Acidity of Microenvironment as a Further Driver of Tumor Metabolic Reprogramming

Abstract

In the last decade, experimental research has intensely focused on metabolic reprogramming of tumor cells, which contributes to cancer cell adaptation and survival in different and hostile microenvironments. Metabolic reprogramming consists of the switch of tumor cells from aerobic or anaerobic glycolysis to oxidative phosphorylation. A comprehensive vision of the metabolic scenario involving functionally different tumor cell subpopulations was proposed as a necessary premise to the design of new strategies of diagnosis and therapy. Special focus has been put on the role of acidosis of certain tumor regions, a very important although frequently neglected aspect.Despite the progresses in cancer therapy, the escaping of tumor cancer cells from host defense and relapse of disease still represent main issues in tumor-bearing patients. Indeed, malignant cells are provided with a tremendous plasticity that they exploit to survive, replicate and invade in stressed microenvironments. Such plasticity allows cancer cells to easily modify their properties, including metabolism, switching back and forth from aerobic or anaerobic glycolysis to oxidative phosphorylation (OxPhos). It is well ascertained that a suitable metabolic profile of cancer cells is necessary to sustain tumor growth, local invasion and distant colonization. Thus, cancer metabolism needs to be considered in view of the design of new strategies to control tumor progression.Keywords: "Warburg effect"; Glucose level; Hypoxia; Hypoxiainducible factor-1α; Acidosis; Oxidative phosphorylation Tumor Microenvironment and Metabolic Reprogramming of Tumor Cells Warburg effectProliferating tumor cells have been largely shown to adopt "aerobic glycolysis" as the main metabolic profile, the so-called "Warburg effect" [1]. Indeed, most cancer cells use huge amounts of glucose even when oxygen tension is high enough to sustain mitochondrial respiration in normal cells. A link between oncogenesis and glucose metabolism is the activating mutations in phosphoinositide 3-kinase (PI3K) or overexpression of the AKT oncogenes, promoting expression and localization of the high affinity glucose transporters on the plasma membrane [2]. This is followed by lactic acid fermentation in the cytosol and lactate export from the cell [3]. This alteration of glucose metabolism acquired practical importance in clinical settings following the development of 18-fluorodeoxyglucose-positron emission tomography imaging [4,5]. Furthermore, it is well recognized that a high serum level of lactate dehydrogenase (LDH) represents a biomarker of poor prognosis in different cancers [6].When Warburg metabolism is favored, a relatively low level of pyruvate is metabolized in the mitochondria and the energy gain is only 2 ATP per molecule of glucose. Thus, fermentation of glucose to lactic acid is an inefficient pathway, but, very important, it is a fast energy supplier (about 100 folds faster than OxPhos). Moreover, the aerobic glycolytic phenotype confers a significant proliferative advantage a...

Potential Role of HLA Class I Antigens in the Glycolytic Metabolism and Motility of Melanoma Cells

“…In accordance with the elevation of PGC1α, MCT1, an additional Oxphos marker, was over-expressed. MCT1 promotes lactate influx which contributes to provide alternative sources of energy [4,5]. In addition, PDK1 depletion, although present only in HLA-B,C-specific mAb B1.23.2-treated A375-M6 melanoma cells, together with an increase of PDP2, might have a role in triggering a cellular phenotype associated with an enhanced oxygen consumption rate [18].…”

“…Glycolysis becomes the primary source of ATP and, combined to an enhanced glucose uptake, produces large quantities of secreted lactate and H + , reducing extracellular pH of tumors [3]. Acidity of extracellular microenvironment is associated with an enhancement of the aggressive phenotype of cancer cells and a metabolic adaptation to an oxidative phosphorylation [4,5]. Overall, the metabolic dynamic adaptation of tumor cells in different microenvironments represents one of the hallmarks of malignancy.…”

SOX2 as a novel contributor of oxidative metabolism in melanoma cells

“…Cancer cells are characterized by a deregulated metabolism since, unlike normal cells, they largely depend on glycolysis even in the presence of oxygen, a phenomenon referred to as “Warburg effect” or aerobic glycolysis [ 3 ]. Nevertheless, cancer metabolism does not exclusively depend on aerobic glycolysis.…”

“…In this respect, intermediate components of the glycolytic pathway appear to be more significant than its final product pyruvate. Given the limited pyruvate supply, to replenish the tricarboxylic acid cycle (TCA) cancer cells increase glutamine consumption, a key nutrient that provides carbon for acetyl-CoA, citrate production and lipogenesis, nitrogen for purine, pyrimidine and DNA synthesis, and reducing power in the form of NADPH to support cell proliferation [ 3 ]. The particular attitude of proliferating cancer cells to use aerobic glycolysis favors a microenvironment enriched in lactate and protons, with a subsequent pH reduction.…”

Diverse Stakeholders of Tumor Metabolism: An Appraisal of the Emerging Approach of Multifaceted Metabolic Targeting by 3-Bromopyruvate

“…Consequent pumping of these protons to the exterior causes the pH of the external milieu to reach the range of 6.5 to 6.9, designated as tumor acidosis (Damaghi et al, 2013). Interestingly, tumor acidosis also contributes to the manifestation of metabolic reprogramming of cancer cells (Peppicelli et al, 2017). Besides the significant contribution of accelerated metabolism in lowering pH, many other factors also contribute to the modulation of pH in cancer cells, which include, but is not limited to, hypoxia, hypercapnia, and a reduced diffusion of gases in the TME (Damaghi et al, 2013; Swietach et al, 2014; Damaghi et al, 2015).…”