Collagen type I induces disruption of E-cadherin-mediated cell-cell contacts and promotes proliferation of pancreatic carcinoma cells
Collagen type I induces disruption of E-cadherin-mediated cell-cell contacts and promotes proliferation of pancreatic carcinoma cells
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DOI：
10.1158/0008-5472.can-05-2804
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发表时间：
2006-05-01
期刊：
影响因子：
11.2
通讯作者：
Menke, Andre
中科院分区：
文献类型：
--
作者：
Koenig, Alexander;Mueller, Claudia;Menke, Andre
胰腺癌的特征在于其侵袭性、早期转移和大量细胞外基质（ECM）的产生。我们分析了I型胶原和纤连蛋白对胰腺癌细胞系中细胞粘附调节的影响，以表征ECM蛋白在胰腺癌发展中的作用。我们发现，I型胶原蛋白能够启动胰腺癌细胞中的E-钙粘蛋白粘附复合物的破坏。这是由于复合蛋白β-连环蛋白的酪氨酸磷酸化增加，其与粘着斑激酶的I型胶原依赖性活化及其与E-钙粘蛋白复合物的结合相关。粘着斑激酶的活化和募集依赖于I型胶原与含β 1整合素的相互作用以及整合素介导的细胞激酶Src的活化。E-钙粘蛋白粘附复合物的分解与β-连环蛋白的核转位相关，这导致β-连环蛋白-Lef/Tcf靶基因、细胞周期蛋白D1和c-myc的表达增加。除此之外，在I型胶原上生长的细胞显示出增强的细胞增殖。我们发现，由肿瘤产生的ECM成分通过减少E-钙粘蛋白介导的细胞间粘附和增强胰腺肿瘤细胞的增殖来促进侵袭和转移。
Pancreatic cancer is characterized by its invasiveness, early metastasis, and the production of large amounts of extracellular matrix (ECM). We analyzed the influence of type I collagen and fibronectin on the regulation of cellular adhesion in pancreatic cancer cell lines to characterize the role of ECM proteins in the development of pancreatic cancer. We show that collagen type I is able to initiate a disruption of the E-cadherin adhesion complex in pancreatic carcinoma cells. This is due to the increased tyrosine phosphorylation of the complex protein beta-catenin, which correlates with collagen type I-dependent activation of the focal adhesion kinase and its association with the E-cadherin complex. The activation and recruitment of focal adhesion kinase to the E-cadherin complex depends on the interaction of type I collagen with beta 1-containing integrins and an integrin-mediated activation of the cellular kinase Src. The disassembly of the E-cadherin adhesion complex correlates with the nuclear translocation of beta-catenin, which leads to an increasing expression of the beta-catenin-Lef/Tcf target genes, cyclin D1 and c-myc. In addition to that, cells grown on collagen type I show enhanced cell proliferation. We show that components of the ECM, produced by the tumor, contribute to invasiveness and metastasis by reducing E-cadherin-mediated cell-cell adhesion and enhance proliferation in pancreatic tumor cells.