Invasion distinguishes malignant from benign primary brain tumors. The molecular mechanisms which permit malignant brain tumor cells to escape from the primary tumor mass and by which they can migrate through normal brain tissue are largely unknown. 13-cis retinoic acid (cRA) can induce morphological, biochemical and functional differentiation characteristics in various malignant tumors. Upon treatment of diffusely invasive hamster glial cells (CxT24neo3) with 30 mu M cRA, we found a significant reduction in cell proliferation in monolayer and spheroid cultures. cRA also inhibits invasion of CxT24neo3 through a reconstituted basement membrane (Matrigel(R)) in a dose dependent manner. Homotypic cell-cell adhesion, on the contrary, is stimulated in the absence of 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 cell-cell contact. This phenomenon is observed following immunohistochemical staining for N-CAM of CxT24neo3 cells that were treated with cRA in monolayer cultures. The relationship between reduction of proliferation and invasion in vitro and the increased homotypic cell-cell adhesion with clustering of N-CAM implicates N-CAM as a molecular effector molecule for reduction of malignancy by cRA.

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