-activatable drugs and nanomedicines, and (4) inhibiting metabolic processes responsible for generating acids in the first place.
虽然癌症通常被描述为“一种基因疾病”，但它也与大规模的代谢重编程有关，而代谢重编程现在被认为是一种疾病的“标志性特征”。这种编程非常复杂，通常涉及癌细胞与其周围基质之间的代谢协作。事实上，越来越多的临床证据表明，中断癌症的代谢程序可以改善患者的预后。在癌症中最常见和研究最充分的代谢适应性是葡萄糖发酵为乳酸，即使在有氧气的情况下，也称为“有氧糖酵解”或“Warburg 效应”。关于 Warburg 效应的机制已经有很多文献报道，这仍然是一个争论的话题。然而，在这里，我们将重点关注这种代谢程序的一个重要后果：肿瘤微环境的酸化。现在人们认识到，这种酸中毒不再是一种偶然现象，而是癌症体细胞进化和恶性转化的关键因素。对酸中毒的适应会诱导和选择恶性行为，如增加侵袭和转移、化疗耐药性以及免疫监视抑制。然而，适应酸中毒过程中发生的代谢重编程也引入了治疗弱点。因此，肿瘤酸中毒是一个相关的治疗靶点，我们在本文中描述了四种实现这一目标的方法：（1）用缓冲剂直接中和酸，（2）靶向酸中毒揭示的代谢弱点，（3）开发酸激活药物和纳米药物，以及（4）抑制首先产生酸的代谢过程。
