Friedlander D R, Zagzag D, Shiff B, Cohen H, Allen J C, Kelly P J, Grumet M
Department of Pharmacology, New York University Medical Center, 10016,USA.
Cancer Res. 1996 Apr 15;56(8):1939-47.
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 extra-cellular 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 micrometers/16 h: n = 16) than cells from lower grade astrocytomas (28.9 +/- 3.9 micrometers/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 micrometers/16 h) and cells from high-grade astrocytomas at higher levels (24.4 +/- 5.2 micrometers;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 micrometers/16 h; P = 0.03), in particular, on collagens (108.4 +/- 20.2 versus 28.0 +/- 6.1 micrometers/16 h; P= 0.001). Specific monoclonal antibodies to alphaV and beta1 integrin monomers completely inhibited the migration of astrocytoma cells on most substrates, suggesting that alphaV and beta1 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.
脑肿瘤恶性程度的一个重要因素是其浸润脑实质的能力。细胞表面的细胞外基质分子和细胞黏附分子在细胞迁移中起关键作用。在本研究中，我们使用新鲜切除的人脑肿瘤解离细胞的重聚体，分析不同类型和级别的人脑肿瘤细胞在吸附于玻璃基质上的多种不同黏附蛋白上的迁移情况。选择这些蛋白质是基于它们在正常或肿瘤性神经组织中的存在情况，包括细胞外基质分子纤连蛋白、胶原蛋白、纤维蛋白原、层粘连蛋白、腱生蛋白-C、血小板反应蛋白，以及神经元-胶质细胞黏附分子Ng-CAM。星形细胞瘤细胞（n = 24）在多种基质上迁移，而原始神经外胚层肿瘤细胞（n = 6）仅在层粘连蛋白、纤连蛋白或IV型胶原上迁移良好，在其他基质上则不然。通常，各级星形细胞瘤的迁移细胞有长而细的突起，通常为双极，其细胞体在任何基质上都不能很好地铺展。尽管同一级别的星形细胞瘤细胞迁移存在差异，但高级别星形细胞瘤细胞（42.3±4.7微米/16小时；n = 16）比低级别星形细胞瘤细胞（28.9±3.9微米/16小时；P = 0.07；n = 8）迁移更广泛；在胶原基质上观察到最显著的差异，低级别星形细胞瘤细胞在胶原基质上迁移水平极低（7.6±2.6微米/16小时），而高级别星形细胞瘤细胞迁移水平较高（24.4±5.2微米；P = 0.01）。与胶质母细胞瘤原代细胞（n = 13）不同，胶质母细胞瘤细胞系（n = 10）始终能在各种基质上铺展并高水平迁移（69.5±7.6对46.4±5.7微米/16小时；P = 0.03），尤其是在胶原上（108.4±20.2对28.0±6.1微米/16小时；P = 0.001）。针对αV和β1整合素单体的特异性单克隆抗体完全抑制了星形细胞瘤细胞在大多数基质上的迁移，表明αV和β1整合素在脑肿瘤浸润中起关键作用。这些研究还表明，尽管大量细胞外基质分子可能促进肿瘤细胞迁移，但仅破坏少数肿瘤细胞受体的功能可能对脑肿瘤浸润至关重要。
