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Thromboxane synthase regulates the migratory phenotype of human glioma cells

Departments of Neurosurgery [A.G., E.L.K., S.Z., J.D., M.W.] and Neuropathology [C.H.], University Hospital Eppendorf, 20246 Hamburg, Germany; Neuro-Oncology Laboratory [M.E.B.], Barrow Neurological Institute, Phoenix, AZ 85013-4496

² Address correspondence and reprint requests to Alf Giese, MD, Laboratory for Brain Tumor Biology, Department of Neurosurgery, University Hospital Eppendorf, 20246 Hamburg, Germany.

Abstract

The capacity of glial tumor cells to migrate and diffusely infiltrate normal brain compromises surgical eradication of the disease. Identification of genes associated with invasion may offer novel strategies for anti-invasive therapies. The gene for TXsyn, an enzyme of the arachidonic acid pathway, has been identified by differential mRNA display as being overexpressed in a glioma cell line selected for migration. In this study TXsyn mRNA expression was found in a large panel of glioma cell lines but not in a strain of human astrocytes. Immunohistochemistry demonstrated TXsyn in the parenchyma of glial tumors and in reactive astrocytes, whereas it could not be detected in quiescent astrocytes and oligodendroglia of normal brain. Glioma cell lines showed a wide range of thromboxane B₂ formation, the relative expression of which correlated with migration rates of these cells. Migration was effectively blocked by specific inhibitors of TXsyn, such as furegrelate and dazmegrel. Other TXsyn inhibitors and cyclooxygenase inhibitors were less effective. Treatment with specific inhibitors also resulted in a decrease of intercellular adhesion in glioma cells. These data indicate that TXsyn plays a crucial role in the signal transduction of migration in glial tumors and may offer a novel strategy for anti-invasive therapies.

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