The principal investigator's recently obtained data to suggest that glioma cells derived from patient biopsies express a novel C1' channel that is biophysically and pharmacologically distinct from other C1' channels reported to date. Based on preliminary whole-cell studies, glioma C1' channels (GCC) are selectively expressed in cells derived from human glioma biopsies but are not present in normal glial cells nor in cells derived from several non-glial tumors. This leads us to hypothesize that GCC expression is a unique and specific feature of glioma cells that may be related to the neoplastic transformation of glia cells to form gliomas. They have developed several working hypotheses regarding the function of GCC in glioma cells which include roles in glioma cell migration and cell volume regulation in response to peritumoral edema. To test these hypotheses and to demonstrate the glioma-specific expression of GCC they propose to use a combination of electrophysiological techniques and immunohistochemical approaches to: 1.) Characterize properties of this novel glioma C1' channel with special emphasis on (a) single channel properties, (b) specific bloc by the scorpion toxin chlorotoxin, (c) Ca2+-dependence, (d)regulation by changes in cell volume, and (e) interactions of the channel with the cytoskeleton. 2.) Establish the tissue specific expression in glioma cells in situ, with special emphasis on (a) the expression of GCC in acute slices from biopsy tissue, (b) the relationship between GCC expression and tumor grade, (c) GCC expression in metastatic brain tumors, and (d) GCC expression in experimental tumors derived from Lace-transfected glioma cells in SCID mice. These studies are an essential first step for the future functional characterization, purification and molecular cloning of this C1' channel. In light of the overwhelming heterogeneity of glioma cells, the demonstration of a glioma-specific ion channel has remarkable potential. GCC may serve as a glioma- specific marker and, possibly, as a future diagnostic or therapeutic target. Additionally, if GCCs play a role in glioma cell migration and/or volume regulation, modulation of GCC activity could be a means to limit glioma invasion and peritumoral edema.
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