Epithelial-to-mesenchymal transition in pancreatic ductal adenocarcinoma and pancreatic tumor cell lines: the role of neutrophils and neutrophil-derived elastase.
Epithelial-to-mesenchymal transition in pancreatic ductal adenocarcinoma and pancreatic tumor cell lines: the role of neutrophils and neutrophil-derived elastase.
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DOI：
10.1155/2012/720768
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发表时间：
2012
影响因子：
--
通讯作者：
Gaida MM
中科院分区：
文献类型：
--
作者：
Grosse-Steffen T;Giese T;Giese N;Longerich T;Schirmacher P;Hänsch GM;Gaida MM
胰腺导管腺癌(PDAC)常伴有纤维化和结缔组织增生性间质的显著炎性浸润性病变。此外，在PDAC中，可观察到上皮向间充质转化(EMT)。为了探讨浸润性细胞尤其是中性粒细胞与肿瘤细胞转化之间的可能联系，我们分析了115例弥漫性腹水癌患者的中性粒细胞浸润和β-连环蛋白和ZEB1的核表达。在有密集中性粒细胞浸润物的活检组织中，可以观察到β-连环蛋白和ZEB1的核聚集。为了解决PMN是否可以诱导EMT的问题，从健康捐赠者中分离出PMN，并将其与单层生长的胰腺肿瘤细胞共同培养。肿瘤细胞迅速萎缩，很可能是由于弹性酶介导的E-钙粘附素的降解。同时，转录因子螺旋上调，β-连环蛋白转位进入细胞核，ZEB1出现在细胞核内，角蛋白表达下调。当肿瘤细胞在防止附着在培养板上的条件下生长时，也会诱导EMT。在这里，同样在没有弹性蛋白酶的情况下，E-钙粘附素被下调。PMN以及预防黏附诱导的EMT也在肝癌细胞系中发挥作用。综上所述，PMN通过弹性蛋白酶在体外诱导EMT，很可能是由于失去了细胞与细胞之间的接触。因为在胰腺癌中，向间充质表型的转变与PMN的浸润相一致，因此炎症反应对EMT的诱导以及--暗示--对肿瘤进展的贡献是可能的。
Pancreatic ductal adenocarcinoma (PDAC) is frequently associated with fibrosis and a prominent inflammatory infiltrate in the desmoplastic stroma. Moreover, in PDAC, an epithelial-to-mesenchymal transition (EMT) is observed. To explore a possible connection between the infiltrating cells, particularly the polymorphonuclear neutrophils (PMN) and the tumor cell transition, biopsies of patients with PDAC (n = 115) were analysed with regard to PMN infiltration and nuclear expression of β-catenin and of ZEB1, well-established indicators of EMT. In biopsies with a dense PMN infiltrate, a nuclear accumulation of β-catenin and of ZEB1 was observed. To address the question whether PMN could induce EMT, they were isolated from healthy donors and were cocultivated with pancreatic tumor cells grown as monolayers. Rapid dyshesion of the tumor cells was seen, most likely due to an elastase-mediated degradation of E-cadherin. In parallel, the transcription factor TWIST was upregulated, β-catenin translocated into the nucleus, ZEB1 appeared in the nucleus, and keratins were downregulated. EMT was also induced when the tumor cells were grown under conditions preventing attachment to the culture plates. Here, also in the absence of elastase, E-cadherin was downmodulated. PMN as well as prevention of adhesion induced EMT also in liver cancer cell line. In conclusion, PMN via elastase induce EMT in vitro, most likely due to the loss of cell-to-cell contact. Because in pancreatic cancers the transition to a mesenchymal phenotype coincides with the PMN infiltrate, a contribution of the inflammatory response to the induction of EMT and—by implication—to tumor progression is possible.
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