DPAG’s Pawel Swietach is author on a Nature Reviews Cancer article on tumour acidosis, published ahead of the centennial of Otto Warburg’s discovery of lactic acidosis in cancers. Acidity is, alongside hypoxia, recognised as a chemical signature of the tumour microenvironment. For decades, however, acidosis was in the shadow of hypoxia, often relegated to being a toxic end-product with little feedback on cellular behaviours. It is now becoming apparent that acidity engages distinct regulatory and sensing mechanisms, and forces surviving cancer cells to adapt in unique ways that expose druggable vulnerabilities. The review describes recent progress in the area, and highlights opportunities for better diagnosis and treatment.
In 1924, Warburg reported how tumours generate large amounts of lactic acid, even in the presence of oxygen. This finding was considered unusual because only cells deprived of oxygen were thought to switch to this form of metabolism. With the advent of pH electrodes, tumour acidosis was confirmed experimentally. At first, acidosis was associated with resistance to certain drugs, such as weakly basic chemotherapeutic drugs that include doxorubicin. More recently, sensors and signalling pathways triggered specifically by acidity have been reported. Now, we appreciate that surviving acidosis is a remarkable feat involving changes in gene expression, metabolic remodelling, and selection of fitter phenotypes. Strikingly, many cancer mutations affect how proteins interpret pH; for example, oncogenes that are normally stimulated at alkaline pH becoming activated even at normal pH.
The most exciting opportunities in exploiting tumour acidosis therapeutically relate to better drug targeting by making use of pH sensitive moieties and methods for derailing acid adaptation that inevitably widens the survival advantage of cancer cells over normal cells. A key area of interest is the interplay between hypoxia and acidosis, as these are likely to occur concurrently, but not necessarily in stoichiometric coupling.
The research was funded by the European Research Council (SURVIVE grant).