Behrens J, Weidner K M, Frixen U H, Schipper J H, Sachs M, Arakaki N, Daikuhara Y, Birchmeier W
Institut für Zellbiologie (Tumorforschung), Universitätsklinikum, Essen, Germany.
EXS. 1991;59:109-26. doi: 10.1007/978-3-0348-7494-6_8.
The acquisition of invasive properties by transformed epithelial cells constitutes an essential step in the progression of carcinomas. We have defined 2 types of interferences leading to enhanced motility and invasiveness of epithelial cells: (i) disturbances of intercellular adhesion, and (ii) treatment with "scatter factor", a secretory protein of mesenchymal cells. Invasive properties (invasion of collagen gels or embryonal heart tissue) are acquired by epithelial cells in vitro when intercellular adhesion is inhibited by antibodies that are specific for the cell-cell adhesion molecule E-cadherin. Furthermore, we found that differentiated human carcinoma cell lines are noninvasive and express E-cadherin, whereas dedifferentiated carcinoma lines are invasive and have lost E-cadherin expression. Invasiveness of these latter cells could be prevented by transfection with E-cadherin cDNA and was again induced by treatment of the transfected cells with anti-E-cadherin antibodies. A correlation between the degree of tumor differentiation and the amount of E-cadherin expression was also visualized on frozen sections of ovarian carcinomas, lobular breast carcinomas, and squamous carcinomas of head and neck. Thus, loss of E-cadherin appears to be a critical step in the establishment of an invasive, i.e. fully malignant phenotype. Scatter factor, which is also capable of dissociating epithelial cell colonies in vitro, was isolated from conditional medium of human fibroblasts; it is a 92,000 mol.wt glycoprotein, which is proteolytically cleaved into 62,000 and 34/32,000 mol.wt subunits. The purified glycoprotein induces invasion of MDCK cells into collagen matrices, and induces or enhances the invasive properties of various human carcinoma cell lines. Sequencing of tryptic peptides of scatter factor revealed strong similarity with hepatocyte growth factor. Furthermore, both factors exhibit identical activities, i.e. scatter factor stimulates DNA synthesis of primary hepatocytes and hepatocyte growth factor dissociates and increases the motility of various epithelial cells. Thus scatter factor and hepatocyte growth factor represent identical or closely similar proteins.
转化的上皮细胞获得侵袭特性是癌进展过程中的一个关键步骤。我们已经确定了两种导致上皮细胞运动性和侵袭性增强的干扰类型：（i）细胞间黏附的干扰，以及（ii）用“散射因子”处理，散射因子是间充质细胞的一种分泌蛋白。当细胞间黏附被针对细胞间黏附分子E-钙黏蛋白的特异性抗体抑制时，上皮细胞在体外获得侵袭特性（侵袭胶原凝胶或胚胎心脏组织）。此外，我们发现分化的人癌细胞系是非侵袭性的且表达E-钙黏蛋白，而去分化的癌细胞系是侵袭性的且已失去E-钙黏蛋白表达。用E-钙黏蛋白cDNA转染可阻止这些后者细胞的侵袭性，并用抗E-钙黏蛋白抗体处理转染细胞可再次诱导侵袭性。在卵巢癌、小叶乳腺癌和头颈部鳞状癌的冰冻切片上也观察到肿瘤分化程度与E-钙黏蛋白表达量之间的相关性。因此，E-钙黏蛋白的缺失似乎是建立侵袭性即完全恶性表型的关键步骤。散射因子也能够在体外使上皮细胞集落解离，它是从人成纤维细胞的条件培养基中分离出来的；它是一种92,000分子量的糖蛋白，被蛋白水解切割成62,000和34/32,000分子量的亚基。纯化的糖蛋白诱导MDCK细胞侵袭胶原基质，并诱导或增强各种人癌细胞系的侵袭特性。散射因子胰蛋白酶肽段的测序显示与肝细胞生长因子有很强的相似性。此外，这两种因子表现出相同的活性，即散射因子刺激原代肝细胞的DNA合成，而肝细胞生长因子使各种上皮细胞解离并增加其运动性。因此，散射因子和肝细胞生长因子代表相同或非常相似的蛋白质。
