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首页> 外文期刊>Journal of experimental & clinical cancer research : >Integrin alpha-V is an important driver in pancreatic adenocarcinoma progression
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Integrin alpha-V is an important driver in pancreatic adenocarcinoma progression

机译：整合素alpha-V是胰腺腺癌进展中的重要司机

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Mesothelial E- and P-selectins substantially mediate the intraperitoneal spread of Pancreatic ductal adenocarcinoma (PDA) cells in xenograft models. In the absence of selectins in the host, the integrin subunit alpha-V (ITGAV, CD51) was upregulated in the remaining metastatic deposits. Here we present the first experimental study to investigate if ITGAV plays a functional role in PDA tumor growth and progression with a particular focus on intraperitoneal carcinomatosis. Knockdown of ITGAV was generated using an RNA interference-mediated approach in two PDA cell lines. Tumor growth, intraperitoneal and distant metastasis were analyzed in a xenograft model. Cell lines were characterized in vitro. Gene expression of the xenograft tumors was analyzed. Patient samples were histologically classified and associations to survival were evaluated. The knockdown of ITGAV in PDA cells strongly reduces primary tumor growth, peritoneal carcinomatosis and spontaneous pulmonary metastasis. ITGAV activates latent TGF-β and thereby drives epithelial-mesenchymal transition. Combined depletion of ITGAV on the tumor cells and E- and P-selectins in the tumor-host synergistically almost abolishes intraperitoneal spread. Accordingly, high expression of ITGAV in PDA cells was associated with reduced survival in patients. Combined depletion of ITGAV in PDA cells and E- and P-selectins in host mice massively suppresses intraperitoneal carcinomatosis of PDA cells xenografted into immunodeficient mice, confirming the hypothesis of a partly redundant adhesion cascade of metastasizing cancer cells. Our data strongly encourage developing novel therapeutic approaches for the combined targeting of E- and P-selectins and ITGAV in PDA.
机译：间皮e-和p型选择素基本上介导异种移植模型中胰腺导管腺癌（PDA）细胞的腹膜内扩散。在宿主中没有选择素的情况下，在剩余的转移性沉积中上调整联蛋白亚基α-V（Itgav，CD51）。在这里，我们提出了第一个试验研究，以调查ITGAV在PDA肿瘤生长和进展中对腹膜内癌症的特定重点发挥作用。使用两种PDA细胞系中的RNA干扰介导的方法产生ITGAV的敲低。在异种移植模型中分析肿瘤生长，腹膜内和远处转移。细胞系的特征在体外。分析了异种移植肿瘤的基因表达。患者样品是组织学分类的，并评估生存的关键化。 PDA细胞中ITGAV的敲低强调原发性肿瘤生长，腹膜癌症和自发性肺转移。 ITGAV激活潜伏的TGF-β，从而推动上皮 - 间充质转换。在肿瘤细胞和肿瘤 - 宿主中的肿瘤细胞和e-和p-Selectins上的结合耗尽肿瘤 - 宿主协同互及的腹膜内扩散。因此，PDA细胞中的ITGAV的高表达与患者的存活率降低相关。 Host小鼠中的PDA细胞中ITGAV的组合耗尽大致抑制PDA细胞异种移植到免疫缺陷小鼠的腹腔致癌物质，证实了癌细胞部分冗余粘附级联的假设。我们的数据强烈鼓励开发新的治疗方法，以便在PDA中综合靶向靶向靶向靶向靶向和ITGAV。

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