Tumor Tissue Acidosis as a Factor Determining the Malignant Phenotype and Tumor Resistance to Chemotherapy

This review covers data on the role of reduced extracellular pH (acidosis) in tumor tissue in the development of tumorigenesis. The following processes characterizing the malignant phenotype of the tumor are considered: (1) protease activation causing destruction of the intercellular matrix and disruption of intercellular interactions, which makes invasion and metastasis possible; (2) genome instability; (3) inhibition of the antitumor immune response; (4) activation of exosome synthesis, which plays an important role in intercellular communications and is involved in the formation of “premetastasis niches”; and (5) P-glycoprotein activation and a number of other processes associated with the formation of the malignant tumor phenotype. It is concluded that acidosis plays a leading role in the realization of these malignant tumor properties. The role of pH-sensors in transmitting information about the pH value of the extracellular environment (its acidity) inside the cell is described. The possibility of the leading role of acidosis at the earliest stages of tumor process in overcoming the regulatory action of surrounding normal cells is also described. The therapeutic effect of many antitumor drugs depends on the pH value of the medium in which they act. In this regard, the role of acidosis in the action of various preparations for chemotherapy and the possibility of influencing tumor acidosis in order to enhance the antitumor activity of substances are further discussed.