Mechanisms, consequences and regulation of pH non-uniformity in 3-D tissue structures: implications on cancer therapy

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Our aim is to study the mechanisms that regulate the acid/base balance (pH) in multi-cellular tissue, with particular emphasis on tumours.Living cells produce acid, an end-product of metabolism. Acid must be vented out of cells, to the nearest blood capillary, in order to maintain an intracellular pH (pHi) that is permissive for healthy cell function. Efficient venting of acid is also necessary to maintain uniform pHi across multi-cellular tissue. This is particularly critical for under-perfused and metabolically-active tissues, such as developing tumours, where variable cell-to-capillary diffusion distances predispose to pHi-gradients and core-acidity.Although significant progress has been made in the field of pHi-regulation in isolated cells, little is known about the integrated mechanisms that operate at tissue-level. Molecules likely to contribute to the latter include pH buffers, carbonic anhydrase enzymes, gap junction channels and acid/base membrane transporters. We will investigate these mechanisms using molecular biology, pH imaging and computational modelling. The research will use large, three-dimensional clusters (‘spheroids’) of cancer-derived cells as an in vitro model of developing tumours.The good survival prospects of cancer may suggest that efficient mechanisms for venting acid are implemented in tumours. Inhibiting these mechanisms may offer novel therapeutic strategies for treating cancer. Manipulation of pH within and outside cells may also affect the cellular uptake of certain weakly basic drugs that are currently used in chemotherapy.