Sodium channels and the ionic microenvironment of breast tumours

• Published in: The Journal of physiology Vol. 601; no. 9; pp. 1543 - 1553
• Main Authors: Leslie, Theresa K., Brackenbury, William J.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01-05-2023; John Wiley and Sons Inc
• Subjects: Breast cancer; Breast Neoplasms - metabolism; Cancer; Cell Membrane - metabolism; Clinical trials; Colon cancer; Female; Glutamine; Humans; Intracellular; ion channels; Lung cancer; Membrane potential; Metastases; Metastasis; migration; Na+/K+-exchanging ATPase; proliferation; Review‐Symposium; sodium; Sodium channels; Sodium channels (voltage-gated); Sodium Channels - metabolism; Symposium Section Reviews: New Roles for Ion Channels and Transporters in Health and Disease; Tumor Microenvironment; Tumors; migration; sodium; breast cancer; proliferation; metastasis; ion channels
• ISSN: 0022-3751; 1469-7793; 1469-7793
• DOI: 10.1113/JP282306

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.
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Mechanisms of Na+ channel and transporter‐dependent proliferation, migration and invasion. Na+ enters through VGSC, ENaC and ASIC channels and through the SGLT2 cotransporter and the NHE1 exchanger. These mechanisms may be responsible for elevating intracellular [Na+]. Na+ is removed from the cell via the Na+/K+‐ATPase. VGSCs depolarise the cell membrane potential (Vm), which leads to increased migration. VGSCs also regulate transcription of genes involved in proliferation, migration and invasion. VGSCs increase the activity of NHE1, further elevating intracellular [Na+] and extracellular [H+]. This acidifies the extracellular environment and aids cellular invasion through extracellular matrix. The low extracellular pH will then affect the Na+ channels, increasing the inward Na+ current through these in a positive feedback mechanism which increases intracellular [Na+] and extracellular [H+].