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Previous Article | Next Article
The Journal of Neuroscience, April 1, 1998, 18(7):2370-2376
Expression of a Cleaved Brain-Specific Extracellular Matrix Protein Mediates Glioma Cell Invasion In Vivo
Hong Zhang, Gail Kelly, Cynthia Zerillo, Diane M. Jaworski, and Susan Hockfield Section of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520-8001
Malignant gliomas (primary brain tumors) aggressively invade the surrounding normal brain. This invasive ability is not demonstrated by brain metastases of nonglial cancers. The brain-specific, brain-enriched hyaluronan binding (BEHAB)/brevican gene, which encodes an extracellular hyaluronan-binding protein, is consistently expressed by human glioma and is not expressed by tumors of nonglial origin (). BEHAB/brevican can be cleaved into an N-terminal fragment that contains a hyaluronan-binding domain (HABD) and a C-terminal fragment (). Here, using antisera to peptides in the predicted N-terminal and C-terminal proteolytic fragments, we demonstrate that the BEHAB/brevican protein is cleaved in invasive human and rodent gliomas. A role for this protein in glioma cell invasion was tested by transfecting a noninvasive cell line with the BEHAB/brevican gene. The noninvasive 9L glioma cell was transfected with either full-length BEHAB/brevican or the HABD and tested for invasion in in vitro and in vivo invasion assays. Although both constructs increased invasion in vitro, only the HABD increased invasion by tumors growing in vivo. Experimental intracranial tumors from full-length transfectants showed no increase in invasion over control tumors, whereas tumors from HABD transfectants showed a marked potentiation of tumor invasion, producing new tumor foci at sites distant from the main tumor mass. This work demonstrates a role for a brain-specific extracellular matrix protein in glioma invasion, opening new therapeutic avenues for a uniformly fatal disease.
Key words: glioma; brain tumor; astrocytoma; tumorogenesis; motility; proteoglycan; BEHAB; brevican; invasion; extracellular matrix
Copyright © 1998 Society for Neuroscience 0270-6474/98/1872370-07$05.00/0
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