An Unexpected Role for Ion Channels in Brain Tumor Metastasis

Abstract

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.