Glutamate Transporters and Receptors, Microdialysis
John Frederick deGroot, M.D.
My research focuses on some of the molecular mechanisms involved in the growth and proliferation of glioma tumors. A particular focus is the role of glutamate transporters and receptors in glioma growth and motility. Accumulating evidence suggests that glutamate plays a key role in the proliferation and invasion of glioblastoma tumors. Astrocytic tumors release glutamate at high levels, which may stimulate tumor cell proliferation and motility via autocrine activation of glutamate receptors. Excess glutamate could also facilitate invasion by causing excitotoxic damage to normal brain, thereby paving a pathway for tumor migration.
We have shown that high-grade human gliomas have decreased expression of the most abundant excitatory amino acid glutamate transporter-2 (EAAT-2), and EAAT-2 expression was inversely correlated with tumor grade. Restoration of functional EAAT-2 resulted in a subsequent dose-dependent reduction in cell proliferation and induction of apoptosis in all glioma cell lines tested. From a clinical standpoint, understanding the role of glutamate in glioma may provide useful prognostic information and provide alternative therapeutic targets.
A second area of research involves the use of in vivo microdialysis to measure drug levels in glioma tissue. Chemotherapy has been used as adjunct therapy for the treatment of brain tumors with variable success. Two of the many factors determining the response of a tumor to chemotherapy are delivery of drug across the blood-brain barrier at effective tumor tissue drug concentrations and intra-tumoral metabolism of the drug.
Microdialysis is a safe and reproducible method that can be used to study drug distribution to tissues and it allows continuous, real-time quantification of drug delivery to tumor and brain. We are currently using microdialysis to study tissue distribution of chemotherapeutic agents in normal brain and tumor in a mouse xenograft model. In collaboration with Dr. Mark Gilbert, we will be performing microdialysis studies in human glioblastoma tumors to determine tumor tissue levels of systemically administered chemotherapy. A better understanding of drug delivery of chemotherapy in brain tumors will help in the selection of chemotherapeutic agents for clinical trials and may help to predict tumor response.
Liu T.J., Lafortune T., Honda T., Ohmori O., Hatakeyama, S., Meyer, T., Jackson, D., de Groot, J., Yung W.K. Inhibition of both focal adhesion kinase and insulin-like growth factor-I receptor kinase suppresses glioma proliferation in vitro and in vivo. Mol Cancer Ther. 6(4): 1357-1367, 2007.
Koul D, Shen R, Bergh S, Sheng X, Shishodia S, Lafortune TA, Lu Y, de Groot J, Mills GB, Yung WK. Inhibition of Akt survival pathway by a small-molecule inhibitor in human glioblastoma. Mol Cancer Ther. 5(3): 637-44, 2006.
de Groot J, Liu TJ, Fuller G, Yung WKA. The excitatory amino acid transporter-2 induces apoptosis and decreases glioma growth in vitro and in vivo. Cancer Research 65(5): 1934-1940, 2005.
Koul D., Shen R., Bergh S., Liu Y., de Groot J, Liu T.J., Mills G.B., Yung W.K. Targeting integrin–linked kinase inhibits Akt signaling pathways and decreases tumor progression of human glioblastoma, Mol Cancer Ther 4(11): 1681-8, 2005.
Benjamin R, Hochberg F, Fox E, Collins J, Bungay P, Pelletier R, Hickner R, Elmquist W, Stewart C, Vespa P, Goodman JC, Ungerstedt U, Zamboni W, Gallo J, Colvin M, de Groot J, Cavus I, Grossman S, Microdialysis in Brain Tumors “From Concept to Application”. Neuro-Oncology 6:1, 2004