Djamgoz Mustafa B A, Fraser Scott P, Brackenbury William J
Department of Life Sciences, Neuroscience Solutions to Cancer Research Group, Imperial College London, South Kensington Campus, London SW7 2AZ, UK.
Department of Biology and York Biomedical Research Institute, University of York, Heslington, York, YO10 5DD, UK.
Cancers (Basel). 2019 Oct 28;11(11):1675. doi: 10.3390/cancers11111675.
A wide body of evidence suggests that voltage-gated sodium channels (VGSCs) are expressed de novo in several human carcinomas where channel activity promotes a variety of cellular behaviours integral to the metastatic cascade. These include directional motility (including galvanotaxis), pH balance, extracellular proteolysis, and invasion. Contrary to the substantial in vitro data, however, evidence for VGSC involvement in the cancer process in vivo is limited. Here, we critically assess, for the first time, the available in vivo evidence, hierarchically from mRNA level to emerging clinical aspects, including protein-level studies, electrolyte content, animal tests, and clinical imaging. The evidence strongly suggests that different VGSC subtypes (mainly Nav1.5 and Nav1.7) are expressed de novo in human carcinoma tissues and generally parallel the situation in vitro. Consistent with this, tissue electrolyte (sodium) levels, quantified by clinical imaging, are significantly higher in cancer vs. matched non-cancer tissues. These are early events in the acquisition of metastatic potential by the cancer cells. Taken together, the multi-faceted evidence suggests that the VGSC expression has clinical (diagnostic and therapeutic) potential as a prognostic marker, as well as an anti-metastatic target. The distinct advantages offered by the VGSC include especially (1) its embryonic nature, demonstrated most clearly for the predominant neonatal Nav1.5 expression in breast and colon cancer, and (2) the specifically druggable persistent current that VGSCs develop under hypoxic conditions, as in growing tumours, which promotes invasiveness and metastasis.
大量证据表明，电压门控钠通道（VGSCs）在几种人类癌症中从头表达，通道活性促进了转移级联中不可或缺的多种细胞行为。这些行为包括定向运动（包括趋电性）、pH平衡、细胞外蛋白水解和侵袭。然而，与大量体外数据相反，VGSCs在体内癌症过程中参与的证据有限。在这里，我们首次从mRNA水平到新兴临床方面，包括蛋白质水平研究、电解质含量、动物试验和临床成像，对现有的体内证据进行了严格评估。证据有力地表明，不同的VGSC亚型（主要是Nav1.5和Nav1.7）在人类癌组织中从头表达，总体上与体外情况相似。与此一致的是，通过临床成像定量的组织电解质（钠）水平在癌症组织与匹配的非癌组织中显著更高。这些是癌细胞获得转移潜能的早期事件。综上所述，多方面的证据表明，VGSC表达作为一种预后标志物以及抗转移靶点具有临床（诊断和治疗）潜力。VGSC具有的独特优势尤其包括：（1）其胚胎性质，在乳腺癌和结肠癌中主要的新生儿Nav1.5表达中最为明显；（2）VGSCs在低氧条件下（如在生长的肿瘤中）产生的可特异性药物作用的持续电流，这种电流促进侵袭和转移。
