Department of Life Sciences, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK.
Cancer Metastasis Rev. 2024 Dec;43(4):1579-1591. doi: 10.1007/s10555-024-10195-6. Epub 2024 Jul 8.
The normal functioning of every cell in the body depends on its bioelectric properties and many diseases are caused by genetic and/or epigenetic dysregulation of the underlying ion channels. Metastasis, the main cause of death from cancer, is a complex multi-stage process in which cells break away from a primary tumour, invade the surrounding tissues, enter the circulation by encountering a blood vessel and spread around the body, ultimately lodging in distant organs and reproliferating to form secondary tumours leading to devastating organ failure. Such cellular behaviours are well known to involve ion channels. The CELEX model offers a novel insight to metastasis where it is the electrical excitation of the cancer cells that is responsible for their aggressive and invasive behaviour. In turn, the hyperexcitability is underpinned by concomitant upregulation of functional voltage-gated sodium channels and downregulation of voltage-gated potassium channels. Here, we update the in vitro and in vivo evidence in favour of the CELEX model for carcinomas. The results are unequivocal for the sodium channel. The potassium channel arm is also broadly supported by existing evidence although these data are complicated by the impact of the channels on the membrane potential and consequent secondary effects. Finally, consistent with the CELEX model, we show (i) that carcinomas are indeed electrically excitable and capable of generating action potentials and (ii) that combination of a sodium channel inhibitor and a potassium channel opener can produce a strong, additive anti-invasive effect. We discuss the possible clinical implications of the CELEX model in managing cancer.
体内每个细胞的正常功能都依赖于其生物电特性，许多疾病是由离子通道的遗传和/或表观遗传失调引起的。转移是癌症死亡的主要原因，是一个复杂的多阶段过程，在此过程中，细胞从原发性肿瘤中脱离，侵袭周围组织，遇到血管进入循环并在全身扩散，最终在远处器官中定植并重新增殖形成继发性肿瘤，导致毁灭性的器官衰竭。众所周知，这种细胞行为涉及离子通道。CELEX 模型为转移提供了一个新的见解，即癌细胞的电兴奋是其侵袭性行为的原因。反过来，伴随功能性电压门控钠离子通道的上调和电压门控钾离子通道的下调，细胞的过度兴奋得到支持。在这里，我们更新了支持癌的 CELEX 模型的体外和体内证据。结果对钠通道是明确的。钾通道臂也得到了现有证据的广泛支持，尽管这些数据因通道对膜电位的影响及其后续的二次效应而变得复杂。最后，与 CELEX 模型一致，我们表明 (i) 癌确实是可兴奋的，能够产生动作电位，(ii) 钠通道抑制剂和钾通道开放剂的联合使用可以产生强烈的、相加的抗侵袭作用。我们讨论了 CELEX 模型在癌症管理中的可能临床意义。
