The impact of tumour pH on cancer progression: strategies for clinical intervention

Abstract

Dysregulation of cellular pH is frequent in solid tumours and provides potential opportunities for therapeutic intervention. The acidic microenvironment within a tumour can promote migration, invasion and metastasis of cancer cells through a variety of mechanisms. Pathways associated with the control of intracellular pH that are under consideration for intervention include carbonic anhydrase IX, the monocarboxylate transporters (MCT, MCT1 and MCT4), the vacuolar-type H⁺-ATPase proton pump, and the sodium-hydrogen exchanger 1. This review will describe progress in the development of inhibitors to these targets.

Keywords: Tumour pH; acidosis; carbonic anhydrase IX; hypoxia; inhibitor; monocarboxylate transporter 1; monocarboxylate transporter 4; sodium-hydrogen exchanger 1; vacuolar-type H+-ATPase proton pump.

Figure 1.

Cancer cell metabolism, HIF and pH. As cancer cells proliferate, some cells are pushed further away from blood vessels, decreasing the levels of O₂ and nutrients available to these cells. Normoxic cells can produce energy through oxidative phosphorylation (OXPHOS); hypoxic cancer cells are unable to acquire energy through OXPHOS due to low O₂ levels. Activation of the HIF family of transcription factors is one of the principle oxygen-responsive signalling pathways that allows the adaptation of hypoxic cancer cells to this hostile microenvironment. HIF signalling shifts energy production from OXPHOS in the mitochondria towards glycolysis, allowing hypoxic cancer cells to continue to produce energy despite the low O₂ levels. The increased dependency on glycolysis in hypoxic cells leads to the production of increased amounts of H⁺ ions, which can lead to changes in the pHi of cancer cells if not dealt with. To help cope with the excess H⁺ ions being produced, cancer cells upregulate/activate a number of pH regulating proteins; these proteins include CAIX, NHE1, MCT4 and V-ATPase

Figure 2.

The effects of acidic pHe on tumour development and treatment. Acidosis is a microenvironmental factor that impacts tumour progression greatly, contributing to tumour growth and negatively affecting both radiotherapy and chemotherapy treatment

Figure 3.

Inhibitors targeted against pH regulatory molecules with the cell. Various drugs targeting the main pH regulating proteins of cancer cells are outlined, along with the effects that alkaline pHi/acidic pHe have on tumour development and treatment