Alternating pH landscapes shape epithelial cancer initiation and progression: Focus on pancreatic cancer

We present here the hypothesis that the unique microenvironmental pH landscape of acid-base transporting epithelia is an important factor in development of epithelial cancers, by rendering the epithelial and stromal cells pre-adapted to the heterogeneous extracellular pH (pH_e ) in the tumor microenvironment. Cells residing in organs with net acid-base transporting epithelia such as the pancreatic ductal and gastric epithelia are exposed to very different, temporally highly variable pH_e values apically and basolaterally. This translates into spatially and temporally non-uniform intracellular pH (pH_i ) patterns. Disturbed pH_e - and pH_i -homeostasis contributes to essentially all hallmarks of cancer. Our hypothesis, that the physiological pH_e microenvironment in acid-base secreting epithelia shapes cancers arising in these tissues, can be tested using novel imaging tools. The acidic tumor pH_e in turn might be exploited therapeutically. Pancreatic cancers are used as our prime example, but we propose that this concept is also relevant for other cancers of acid-base transporting epithelia.