OVEREXPRESSION OF A TRANSMEMBRANE ISOFORM OF NEURAL CELL-ADHESION MOLECULE ALTERS THE INVASIVENESS OF RAT CNS-1 GLIOMA

CNS-1 is a highly invasive neural cell adhesion molecule (NCAM)-positi ve rat glioma that exhibits similarities in its pattern of infiltratio n to human gliomas, To investigate whether increasing NCAM expression alters invasive behavior, retroviruses encoding human NCAM 140 and a c ytoplasmic truncation of NCAM 140 were used to transduce a population of CNS-1 glioma cells that had a relatively low endogenous level of NC AM. Compared to cells transduced with a control virus, cells overexpre ssing either intact or truncated human NCAM 140 showed decreased invas ion of a reconstituted basal lamina, Changes in growth rate or in key matrix metalloproteinase activities could not account for this result. In a migration assay on type IV collagen, cells exhibited a substrate concentration-dependent increase in the rate of migration; however, o verexpression of NCAM 140 or truncated NCAM 140 inhibited motility at higher substrate concentrations. Consistent with these findings was th e decreased spread of NCAM 140 overexpressers in vivo following instil lation of cells into the right frontal cortex of rat brain. NCAM 140 o verexpressers showed considerably more restricted perivascular and per iventricular spread than cells transduced with a control virus, Howeve r, NCAM-140-overexpressing tumor exhibited a less cohesive pattern of growth near the site of tumor instillation and more individual cell in filtration of brain parenchyma with more pronounced perineuronal satel litosis. The stability of recombinant NCAM expression was confirmed by recovering tumor cells from tumor-bearing animals and measuring NCAM levels by flow cytometry. These observations show that overexpression of NCAM 140 decreases the long-range spread of CNS-1 glioma along basa l lamina pathways but enhances local infiltration of neuropil.