Role of extracellular matrix in tumor invasion: migration of glioma cells along fibronectin-positive mesenchymal cell processes.

Abstract

The major morbidity of glioma lies in its infiltrative growth. One of the major patterns of this invasive growth is the formation of Scherer's secondary structures associated with the blood vessels and the leptomeninges. To better understand the role of extracellular matrix (ECM) in glioma invasion, we investigated in vitro the interaction between glioma cells and the meningeal mesenchymal tissue from the brain. As an aid to this study, ECM in glioma cell line spheroids was compared with that in primary fetal brain aggregates. To study the expression of ECM, four glioma cell lines (U-87 MG, U-251 MG, AN1/lac-z, and HF-66) and primary cells from fetal rat brain were grown as spheroids and monolayers. To sudy the role of ECM in glioma invasion, spheroids from the glioma cell lines were grown over established cultures of fetal meningeal and mesenchymal tissue. Expression of fibronectin, laminin, tenascin, collagen VI, and chondroitin sulfate proteoglycan was studied by immunofluorescence. Expression of ECM by the spheroids was variable. U-87 MG expressed most of the ECM components robustly, whereas AN1/lac-z expressed them all weakly. Fetal rat brain aggregates produced minimal ECM. In cocultures of glioma spheroids and fetal meningeal mesenchymal tissue, individual cells from the glioma spheroids that expressed least fibronectin (AN1/lac-z and U-251 MG) migrated along the fibronectin-positive mesenchymal cells in the culture dish. Cells from the other two lines (U-87 MG and HF-66) that expressed fibronectin strongly did not demonstrate such behavior. None of the other ECM components showed a similar association; mesenchymal cells did not express laminin as strongly as fibronectin, and glioma cells were not observed to align with the laminin-positive structures. This study suggests that fibronectin may play a key role in intracerebral invasion of glioma cells.