EXPRESSION OF A CLEAVED BRAIN-SPECIFIC EXTRACELLULAR-MATRIX PROTEIN MEDIATES GLIOMA CELL INVASION IN-VIVO

Malignant gliomas (primary brain tumors) aggressively invade the surro unding normal brain, This invasive ability is not demonstrated by brai n metastases of nonglial cancers, The brain-specific, brain-enriched h yaluronan binding (BEHAB)/brevican gene, which encodes an extracellula r hyaluronan-binding protein, is consistently expressed by human gliom a and is not expressed by tumors of nonglial origin (Jaworski et al., 1996). BEHAB/brevican can be cleaved into an N-terminal fragment that contains a hyaluronan-binding domain (HABD) and a C-terminal fragment (Yamada et al., 1995). Here, using antisera to peptides in the predict ed N-terminal and C-terminal proteolytic fragments, we demonstrate tha t the BEHAB/brevican protein is cleaved in invasive human and rodent g liomas. 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 BE HAB/brevican or the HABD and tested for invasion in in vitro and in vi vo invasion assays. Although both constructs increased invasion in vit ro, only the HABD increased invasion by tumors growing in vivo, Experi mental intracranial tumors from full-length transfectants showed no in crease in invasion over control tumors, whereas tumors from HABD trans fectants showed a marked potentiation of tumor invasion, producing new tumor fool at sites distant from the main tumor mass, This work demon strates a role for a brain-specific extracellular matrix protein in gl ioma invasion, opening new therapeutic avenues for a uniformly fatal d isease.