Aerobic glycolysis and high level of lactate in cancer metabolism and microenvironment

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Abstract

Metabolic abnormalities is a hallmark of cancer. About 100 years ago, Nobel laureate Otto Heinrich Warburg first described high rate of glycolysis in cancer cells. Recently more and more novel opinions about cancer metabolism supplement to this hypothesis, consist of glucose uptake, lactic acid generation and secretion, acidification of the microenvironment and cancer immune evasion. Here we briefly review metabolic pathways generating lactate, and discuss the function of higher lactic acid in cancer microenvironments.

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Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes.

Arianna Calcinotto, Paola Filipazzi, Matteo Grioni … (2012)

Stimulating the effector functions of tumor-infiltrating T lymphocytes (TIL) in primary and metastatic tumors could improve active and adoptive T-cell therapies for cancer. Abnormal glycolysis, high lactic acid production, proton accumulation, and a reversed intra-extracellular pH gradient are thought to help render tumor microenvironments hostile to roving immune cells. However, there is little knowledge about how acidic microenvironments affect T-cell immunity. Here, we report that lowering the environmental pH to values that characterize tumor masses (pH 6-6.5) was sufficient to establish an anergic state in human and mouse tumor-specific CD8(+) T lymphocytes. This state was characterized by impairment of cytolytic activity and cytokine secretion, reduced expression of IL-2Rα (CD25) and T-cell receptors (TCR), and diminished activation of STAT5 and extracellular signal-regulated kinase (ERK) after TCR activation. In contrast, buffering pH at physiologic values completely restored all these metrics of T-cell function. Systemic treatment of B16-OVA-bearing mice with proton pump inhibitors (PPI) significantly increased the therapeutic efficacy of both active and adoptive immunotherapy. Our findings show that acidification of the tumor microenvironment acts as mechanism of immune escape. Furthermore, they illustrate the potential of PPIs to safely correct T-cell dysfunction and improve the efficacy of T-cell-based cancer treatments. ©2012 AACR

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Tumor-derived lactic acid modulates dendritic cell activation and antigen expression.

Eva Gottfried, Leoni A. Kunz-Schughart, Stephanie Ebner … (2006)

The tumor milieu can influence dendritic cell (DC) differentiation. We analyzed DC differentiation in a 3-dimensional tumor model and propose a new mechanism of DC modulation by the tumor environment. Monocytes were cultured in the presence of IL-4 and GM-CSF within multicellular tumor spheroids (MCTSs) generated from different tumor cell lines. Monocytes invaded the MCTSs and differentiated into tumor-associated dendritic cells (TADCs). The antigen expression was altered on TADCs independent of the culture conditions (immature/mature DCs, Langerhans cells) and IL-12 secretion was reduced. Supernatants of MCTSs could partially transfer the suppressive effect. Conditioned media from urothelial carcinoma cell lines contained high levels of M-CSF and IL-6, both cytokines known to modulate DC differentiation. In contrast, melanoma and prostate carcinoma MCTS cocultures produced little M-CSF and IL-6, but high levels of lactic acid. Indeed, addition of lactic acid during DC differentiation in vitro induced a phenotype comparable with TADCs generated within melanoma and prostate carcinoma MCTSs. Blocking of lactic acid production in melanoma MCTS cocultures reverted the TADC phenotype to normal. We therefore conclude that tumor-derived lactic acid is an important factor modulating the DC phenotype in the tumor environment, which may critically contribute to tumor escape mechanisms.

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The effects of extracellular pH on immune function.

A Lardner (2001)

The effect of alterations in extracellular pH on cellular and humoral immune function is reviewed. Because acidic pH predominates at inflammatory loci and other sites of immune activity, most studies to date focus on the effect of acidic rather than alkaline pH. Investigations on polymorphonuclear leukocytes demonstrate mainly inhibition of chemotaxis, respiratory activity, and bactericidal capacity at reduced pH. Evidence of impaired lymphocyte cytotoxicity and proliferation at acidic pH is also beginning to emerge. Many of the clinical acidoses are accompanied similarly by immunodeficiency. Studies on macrophages and eosinophils are few and inconclusive. A small number of studies demonstrate acid-induced activation of complement proteins and the alternative complement pathway, plus increased antibody-binding to leukocytes at lowered pH. A differential effect of acidic pH on humoral and cellular immunity may, therefore, exist. Increasing recognition of the significance of extracellular pH in relation to immune function warrants further studies in this presently incomplete but rewarding field.

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Author and article information

Journal

Journal ID (nlm-ta): Genes Dis

Journal ID (iso-abbrev): Genes Dis

Title: Genes & Diseases

Publisher: Chongqing Medical University

ISSN (Electronic): 2352-3042

Publication date PMC-release: 14 February 2017

Publication date Collection: March 2017

Publication date (Electronic): 14 February 2017

Volume: 4

Issue: 1

Pages: 25-27

Affiliations

[1]Department of Oncology, Avis General Hospital, Beijing, China

Article

Publisher ID: S2352-3042(17)30010-7

DOI: 10.1016/j.gendis.2017.02.003

PMC ID: 6136593

PubMed ID: 30258905

SO-VID: a8ee17c8-9f68-485a-9d53-1a0540d52fa0

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Aerobic glycolysis and high level of lactate in cancer metabolism and microenvironment

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Abstract

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Genes & Diseases

Most cited references 18

Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes.

Tumor-derived lactic acid modulates dendritic cell activation and antigen expression.

The effects of extracellular pH on immune function.

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