A distinguishing phenotype of solid
tumors is the presence of an alkaline cellular feature despite the surrounding acidic microenvironment. This phenotypic characteristic of
tumors, originally described by Otto Warburg, arises due to alterations in metabolism of solid
tumors. Hypoxic regions of solid
tumors develop due to poor vascularization and in turn regulate the expression of numerous genes via the
transcription factor HIF-1. Ultimately, the tumor microenvironment directs the development of
tumor cells adapted to survive in an acidic surrounding where normal cells perish. The provision of unique pH characteristics in
tumor cells provides a defining trait that has led to the pursuit of treatments that target metabolism,
hypoxia, and pH-related mechanisms to selectively kill
cancer cells. Numerous studies over the past decade involving the
cancer-specific
carbonic anhydrase IX have re-kindled an interest in pH disruption-based
therapies. Although an acidification of the intracellular compartment is established as a means to induce normal cell death, the defining role of
acid-base disturbances in
tumor physiology and survival remains unclear. The aim of this review is to summarize recent data relating to the specific role of pH regulation in
tumor cell survival. We focus on membrane transport and
enzyme studies in an attempt to elucidate their respective functions regarding
tumor cell pH regulation. These data are discussed in the context of future directions for the field of
tumor cell
acid-base-related research.