Nabeshima K, Inoue T, Shimao Y, Kataoka H, Koono M
Department of Pathology, Miyazaki Medical College, Japan.
Histol Histopathol. 1999 Oct;14(4):1183-97. doi: 10.14670/HH-14.1183.
Active migration of tumor cells is usually assessed as single cell locomotion in vitro using Boyden chamber-type assays. In vivo, however, carcinoma cells, malignant cells of epithelial origin, frequently invade the surrounding tissue as coherent clusters or nests of cells. We have called this type of movement "cohort migration". In our work, the invasion front of colon carcinomas consisted of compact tumor glands, partially resolved glands or markedly resolved glands with scattered tumor cell clusters or single cells lying ahead. In the former two types, which constituted about a half of all cases, cohort migration seems to be the predominant mechanism, whereas both cohort migration and single cell locomotion may be involved in the last one. In this light, it is very advantageous to investigate the mechanisms involved in the cohort migration. In this review, we present a two-dimensional motility assay as a cohort migration model, in which human colorectal carcinoma cells move outwards from the cell islands mainly as localized coherent sheets of cells when stimulated with 12-O-tetradecanoylphorbol-13-acetate (TPA) or hepatocyte growth factor/scatter factor (HGF/SF). Within the migrating cell sheets, wide intercellular gaps occur at the lower portion of the cells to allow the cells to extend leading lamellae forward while close cell-cell contacts remain at the upper portion of the cells. This localized modulation of cell-cell adhesion at the lower portion of the cells is associated with increased tyrosine phosphorylation of the E-cadherin-catenin complex in TPA-induced cohort migration and with reduced alpha-catenin complexed with E-cadherin in HGF/SF-induced cohort migration. Furthermore, fibronectin deposited by migrating cells is essential for their movement, and on the gelatin-coated substrate even degradation and remodeling of the substrate by matrix metalloproteinases are also needed. Thus, in cohort migration it is likely that cells are released from cell-cell adhesion only at the lower portion of the cells via modulation of E-cadherin-catenin-based mechanism, and this change allows the cells to extend leading lamellae onto the extracellular matrix substrate remodeled by deposition of fibronectin and organized digestion.
肿瘤细胞的主动迁移通常在体外使用博伊登室型试验评估为单细胞运动。然而，在体内，癌细胞（上皮来源的恶性细胞）经常以连贯的细胞簇或巢状形式侵入周围组织。我们将这种运动类型称为“群体迁移”。在我们的研究中，结肠癌的侵袭前沿由紧密的肿瘤腺体、部分解离的腺体或明显解离的腺体组成，前面有散在的肿瘤细胞簇或单个细胞。在前两种类型（约占所有病例的一半）中，群体迁移似乎是主要机制，而在最后一种类型中，群体迁移和单细胞运动可能都参与其中。有鉴于此，研究群体迁移所涉及的机制非常有利。在本综述中，我们提出了一种二维运动分析方法作为群体迁移模型，其中人结肠癌细胞在受到12-O-十四酰佛波醇-13-乙酸酯（TPA）或肝细胞生长因子/散射因子（HGF/SF）刺激时，主要以局部连贯的细胞片形式从细胞岛向外移动。在迁移的细胞片中，细胞下部会出现较宽的细胞间隙，以使细胞能够向前延伸前缘片层，而细胞上部则保持紧密的细胞间接触。在TPA诱导的群体迁移中，细胞下部细胞间粘附的这种局部调节与E-钙粘蛋白-连环蛋白复合物酪氨酸磷酸化增加有关，而在HGF/SF诱导的群体迁移中，与与E-钙粘蛋白结合的α-连环蛋白减少有关。此外，迁移细胞沉积的纤连蛋白对其运动至关重要，在明胶包被的底物上，甚至基质金属蛋白酶对底物的降解和重塑也是必需的。因此，在群体迁移中，细胞可能仅在细胞下部通过基于E-钙粘蛋白-连环蛋白机制的调节从细胞间粘附中释放出来，这种变化使细胞能够将前缘片层延伸到通过纤连蛋白沉积和有组织的消化而重塑的细胞外基质底物上。
