Sontheimer Harald
The University of Alabama at Birmingham, Department of Neurobiology & Center for Glial Biology in Medicine, 1719 6th Avenue S., CIRC 410, Birmingham, AL 35294-0021, USA.
Exp Biol Med (Maywood). 2008 Jul;233(7):779-91. doi: 10.3181/0711-MR-308. Epub 2008 Apr 29.
Over the past two decades it has become apparent that essentially all living cells express voltage-activated ion channels. While the role of ion channels for electrical signaling between excitable cells is well known, their function in non-excitable cells is somewhat enigmatic. Research on cancer cells suggests that certain ion channels, K+ channels in particular, may be involved in aberrant tumor growth and channel inhibitors often lead to growth arrest. An unsuspected role for K+ and Cl(-) channels has now been documented for primary brain tumors, glioma, where the concerted activity of these channels promotes cell invasion and the formation of brain metastasis. Specifically, Ca2+-activated K+ (BK) channels colocalize with ClC-3 Cl(-) channels to the invading processes of these tumor cells. Upon a rise in intracellular Ca2+, these channels activate and release K+ and Cl(-) ions together with obligated water causing a rapid shrinkage of the leading process. This in turn facilitates the invasion of the cell into the narrow and tortuous extracellular brain spaces. The NKCC1 cotransporter accumulates intracellular Cl(-) to unusually high concentrations, thereby establishing an outward directed gradient for Cl(-) ions. This allows glioma cells to utilize Cl(-) as an osmotically active anion during invasion. Importantly, the inhibition of Cl(-) channels retards cell volume changes, and, in turn, compromises tumor cell invasion. These findings have led to the clinical evaluation of a Cl(-) channel blocking peptide, chlorotoxin, in patients with malignant glioma. Data from this clinical trial shows remarkable tumor selectivity for chlorotoxin. The experimental therapeutic was well tolerated and is now evaluated in a multi-center phase II clinical trial. A similar role for Cl(-) and K+ channels is suspected in other metastatic cancers, and lessons learned from studies of gliomas may pave the way towards the development of novel therapeutics targeting ion channels.
在过去二十年中，显而易见的是，几乎所有活细胞都表达电压激活离子通道。虽然离子通道在可兴奋细胞间电信号传导中的作用已广为人知，但其在非可兴奋细胞中的功能却有些神秘莫测。对癌细胞的研究表明，某些离子通道，尤其是钾离子通道，可能参与异常肿瘤生长，而通道抑制剂常常导致生长停滞。现已证明，钾离子通道和氯离子通道在原发性脑肿瘤——神经胶质瘤中发挥了意想不到的作用，这些通道的协同活动促进了细胞侵袭和脑转移的形成。具体而言，钙激活钾离子（BK）通道与氯离子通道ClC-3在这些肿瘤细胞的侵袭过程中共定位。细胞内钙离子浓度升高时，这些通道激活，释放钾离子和氯离子以及结合水，导致前端迅速收缩。这反过来又促进细胞侵入狭窄而曲折的细胞外脑间隙。NKCC1共转运体将细胞内氯离子积累到异常高的浓度，从而建立起氯离子的外向梯度。这使得神经胶质瘤细胞在侵袭过程中能够将氯离子用作渗透活性阴离子。重要的是，抑制氯离子通道会减缓细胞体积变化，进而损害肿瘤细胞侵袭。这些发现促使人们对一种氯离子通道阻断肽——氯毒素，在恶性神经胶质瘤患者中进行临床评估。该临床试验的数据显示氯毒素具有显著的肿瘤选择性。这种实验性治疗耐受性良好，目前正在多中心II期临床试验中进行评估。在其他转移性癌症中，人们怀疑氯离子通道和钾离子通道也发挥类似作用，从神经胶质瘤研究中吸取的经验教训可能为开发针对离子通道的新型治疗方法铺平道路。
