Department of Neurobiology and Center for Glial Biology in Medicine, University of Alabama at Birmingham, USA.
Am J Physiol Cell Physiol. 2011 Sep;301(3):C541-9. doi: 10.1152/ajpcell.00102.2011. Epub 2011 May 4.
A hallmark of high-grade cancers is the ability of malignant cells to invade unaffected tissue and spread disease. This is particularly apparent in gliomas, the most common and lethal type of primary brain cancer affecting adults. Migrating cells encounter restricted spaces and appear able to adjust their shape to accommodate to narrow extracellular spaces. A growing body of work suggests that cell migration/invasion is facilitated by ion channels and transporters. The emerging concept is that K(+) and Cl(-) function as osmotically active ions, which cross the plasma membrane in concert with obligated water thereby adjusting a cell's shape and volume. In glioma cells Na(+)-K(+)-Cl(-) cotransporters (NKCC1) actively accumulate K(+) and Cl(-), establishing a gradient for KCl efflux. Ca(2+)-activated K(+) channels and voltage-gated Cl(-) channels are largely responsible for effluxing KCl promoting hydrodynamic volume changes. In other cancers, different K(+) or even Na(+) channels may function in concert with a variety of Cl(-) channels to support similar volume changes. Channels involved in migration are frequently regulated by Ca(2+) signaling, most likely coupling extracellular stimuli to cell migration. Importantly, the inhibition of ion channels and transporters appears to be clinically relevant for the treatment of cancer. Recent preclinical data indicates that inhibition of NKCC1 with an FDA-approved drug decreases neoplastic migration. Additionally, ongoing clinical trials demonstrate that an inhibitor of chloride channels may be a therapy for the treatment of gliomas. Data reviewed here strongly indicate that ion channels are a promising target for the development of novel therapeutics to combat cancer.
高级别癌症的一个标志是恶性细胞能够侵袭未受影响的组织并传播疾病。这在神经胶质瘤中尤为明显，神经胶质瘤是成年人中最常见和最致命的原发性脑癌。迁移细胞遇到受限的空间，似乎能够调整其形状以适应狭窄的细胞外空间。越来越多的工作表明，细胞迁移/侵袭是由离子通道和转运体促进的。新出现的概念是，K(+)和 Cl(-)作为渗透活性离子起作用，它们与必需的水一起穿过质膜，从而调节细胞的形状和体积。在神经胶质瘤细胞中，Na(+)-K(+)-Cl(-)共转运体（NKCC1）主动积累 K(+)和 Cl(-)，为 KCl 外排建立梯度。Ca(2+)-激活的 K(+)通道和电压门控 Cl(-)通道主要负责外排 KCl，促进流体动力体积变化。在其他癌症中，不同的 K(+)甚至 Na(+)通道可能与各种 Cl(-)通道协同作用，以支持类似的体积变化。参与迁移的通道通常受 Ca(2+)信号转导的调节，很可能将细胞外刺激与细胞迁移偶联。重要的是，离子通道和转运体的抑制似乎与癌症的治疗临床相关。最近的临床前数据表明，用 FDA 批准的药物抑制 NKCC1 可减少肿瘤迁移。此外，正在进行的临床试验表明，氯离子通道抑制剂可能是治疗神经胶质瘤的一种疗法。这里审查的数据强烈表明，离子通道是开发新型治疗方法以对抗癌症的有希望的靶标。
