Causes, consequences, and therapy of tumors acidosis

Smitha R. Pillai, Mehdi Damaghi, Yoshinori Marunaka, Enrico Pierluigi Spugnini, Stefano Fais, Robert J. Gillies

Research output: Contribution to journalReview articlepeer-review

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.

Original languageEnglish
Pages (from-to)205-222
Number of pages18
JournalCancer and Metastasis Reviews
Volume38
Issue number1-2
DOIs
Publication statusPublished - Jun 15 2019

Keywords

  • Anti-acidic therapy
  • Cancer
  • Exosomes
  • Microenvironment acidity

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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