INHIBITION OF INVASION IN-VITRO AND STIMULATION OF AGGREGATION BY 13-CIS RETINOIC ACID CORRELATES WITH THE CLUSTERING OF N-CAM IN C-HA-RAS TRANSFORMED GLIAL-CELLS

Invasion distinguishes malignant from benign primary brain tumors. The molecular mechanisms which permit malignant brain tumor cells to esca pe from the primary tumor mass and by which they can migrate through n ormal brain tissue are largely unknown. 13-cis retinoic acid (cRA) can induce morphological, biochemical and functional differentiation char acteristics in various malignant tumors. Upon treatment of diffusely i nvasive hamster glial cells (CxT24neo3) with 30 mu M cRA, we found a s ignificant reduction in cell proliferation in monolayer and spheroid c ultures. cRA also inhibits invasion of CxT24neo3 through a reconstitut ed basement membrane (Matrigel(R)) in a dose dependent manner. Homotyp ic cell-cell adhesion, on the contrary, is stimulated in the absence o f extracellular Ca++ by either treatment or pretreatment of CxT24neo3 with cRA. These phenotypic changes correlate with the induction of the clustering of the neural cell adhesion molecule: N-CAM at sites of ce ll-cell contact. This phenomenon is observed following immunohistochem ical staining for N-CAM of CxT24neo3 cells that were treated with cRA in monolayer cultures. The relationship between reduction of prolifera tion and invasion in vitro and the increased homotypic cell-cell adhes ion with clustering of N-CAM implicates N-CAM as a molecular effector molecule for reduction of malignancy by cRA.