Role of fibrillar Tenascin-C in metastatic pancreatic cancer
Role of fibrillar Tenascin-C in metastatic pancreatic cancer
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DOI：
10.3892/ijo_00000228
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发表时间：
2009-04-01
影响因子：
5.2
通讯作者：
Li, Xiaowu
中科院分区：
文献类型：
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作者：
Chen, Jian;Chen, Zhiyu;Li, Xiaowu
癌细胞与基质细胞的相互作用通过重建现有的细胞外基质（ECM）微环境来促进肿瘤的进展。在肿瘤中，Tenascin-C （Tn-C）表达上调可能会改变肿瘤行为。然而，肿瘤-基质相互作用影响肿瘤微环境的分子机制尚未得到很好的表征。在这项研究中，我们分析了纤原性Tn-C （fTn-C）在人转移性胰腺癌中的表达。我们将两种胰腺癌细胞系，高转移性BxPc3细胞和非转移性PaCa2细胞与基质成纤维细胞（SF）共培养，评估基质金属蛋白酶2 （MMP-2）激活和基质成纤维细胞SF在促进tnc组织中的作用。接下来，我们通过细胞粘附和迁移试验评估纤原蛋白Tn-C是否促进胰腺癌细胞的运动。最后，我们通过将BxPc3和PaCa2细胞注射到裸鼠体内，观察体内MMP-2活化与fTn-C形成的关系。我们发现fTn-C在转移性胰腺癌中增加。fTn-C表达与MMP-2活性相关。在体外共培养中，fTn-C组织仅在BxPc3/SF共培养中发现，并且需要活性MMP-2的参与。fTn-C通过降低整合素α 6 β 1与ECM之间的粘附相互作用来降低细胞粘附并促进胰腺癌细胞迁移。体内肿瘤发生分析显示，与PaCa2肿瘤相比，BxPc3肿瘤中fTn-C的形成和活性MMP-2明显增加。这些结果表明，Tn-C在ECM中的沉积需要活性MMP-2和SF的参与。沉积的Tn-C可促进胰腺癌的进展。
Interaction of cancer cells with stroma cells facilitates tumor progression by rebuilding the existing extracellular matrix (ECM) microenvironment. In the tumor, upregulation of Tenascin-C (Tn-C) expression potentially can alter tumor behavior. However, the molecular mechanisms by which tumor-stroma interactions affect the tumor microenvironment have not been well characterized. In this study, we analyzed the expression of fibrillar Tn-C (fTn-C) in human metastatic pancreatic cancers. After co-culturing two pancreatic cancer cell lines, highly metastatic BxPc3 cells and non-metastatic PaCa2 cells, with stromal fibroblasts (SF), we evaluated the roles of matrix metalloproteinase 2 (MMP-2) activation and SF in promoting Tn-C organization. Next, we evaluated whether fibrillar Tn-C promotes pancreatic cancer cell movement using cell adhesion and migration assays. Finally, we observed the relationship between MMP-2 activation and fTn-C formation in vivo by injecting the BxPc3 and PaCa2 cells into nude mice. We found that fTn-C was increased in metastatic pancreatic cancer. The fTn-C expression correlated with MMP-2 activity. In the in vitro co-culture, fTn-C organization was found only in BxPc3/SF co-cultures, and required the participation of active MMP-2. The fTn-C reduced cell adhesion and promote pancreatic cancer cell migration by decreasing the adhesive interactions between integrin alpha 6 beta 1 and the ECM. The in vivo tumorigenesis analysis showed that the fTn-C formation and active MMP-2 were significantly increased in the BxPc3 tumors, compared to the PaCa2 tumors. These results demonstrate that Tn-C deposition into the ECM requires participation of active MMP-2 and SF. The deposited Tn-C could promote pancreatic cancer progression.