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Migration of Brain Tumor Cells on Extracellular Matrix Proteins in Vitro Correlates with Tumor Type and Grade and Involves _v and ß₁ Integrins¹

Department of Pharmacology [D. R. F., B. S., M. G.], Department of Neurology [D. R. F., J. C. A.], Brain Tumor Research Center [D. R. F., D. Z., J. C. A., P. J. K., M. G.], Department of Pathology, Division of Neuropathology [D. Z.], and the Kaplan Comprehensive Cancer Center [D. Z. J. C. A., P. J. K., M. G.], Department of Neurosurgery [B. S., P. J. K.], and the Clinical Research Center and Environmental Medicine [H. C.], New York University Medical Center, New York, New York 10016

An important contributor to the malignancy of brain tumors is their ability 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 from 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 included the extracellular matrix molecules fibronectin, collagens, fibrinogen, laminin, tenascin-C, thrombospondin, and the neuron-glia cell adhesion molecule, Ng-CAM. Cells from astrocytomas (n = 24) migrated on a variety of substrates, in contrast to cells from primitive neuroectodermal tumors cells (n = 6), which only migrated well on laminin, fibronectin, or type IV collagen but not on the other substrates. Typically, migrating cells from astrocytomas of all grades had long, slender processes, were usually bipolar, and their cell bodies did not spread well on any substrate. Although there was variability in the migration of cells from astrocytomas of the same grade, cells from high-grade astrocytomas tended to migrate more extensively (42.3 ± 4.7 µm/16 h; n = 16) than cells from lower grade astrocytomas (28.9 ± 3.9 µm/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 µm/16 h) and cells from high-grade astrocytomas at higher levels (24.4 ± 5.2 µm/16 h; P = 0.01). In contrast to primary cells from glioblastomas (n = 13), glioblastoma cell lines (n = 10) consistently spread on various substrates and migrated at high levels (69.5 ± 7.6 versus 46.4 ± 5.7 µm/16 h; P = 0.03), in particular, on collagens (108.4 ± 20.2 versus 28.0 ± 6.1 µm/16 h; P = 0.001). Specific monoclonal antibodies to _v and ß₁ integrin monomers completely inhibited the migration of astrocytoma cells on most substrates, suggesting that _v and ß₁ integrins play a crucial role in brain tumor infiltration. These studies also suggest that although a large number of extracellular matrix molecules may promote tumor cell migration, disrupting the function of only a few tumor cell receptors may be critical for tumor infiltration in the brain.

¹ This work was supported by grants from NIH (NS 31088), The Children's Brain Tumor Foundation, and The Long Island League Against Cancer.

² To whom requests for reprints should be Addressed, at Department of Pharmacology, New York University Medical Center, New York, NY 10016.

Received 12/ 5/95. Accepted 2/16/96.

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