Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Recent studies have shown that ion channels can regulate many malignant features of tumor cells. TRPM7, a subfamily member of the transient receptor potential (TRP), has a very high permeability for both Ca(2+) and Mg(2+). In addition to its channel activity, it contains a functional ?-kinase domain within its C terminus. Using A172 and U87 MG, two human glioma cell lines, we found strong evidence supporting the expression of functional Ca(2+) sensing ion channel in these cells. Moreover, electrophysiological and pharmacological data strongly indicated the involvement of TRPM7 channels in mediating the Ca (2+)-sensing current in glioma cells. Suppression of TRPM7 channels inhibit proliferation, migration, and invasion of malignant human gliomas, indicating that TRPM7 channels may represent a novel and promising target for therapeutic intervention of malignant glioma. In addition, we found that TRPM7 channels regulate glioma stem cell (GSC) growth/proliferation through STAT3 and Notch signaling pathways. These observations led us to test the OVERALL HYPOTHESIS that TRPM7 activity may mediate GBM progression through JAK2/STAT3 and Notch1 pathways and that TRPM7 may be a novel GBM drug target. However, the genetic profiles tend to change dramatically when existing human glioma cell lines are placed in serum-based culture for extended time whereas glioma patient-derived xenolines (PDX) generated by new techniques preserve relatively constant genetic profiles over long periods. Therefore, we will test our hypothesis using a suitable range of disaggregated xenograft lines and validate with human GBM cells. The significance of this study is that its completion will greatly enhance our understanding of the development and progression of glioma, which may lead to novel and useful biomarkers and/or therapeutic targets in the context of GBM. The two specific aims are: [1] Determine the role for TRPM7 in regulation of Ca(2+) and Mg(2+) homeostasis in GBM patient-derived xenolines (PDX) and PDX-derived cancer stem cells (GSC). [2] Determine JAK2/STAT3 and Notch signaling pathways regulated by TRPM7 in the development and progression of glioma and maintenance of self-renewal capability and tumorigenicity of GSC using PDX and PDX-derived GSC.
Despite decades of research on tumor biology and treatment, glioblastoma multiforme (GBM), the most common and aggressive primary brain tumor with a median survival time of 14.6 months, still has a poor prognosis and no effective treatment has been developed for GBM patients. We were first to report that the suppression of TRPM7 expression significantly inhibited the growth, proliferation, migration, and invasion of human glioma cells, which indicate that the TRPM7 channels may represent a novel and a promising target for therapeutic intervention in malignant glioma. The proposed study will clarify the role of TRPM7 in the progression of malignant glioma and identify mechanisms mediating its function.
