MIGRATION OF BRAIN-TUMOR CELLS ON EXTRACELLULAR-MATRIX PROTEINS IN-VITRO CORRELATES WITH TUMOR TYPE AND GRADE AND INVOLVES ALPHA(V) AND BETA(1) INTEGRINS

An important contributor to the malignancy of brain tumors is their ab ility to infiltrate the brain, Extracellular matrix molecules and cell adhesion molecules on cell surfaces play key roles in cell migration. In the present study, we used reaggregates of dissociated cells from freshly excised human brain tumors to analyze the migration of cells f rom human brain tumors of different types and grades on many different adhesion proteins adsorbed to glass substrates. Proteins were chosen based on their presence in normal or neoplastic nervous tissue, and in cluded the extracellular matrix molecules fibronectin, collagens, fibr inogen, laminin, tenascin-C, thrombospondin, and the neuron-glia cell adhesion molecule, Ng-CAM. Cells from astrocytomas (n = 24) migrated o n a variety of substrates, in contrast to cells from primitive neuroec todermal tumors cells (rt = 6), which only migrated well on laminin, f ibronectin, or type IV collagen but not on the other substrates. Typic ally, migrating cells from astrocytomas of all grades had long, slende r processes, were usually bipolar, and their cell bodies did not sprea d well on any substrate. Although there was variability in the migrati on of cells from astrocytomas of the same grade, cells from high-grade astrocytomas tended to migrate more extensively (42.3 +/- 4.7 mu m/16 h; n = 16) than cells from lower grade astrocytomas (28.9 +/- 3.9 mu m/16 h; P = 0.07; n = 8); the most striking differences were observed for collagen substrates, on which cells from lower grade astrocytomas migrated at very low levels (7.6 +/- 2.6 mu m/16 h) and cells from hig h-grade astrocytomas at higher levels (24.4 +/- 5.2 mu m/16 h; P = 0.0 1). In contrast to primary cells from glioblastomas (n = 13), glioblas toma cell lines (n = 10) consistently spread on various substrates and migrated at high levels (69.5 +/- 7.6 versus 46.4 +/- 5.7 mu m/16 h; P = 0.03), in particular, on collagens (108.4 +/- 20.2 versus 28.0 +/- 6.1 mu m/16 h; P = 0.001). Specific monoclonal antibodies to cu, and P, integrin monomers completely inhibited the migration of astrocytoma cells on most substrates, suggesting that alpha(v) and beta(1) integr ins play a crucial role in brain tumor infiltration. These studies als o suggest that although a large number of extracellular matrix molecul es may promote tumor cell migration, disrupting the function of only a few tumor cell receptors may be critical for tumor infiltration in th e brain.