RESUMEN
Human gliomas are characterized by their invasion of normal brain structures irrespective of their grade of malignancy. Factors involved in the control of this invasive behavior are poorly documented. Human gliomas have also been found to express CD44 adhesion molecules. Expression of splice variants of CD44 has been correlated to metastasis in nonglial solid tumors. In this study, 8-microns porosity polycarbonate filters incorporated in modified Boyden chambers and coated with the extracellular matrix composite Matrigel were used to investigate the role of CD44 in invasion of eight human glioma cell lines in vitro. Invasion of Matrigel was found to be inhibited to different extents by a CD44 monoclonal antibody. Moreover, this invasion was highly inhibited in two cell lines and completely arrested in five other glioma cell lines by a CD44-specific antisense oligonucleotide which inhibited CD44 expression. In addition, adhesion of glioma cells to fibronectin, laminin, vitronectin, and collagen I was inhibited by the CD44 monoclonal antibody. These results strongly suggest that CD44 is involved in human glioma cell invasion in vitro, probably through its role in cell interactions with extracellular matrix proteins. Interference with glioma invasion, by targeting CD44 expression, may be envisaged in animal models.
Asunto(s)
Proteínas Portadoras/fisiología , Glioma/patología , Invasividad Neoplásica , Receptores de Superficie Celular/fisiología , Receptores Mensajeros de Linfocitos/fisiología , Secuencia de Bases , Proteínas Portadoras/antagonistas & inhibidores , Adhesión Celular/inmunología , Colágeno , Cámaras de Difusión de Cultivos , Combinación de Medicamentos , Glioma/inmunología , Humanos , Receptores de Hialuranos , Laminina , Datos de Secuencia Molecular , Invasividad Neoplásica/inmunología , Invasividad Neoplásica/patología , Oligonucleótidos Antisentido/farmacología , Proteoglicanos , Receptores de Superficie Celular/antagonistas & inhibidores , Receptores Mensajeros de Linfocitos/antagonistas & inhibidores , Células Tumorales CultivadasRESUMEN
Factors involved in the control of the biological properties of gliomas, the major form of brain tumour in man, are poorly documented. We investigated the role of transforming growth factor beta 1 (TGF-beta 1) in the control of proliferation of human glioma cell lines as well as normal human fetal brain cells. The data presented show that TGF-beta 1 exerts a growth-inhibitory action on both human fetal brain cells and three cell lines derived from human glioma of different grades of malignancy. In addition, this growth-inhibitory effect is dose dependent and serum independent. Since TGF-beta 1 is known to be involved in the control of cell migration during ontogenesis and oncogenesis, we investigated the role of this factor in the motile and invasive behaviour that characterises human gliomas in vivo. TGF-beta 1 was found to elicit a strong stimulation of migration and invasiveness of glioma cells in vitro. In combination with recent data showing an inverse correlation between TGF-beta 1 expression in human gliomas and survival, these findings may suggest that TGF-beta 1 plays an important role in the malignant progression of gliomas in man. A study of the molecular mechanisms involved in the antiproliferative action and the invasion-promoting action of TGF-beta 1 may help to identify new targets in therapy for brain tumours. A combined antiproliferative and anti-invasive therapy could be envisaged.