Astrocytomas often show high rates of local invasion that lead to local recurrence of the disease. Histologically, the most highly invasive astvocytoma cells are detected in isolation rather than as nests of tumor. Our study attempted to determine whether the migratory response to extracellular substrates influences the proliferative behavior of these highly invasive cells. The preferential and specific migratory response of human astrocytoma cells to extracellular matrix proteins was assessed by P microliter scale migration assay. Growth curve studies on protein ligands permissive (merosin) for cell migration indicated that the lag phase was protracted compared with cells seeded on nowpermissive proteins (vitronectin). Once a certain cell density was reached, logarithmic proliferation was indistinguishable on the different proteins. The proliferation index of populations of cells migrating on merosin and vitronectin was measured by both BrdU incorporation and MIB-l irnmunocytochemistry labeling. Cells seeded on vitronectin showed higher proliferation throughout the population than cells seeded an merosin. On merosin, the more migratory cells at the periphery were less proliferative than non-migratory cells in the central region of that population. The integrin-associated signal transduction protein, p I 25FAK, was heavily localized in the membrane of non-migrating cells and largely absent in migrating astrocytoma cells. We conclude that temporally, proliferation and migration are mutually exclusive behaviors. Cell density or non-permissiwe substrates that inhibit cell motility favor a more proliferative phenotype. Conversely, active migration suppresses cell proliferation.
o 1996 Wiley-lhs, Inc.
Extracellular maltrix (ECM), with its protein and nonprotein components, controls many aspects of cell behavior, such as differentiation, proliferation, cell shape, and cell attachment (Lin and Bissell, 1993). Some of these events are linked in a cascade-like fashion. For example, motility requires a cell to identify and attach to an extracellular ligand, then spread, devellop focal adhesion contacts, and adopt a shape that facilitates movement (Tawil et al., 1993). Integrin receptors are the dominant family of adhesion molecules that bind to protein components of the ECM (Hynes, 1987). These receptors are not only involved in recognition and cell adhesion to protein ligands, but they also directly mediate substratedependent cell motility.
Adhesion to ECM is required for cell cycle progression through G, (Guadagno et al., 1993). Ligand-induced clustering of integrins into adhesion contacts is the necessary signal for Go/Gl transition (McNamee et al., 1993), while integrindependent cell spreading regulates mid-late GI progression. Integrin receptors also mediate or have co-stimulatory effects on mitogenesis. The proliferative effect mediated by the