Division of Cell and Molecular Biology, Neuroscience Solutions to Cancer Research Group, Sir Alexander Fleming Building, South Kensington Campus, Imperial College London, London SW7 2AZ, UK.
Eur J Pharmacol. 2009 Dec 25;625(1-3):206-19. doi: 10.1016/j.ejphar.2009.08.040. Epub 2009 Oct 14.
A variety of ion channels have been detected in cancer cells. In particular, upregulation of voltage-gated sodium channels (VGSCs) has been associated pathophysiologically with several strongly metastatic carcinomas. This review emphasises breast cancer. Inhibiting VGSC activity in a number of independent ways, using the highly selective tetrodotoxin (TTX), gene silencing and a blocking polyclonal antibody, suppressed a range of cellular behaviors, especially directional motility and invasion, integral to the metastatic cascade. Conversely, transfecting a VGSC into a weakly invasive human prostate cancer cell line significantly increased invasiveness. In vivo, also, VGSC expression has been correlated positively with metastatic status. It has been suggested, therefore (i) that VGSC upregulation is an early event in metastatic progression and (ii) that VGSC expression is a 'switch,' necessary and sufficient for engaging cancer cells in a highly invasive state. Importantly, where studied, mainly prostate and breast cancers, the dominant VGSC (Nav1.7 and Nav1.5, respectively) was found to be an embryonic/neonatal splice variant, consistent with the gene expression being "oncofoetal." In breast cancer, the molecular difference between the adult and neonatal isoforms of the VGSC/Nav1.5 is largest (31 base pairs, generating 7 amino acid differences). We propose that neonatal Nav1.5 is a novel marker with significant clinical potential for management of metastatic breast cancer and describe a number of approaches which may enable tumour-specific targeting. These include various small-molecule drugs, small-interfering RNA, monoclonal antibody and natural neurotoxins.
已经在癌细胞中检测到多种离子通道。特别是，电压门控钠离子通道（VGSCs）的上调与几种具有强烈转移性的癌在病理生理学上有关。这篇综述强调了乳腺癌。通过多种独立方式抑制 VGSC 活性，使用高度选择性的河豚毒素（TTX）、基因沉默和阻断多克隆抗体，抑制了一系列细胞行为，特别是对转移级联至关重要的定向运动和侵袭。相反，将 VGSC 转染到侵袭性较弱的人前列腺癌细胞系中显著增加了侵袭性。在体内，VGSC 表达也与转移状态呈正相关。因此，有人提出 (i) VGSC 上调是转移进展的早期事件，以及 (ii) VGSC 表达是一种“开关”，对于使癌细胞进入高度侵袭状态是必要且充分的。重要的是，在所研究的主要是前列腺癌和乳腺癌中，发现占主导地位的 VGSC（分别为 Nav1.7 和 Nav1.5）是一种胚胎/新生剪接变体，与基因表达“致癌性胎儿”一致。在乳腺癌中，VGSC/Nav1.5 的成年和新生同工型之间的分子差异最大（31 个碱基对，产生 7 个氨基酸差异）。我们提出，新生 Nav1.5 是一种具有显著临床潜力的新型标志物，可用于管理转移性乳腺癌，并描述了一些可能实现肿瘤特异性靶向的方法。这些方法包括各种小分子药物、小干扰 RNA、单克隆抗体和天然神经毒素。
