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Novel Tumor-Specific Isoforms of BEHAB/Brevican Identified in Human Malignant Gliomas

Departments of ¹ Neurobiology and ² Neurosurgery, Yale University School of Medicine, New Haven, Connecticut

Requests for reprints: Russell T. Matthews, Department of Neurobiology, Yale University School of Medicine, P.O. Box 208001, 333 Cedar Street, SHM C405, New Haven, CT 06520. Phone: 203-785-6896; Fax: 203-785-5263; E-mail: russell.matthews{at}yale.edu.

Malignant gliomas are deadly brain tumors characterized by diffuse invasion into the surrounding brain tissue. Understanding the mechanisms involved in glioma invasion could lead to new therapeutic strategies. We have previously shown that BEHAB/brevican, an extracellular matrix protein in the central nervous system, plays a role in the invasive ability of gliomas. The mechanisms that underlie BEHAB/brevican function are not yet understood, due in part to the existence of several isoforms that may have different functions. Here we describe for the first time the expression of BEHAB/brevican in human brain and characterize two novel glioma-specific isoforms, B/b_sia and B/b_g, which are generated by differential glycosylation and are absent from normal adult brain and other neuropathologies. B/b_sia is an oversialylated isoform expressed by about half the high- and low-grade gliomas analyzed. B/b_g lacks most of the carbohydrates typically present on BEHAB/brevican and is the major up-regulated isoform of this protein in high-grade gliomas but is absent in a specific subset of low-grade, indolent oligodendrogliomas. B/b_g is detected on the extracellular surface, where it binds to the membrane by a mechanism distinct from the other BEHAB/brevican isoforms. The glioma-specific expression of B/b_g, its restricted membrane localization, and its expression in all high-grade gliomas tested to date suggest that it may play a significant role in glioma progression and make it an important new potential therapeutic target. In addition, its absence from benign gliomas prompts its use as a diagnostic marker to distinguish primary brain tumors of similar histology but different pathologic course.

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