In recent years, the acidic tumour microenvironment (TME) created by cancer-specific metabolism has garnered significant attention in the field of cancer therapy. In this blog post, we delve into a research topic focused on cancer metabolism, specifically highlighting the impact of TME acidity on cancer pathology.
Understanding Cancer Development:
Otto Warburg's groundbreaking work on the origin of cancer cells revealed a crucial point: cancer cells develop in an oxygen-deficient environment but with an adequate supply of nutrients. These cancer cells primarily rely on glycolysis, known as fermentation, instead of oxidative phosphorylation through cellular respiration. This dependence stems from the presence of mitochondria in eukaryotic cells. The theory suggests that cancer cells, lacking functional mitochondria, have adapted to survive and proliferate by choosing an alternative metabolic path. This metabolic switch, driven by Darwinian selection pressure, leads to cancer cells relying on aerobic glycolysis for survival. This unique perspective views cancer as a metabolic disease rather than a purely genetic one.
The Role of Cancer Metabolism:
Cancer cells exhibit a distinctive metabolism that differs from that of normal cells. Enhanced glycolysis in cancer cells leads to the production of large amounts of acidic substances (protons) within the cells. To counteract this acidity, cancer cells expel protons outside the cell through proton transporters, resulting in an alkaline intracellular environment and an acidic extracellular TME. The main proton transporter involved in this phenomenon is the sodium/proton (Na+/H+) exchanger isoform 1. Unlike normal cells, which maintain an extracellular pH of around 7.2 to 7.4, the TME surrounding cancer cells tends to be more acidic, ranging from pH 6.2 to 6.8. This acidification of the TME has been linked to the promotion of cancer progression, resistance to treatments, increased proliferation, and enhanced metastatic potential. Unfortunately, current cancer treatments often fail to target the altered pH balance resulting from cancer-specific metabolism, thus hindering optimal treatment outcomes.
The Potential of Alkalization:
Reversing the pH gradient between the inside and outside of cancer cells, known as extracellular acidification and intracellular alkalinization, can reduce the intracellular concentration of many anticancer drugs and contribute to drug resistance. Conversely, lowering the intracellular pH (raising extracellular pH) of cancer cells may attenuate resistance to anticancer drugs and improve treatment effectiveness. Additionally, an acidic TME is known to suppress anticancer immune responses, whereas alkalinization of the TME is expected to enhance the function of immune cells. Clinical methods for alkalization therapy include the use of alkalizing agents or proton pump inhibitors, as well as considering the influence of diet. Alkalization therapy acts on cancer metabolism and can be combined with conventional cancer treatments, such as chemotherapy and radiation therapy. The effectiveness and safety of alkalization therapy in combination with other therapies warrant further investigation through prospective clinical trials.
References
Hamaguchi R, Uemoto S and Wada H (2023) Editorial: The impact of alkalizing the acidic tumor microenvironment to improve efficacy of cancer treatment. Front. Oncol. 13:1223025. doi: 10.3389/fonc.2023.1223025