Mareel M, Vleminckx K, Vermeulen S, Yan G, Bracke M, van Roy F
Laboratory of Experimental Cancerology, University of Gent, Belgium.
Princess Takamatsu Symp. 1994;24:63-80.
The invasion-suppressor molecule E-cadherin (E-CAD) can be regulated at multiple levels: synthesis, processing and stability of mRNA; synthesis, processing and stability of protein; localization and posttranslational modification of protein; binding to catenins (E-CAD-associated proteins); and size and charge of cell surface glycosaminoglycans. Loss of E-CAD antigen and of E-CAD function in vivo has been observed with cell lines that homogeneously expressed functional E-CAD in vitro. These observations led to the idea that factors in the host may downmodulate E-CAD on the cancer cells, thereby promoting cell invasion. Nude mouse cancers that were homogeneously E-CAD-positive and noninvasive in vitro, formed by epithelioid MDCK or NMuMG cells, stained heterogeneously for E-CAD; such cancers were invasive and metastatic. The in vivo downmodulation appeared to be transient. Ex vivo cultures from primary cancers, as well as from metastases, produced homogeneously E-CAD-positive and noninvasive cells. Downmodulation did not occur when cells were micro-encapsulated and then implanted in the mouse, suggesting a role for immediate cancer cell-host cell contact. Similar in vitro/in vivo/ex vivo experiments with mouse MO4 fibrosarcoma cells, transfected with E-CAD cDNA under the control of a b-actin promotor, showed downregulation at the transcriptional or mRNA stability level. This downregulation was rapidly reversible upon ex vivo culture of the tumor cells. TGF-bl and IGF-I were found, respectively, to downregulate and upregulate the expression or the function of E-CAD. We speculate that IGF-1 restores the function of E-CAD through interaction of the IGF-I tyrosine kinase receptor with the catenin-actin cytoskeletal complex. In human cancers, immunohistochemistry has revealed changes in E-cadherin that agree with the experimental data on transient downmodulation of the invasion-suppressor function of E-cadherin by host factors.
侵袭抑制分子E-钙黏蛋白（E-CAD）可在多个水平受到调控：mRNA的合成、加工及稳定性；蛋白质的合成、加工及稳定性；蛋白质的定位及翻译后修饰；与连环蛋白（E-CAD相关蛋白）的结合；以及细胞表面糖胺聚糖的大小和电荷。在体外均匀表达功能性E-CAD的细胞系中，已观察到体内E-CAD抗原和E-CAD功能的丧失。这些观察结果引发了这样一种观点，即宿主中的因素可能下调癌细胞上的E-CAD，从而促进细胞侵袭。由上皮样MDCK或NMuMG细胞形成的、在体外均匀E-CAD阳性且无侵袭性的裸鼠癌，E-CAD染色呈异质性；此类癌具有侵袭性和转移性。体内下调似乎是短暂的。来自原发性癌以及转移灶的体外培养物产生了均匀E-CAD阳性且无侵袭性的细胞。当细胞被微囊化然后植入小鼠体内时，下调并未发生，这表明癌细胞与宿主细胞的直接接触起了作用。对在β-肌动蛋白启动子控制下转染了E-CAD cDNA的小鼠MO4纤维肉瘤细胞进行的类似体外/体内/体外实验，显示在转录或mRNA稳定性水平存在下调。肿瘤细胞体外培养后，这种下调可迅速逆转。已发现转化生长因子β1（TGF-β1）和胰岛素样生长因子I（IGF-I）分别下调和上调E-CAD的表达或功能。我们推测，IGF-1通过IGF-I酪氨酸激酶受体与连环蛋白-肌动蛋白细胞骨架复合物的相互作用来恢复E-CAD的功能。在人类癌症中，免疫组织化学已揭示E-钙黏蛋白的变化，这与关于宿主因素对E-钙黏蛋白侵袭抑制功能进行短暂下调的实验数据一致。
