Sodium channels and the ionic microenvironment of breast tumours

Cancers of epithelial origin such as breast, prostate, cervical, gastric, colon and lung cancer account for a large proportion of deaths worldwide. Better treatment of metastasis, the main cause of cancer deaths, is therefore urgently required. Several of these tumours have been shown to have an abnormally high concentration of Na⁺ ([Na⁺ ]) and emerging evidence points to this accumulation being due to elevated intracellular [Na⁺ ]. This poses intriguing questions about the cellular mechanisms underlying Na⁺ dysregulation in cancer, and its pathophysiological significance. Elevated intracellular [Na⁺ ] may be due to alterations in activity of the Na⁺ /K⁺ -ATPase, and/or increased influx via Na⁺ channels and Na⁺ -linked transporters. Maintenance of the electrochemical Na⁺ gradient across the plasma membrane is vital to power many cellular processes that are highly active in cancer cells, including glucose and glutamine import. Na⁺ channels are also upregulated in cancer cells, which in turn promotes tumour growth and metastasis. For example, ENaC and ASICs are overexpressed in cancers, increasing invasion and proliferation. In addition, voltage-gated Na⁺ channels are also upregulated in a range of tumour types, where they promote metastatic cell behaviours via various mechanisms, including membrane potential depolarisation and altered pH regulation. Together, recent findings relating to elevated Na⁺ in the tumour microenvironment and how this may be regulated by several classes of Na⁺ channels provide a link between altered Na⁺ handling and poor clinical outcome. There are new opportunities to leverage this altered Na⁺ microenvironment for therapeutic benefit, as exemplified by several ongoing clinical trials.