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Causes, consequences, and therapy of tumors acidosis

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Abstract

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.

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Funding

This work was supported by the Anticancer Fund (RJG), US PHS NIH grants R01 CA077575 (RJG), U54 CA193489 (RJG), and the Florida Health grant 8BC04 (SRP/RJG); the Italian Ministry of Health (SF); and Grants-in-Aid from Japan Society of the Promotion of Science, JSPS KAKENHI grant numbers JP15K15034 and 18H03182 (YM).

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  1. Department of Cancer Physiology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., Tampa, FL, 33602, USA

    Smitha R. Pillai, Mehdi Damaghi & Robert J. Gillies

  2. Research Institute for Clinical Physiology, Kyoto, 604-8472, Japan

    Yoshinori Marunaka

  3. Research Center for Drug Discovery and Pharmaceutical Development Science, Research Organization of Science and Technology, Ritsumeikan University, Kusatsu, 525-8577, Japan

    Yoshinori Marunaka

  4. Department of Molecular Cell Physiology, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan

    Yoshinori Marunaka

  5. SAFU, Regina Elena Cancer Institute, Via delle Messi d’ Oro 156, Rome, Italy

    Enrico Pierluigi Spugnini

  6. Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità (National Institute of Health), Viale Regina Elena, 299, 00161, Rome, Italy

    Stefano Fais

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  1. Smitha R. Pillai
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Dr. Gillies reports a COI with Helix Biopharma, with whom he is a consultant and investor.

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Pillai, S.R., Damaghi, M., Marunaka, Y. et al. Causes, consequences, and therapy of tumors acidosis. Cancer Metastasis Rev 38, 205–222 (2019). https://doi.org/10.1007/s10555-019-09792-7

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