In vivo metabolic imaging of the cancerous pH gradient for diagnostic and therapeutic implications

Tumors hijack physiological chemical reactions, including those that maintain the pH for their own benefit in order to grow and metastasize. While all cells maintain a highly regulated “physiological pH” to enable a normal biochemical function, cancerous cells remodel chemical reactions to maintain this optimal pH internally, while creating an acidic pH outside the tumor that kills the surrounding healthy cells and allows the tumor to propagate. Cancer cells are also known to generate high amounts of lactic acid, a compound that then needs to be disposed to maintain intracellular pH values within physiological limits. Based on recent studies that we have carried out we proposed a hypothesis, according to which, the acidity created by lactate inside cancerous cells in addition to being extruded, is also neutralized by a cascade of new reactions that increase certain chemicals. Using cancer cell lines and other models we have confirmed that an increase in key anti-acidic metabolites –glutamine and ammonia– occurs inside the cells. These findings could potentially suggest new ways of treating cancers by devising scavengers that defeat this cancerous cells survival strategy. In order to develop this hypothesis further we propose to couple treatments that manipulate ammonia and glutamine intracellular concentrations, with emerging magnetic resonance (MR) techniques in 1H and hyperpolarized 13C MRI. This will enable real-time characterization of intra- and extra-cellular pH changes upon manipulating these anti-acidic agents in vitro and in animal models of various cancers. If proven correct, this strategy could be translated to the cancer patients as a novel approach to monitor and treat cancer progression.