Understanding acidity’s role in cancer survival New research into the acidity of cancers could open the door to the development of new treatments and therapeutics. Health © cassis/stock.adobe.com While it is well understood that cancers are acidic, what scientists don’t know is whether this characteristic could play a therapeutic role. “Acidity is a potent, endogenous, broad-spectrum modulator of biological function that is regulated by a relatively small number of proteins – characteristics that should make acidity an ideal candidate for the therapeutic management of tumour growth,” says Pawel Swietach, a professor of Physiology at the University of Oxford. So, why isn’t acidity being used to treat cancer? “Translating the sum of our understanding of acid handling and signalling into therapy is not trivial, and none of the major approved therapies are based explicitly on disrupting acid handling and/or signalling,” explains Swietach. “Reasons for this paradox relate to inadequacies in our understanding of pH handling and signalling in cancer, exacerbated by the experimental challenges associated with pH studies.” Addressing this paradox is the EU-funded Survive project. Led by Swietach, the European Research Council supported project set out to unravel the origins of cancer acidity, understand its impact on the biology of cancer and host cells, and characterise the adaptive strategies used by cancer cells to gain resistance – and a competitive edge – over neighbouring cells. “These adaptations to survival under acidity are unique to many cancer cells, and we hypothesise that blocking these mechanisms will result in beneficial outcomes for patients,” adds Swietach. Acid handling and cancer survival The research team, which was majority female, made significant headway into understanding not only how cancer cells can survive acidic conditions, but how they can exploit this advantage to outcompete host cells and immune defences. “Our approach is guided by the principle that experimental results must be consistent with a reasonable physicochemical framework and be explained mathematically,” notes Swietach. “I believe this rigour gives credence to our discoveries.” One of those discoveries is the pivotal role that carefully exercised acid handling plays in cancer survival. “Dysregulated acid-base balance has been shown to perturb or even kill cancer cells,” remarks Swietach. “Therefore, each cell, based on its acid handling phenotype, can be ascribed a fitness to survive at a particular microenvironmental pH.” Giving physiology a place at the cancer research table According to Swietach, discoveries such as these have set new standards in research methods and introduced techniques for others to use. “The Survive project has given physiology the recognition it deserves as a crucial element of cancer research and, in doing so, has made important strides towards a more thorough understanding of cancer,” he concludes. The project has delivered compelling pilot data that could form the basis of new projects and areas of research. Much of this data has been published in leading scientific journals. These include a series of Cell Reports that describe how cancer cells adapt to acidic conditions, an article in ‘Elife’ that explains how cancer cells team up to mitigate their individual genetic flaws, and guidelines for how best to control pH in experiments. Researchers were also invited to write a review of their work for publication in ‘Nature Reviews Cancer’. Swietach is currently writing proposals for additional funding to further his research and to look towards commercialising some of the Survive project’s achievements. Keywords Survive, physiology, cancer research, cancer, cancer survival, acidity
