Perl A K, Wilgenbus P, Dahl U, Semb H, Christofori G
Research Institute of Molecular Pathology, Vienna, Austria.
Nature. 1998 Mar 12;392(6672):190-3. doi: 10.1038/32433.
Development of malignant tumours is in part characterized by the ability of a tumour cell to overcome cell-cell adhesion and to invade surrounding tissue. E-cadherin is the main adhesion molecule of epithelia, and it has been implicated in carcinogenesis because it is frequently lost in human epithelial cancers. Re-establishing the functional cadherin complex in tumour cell lines results in a reversion from an invasive to a benign epithelial phenotype. However, it remained unresolved whether the loss of E-cadherin-mediated cell adhesion was a cause or a consequence of tumour progression in vivo. Here we report that the loss of E-cadherin expression coincides with the transition from well differentiated adenoma to invasive carcinoma in a transgenic mouse model of pancreatic beta-cell carcinogenesis (Rip1Tag2). Intercrossing Rip1Tag2 mice with transgenic mice that maintain E-cadherin expression in beta-tumour cells results in arrest of tumour development at the adenoma stage, whereas expression of a dominant-negative form of E-cadherin induces early invasion and metastasis. The results demonstrate that loss of E-cadherin-mediated cell adhesion is one rate-limiting step in the progression from adenoma to carcinoma.
恶性肿瘤的发展部分特征在于肿瘤细胞克服细胞间粘附并侵入周围组织的能力。E-钙粘蛋白是上皮细胞的主要粘附分子，它与致癌作用有关，因为它在人类上皮癌中经常缺失。在肿瘤细胞系中重新建立功能性钙粘蛋白复合物会导致从侵袭性上皮表型转变为良性上皮表型。然而，E-钙粘蛋白介导的细胞粘附丧失是体内肿瘤进展的原因还是结果仍未得到解决。在此我们报告，在胰腺β细胞致癌的转基因小鼠模型（Rip1Tag2）中，E-钙粘蛋白表达的丧失与从高分化腺瘤向侵袭性癌的转变同时发生。将Rip1Tag2小鼠与在β肿瘤细胞中维持E-钙粘蛋白表达的转基因小鼠杂交，会导致肿瘤发展在腺瘤阶段停滞，而表达显性负性形式的E-钙粘蛋白会诱导早期侵袭和转移。结果表明，E-钙粘蛋白介导的细胞粘附丧失是从腺瘤进展为癌的一个限速步骤。
