Tumor acidity: From hallmark of cancer to target of treatment

Abstract

Tumor acidity is one of the cancer hallmarks and is associated with metabolic reprogramming and the use of glycolysis, which results in a high intracellular lactic acid concentration. Cancer cells avoid acid stress major by the activation and expression of proton and lactate transporters and exchangers and have an inverted pH gradient (extracellular and intracellular pHs are acid and alkaline, respectively). The shift in the tumor acid–base balance promotes proliferation, apoptosis avoidance, invasiveness, metastatic potential, aggressiveness, immune evasion, and treatment resistance. For example, weak-base chemotherapeutic agents may have a substantially reduced cellular uptake capacity due to “ion trapping”. Lactic acid negatively affects the functions of activated effector T cells, stimulates regulatory T cells, and promotes them to express programmed cell death receptor 1. On the other hand, the inversion of pH gradient could be a cancer weakness that will allow the development of new promising therapies, such as tumor-targeted pH-sensitive antibodies and pH-responsible nanoparticle conjugates with anticancer drugs. The regulation of tumor pH levels by pharmacological inhibition of pH-responsible proteins (monocarboxylate transporters, H+-ATPase, etc.) and lactate dehydrogenase A is also a promising anticancer strategy. Another idea is the oral or parenteral use of buffer systems, such as sodium bicarbonate, to neutralize tumor acidity. Buffering therapy does not counteract standard treatment methods and can be used in combination to increase effectiveness. However, the mechanisms of the anticancer effect of buffering therapy are still unclear, and more research is needed. We have attempted to summarize the basic knowledge about tumor acidity.

Increasing Chemotherapeutic Efficacy Using pH-Modulating and Doxorubicin-Releasing Injectable Chitosan-Poly(ethylene glycol) Hydrogels

“…20 In particular, it has been demonstrated that extracellular acidity reduces the efficacy of weak base chemotherapeutics, such as doxorubicin, mitoxantrone, paclitaxel, vinblastine, and vincristine. 23 Ionization of the extracellular space renders weak base chemotherapeutics, a predominant class of cancer treatment drugs, less capable of permeating through cell membranes due to the protonation of drug. 24−26 This phenomenon is termed "ion trapping" and is responsible for the suppression of drug cytotoxicity, leading to a drug-resistant cancer cell phenotype.…”

“…The body’s inherent bicarbonate pH buffering systems, which interact with acids to produce pH-neutral CO 2 and H 2 O molecules, are overridden by lactic acid production. , A consequence of acid accumulation is low extracellular pH (pH ≈ 6.5–6.8), which is recognized as a hallmark of cancer progression. , The acidity of the tumor microenvironment produces a natural selection of cellular mutations favoring the most aggressive phenotypes. − Cancer cells that proliferate in the low-pH environment express increased invasion, metastasis, immune evasion, and chemoresistance. − Cancer therapies, including chemotherapeutics, are negatively affected by the acidic extracellular pH through reduced drug uptake, increased drug efflux from cancer cells, or altered drug metabolism . In particular, it has been demonstrated that extracellular acidity reduces the efficacy of weak base chemotherapeutics, such as doxorubicin, mitoxantrone, paclitaxel, vinblastine, and vincristine . Ionization of the extracellular space renders weak base chemotherapeutics, a predominant class of cancer treatment drugs, less capable of permeating through cell membranes due to the protonation of drug. − This phenomenon is termed “ion trapping” and is responsible for the suppression of drug cytotoxicity, leading to a drug-resistant cancer cell phenotype.…”

Schisantherin A inhibits cell proliferation by regulating glucose metabolism pathway in hepatocellular carcinoma

“…Metabonomic results indicated that STA treatment decreased the production of D-glucose, lactate, L-alanine, L-proline, and serine. Both lactate and serine have been reported to be associated with the development and exacerbation of tumors ( Woo et al, 2016 ; Bogdanov et al, 2022 ). Herein, these differential metabolites were mainly enriched in fructose and pentose phosphate metabolism and glycolysis/gluconeogenesis.…”

The contradictory roles of macrophages in non-alcoholic fatty liver disease and primary liver cancer—Challenges and opportunities

“…(Nagy et al, 1998;Odegaard et al, 2007) On the other hand, cleavage of PPAR-γ by caspase 1 allows its binding to the mitochondrial protein medium-chain acyl-CoA dehydrogenase (MCAD) resulting in reduced FAO and increased production of lactate, indicative of glycolytic activity. (Niu et al, 2017;Wu et al, 2020;Bogdanov et al, 2022) LXR, a nuclear receptor involved in cholesterol regulation, was suggested to contribute to the phenotype of TREM2 + macrophages in HCC. (Zhou et al, 2022) Interestingly, the transcriptomic profile of TREM2 + macrophages in NASH liver closely resembles TREM2 + TAMs found in HCC, in both patients and mouse models.…”

“…Tumor cells actively contribute to generating an acidic microenvironment by aerobic glycolysis, notably through the generation of lactate. (Hanahan and Weinberg, 2011;Bogdanov et al, 2022) This acidic environment induces the immunosuppressive protein cyclic AMP element modulator (CREM) and enables binding of the myeloid-derived acidic pH selective V-domain immunoglobulin suppressor of T cell activation (VISTA) to its receptor on T cells, suppressing cytotoxicity. (Sawka-Verhelle et al, 2004;Lines et al, 2014;Johnston et al, 2019) In addition, aerobic glycolysis reduces glucose availability for macrophages, thus limiting one of the metabolic pathways leading to the generation of reactive oxygen species (ROS) and the release of inflammatory cytokines.…”