Institute of Pathology, University Medical Center Freiburg, Freiburg, Germany; Comprehensive Cancer Center, Freiburg, Germany.
Institute of Pathology, University Medical Center Freiburg, Freiburg, Germany.
Surgery. 2014 Jul;156(1):97-108. doi: 10.1016/j.surg.2014.02.018. Epub 2014 Feb 28.
Pancreatic ductal adenocarcinoma (PDAC) is characterized by an aggressive biology and poor prognosis. Experimental evidence has suggested a role for the transcriptional repressor Zinc finger E-box binding homeobox 1 (ZEB1) in epithelial-mesenchymal transition, invasion, and metastasis in PDAC. ZEB1 expression has been observed in cancer cells as well as stromal fibroblasts. Our study aimed to evaluate the prognostic value of ZEB1 expression in PDAC tissue.
Patient baseline and follow-up data were extracted from a prospectively maintained database. After clinicopathologic re-review, serial sliced tissue slides were immunostained for ZEB1, E-cadherin, vimentin, and pan-cytokeratin. ZEB1 expression in cancer cells and adjacent stromal fibroblasts was graded separately and correlated to routine histopathologic parameters and survival after resection.
A total of 117 cases of PDAC were included in the study. High ZEB1 expression in cancer cells and in stromal cancer-associated fibroblasts was associated with poor prognosis. There was also a trend for poor prognosis with a lymph node ratio of greater than 0.10. In line with its role as an inducer of epithelial-mesenchymal transition, ZEB1 expression in cancer cells was positively correlated with Vimentin expression and negatively with E-Cadherin expression. In multivariate analysis, stromal ZEB1 expression grade was the only independent factor of survival after resection.
Our data suggest that ZEB1 expression in cancer cells as well as in stromal fibroblasts are strong prognostic factors in PDAC. Stromal ZEB1 expression is identified for the first time as an independent predictor of survival after resection of PDAC. This observation suggests that therapies targeting ZEB1 and its downstream pathways could hit both cancer cells and supporting cancer-associated fibroblasts.
胰腺导管腺癌（PDAC）以侵袭性生物学和预后不良为特征。实验证据表明，转录抑制因子锌指 E 盒结合同源盒 1（ZEB1）在 PDAC 的上皮间质转化、浸润和转移中起作用。ZEB1 表达已在癌细胞以及基质成纤维细胞中观察到。我们的研究旨在评估 PDAC 组织中 ZEB1 表达的预后价值。
从一个前瞻性维护的数据库中提取患者的基线和随访数据。在临床病理重新审查后，对连续切片组织进行 ZEB1、E-钙黏蛋白、波形蛋白和细胞角蛋白的免疫染色。分别对癌细胞和相邻基质成纤维细胞中的 ZEB1 表达进行分级，并与常规组织病理学参数和切除后的生存相关联。
本研究共纳入 117 例 PDAC 病例。癌细胞和基质癌相关成纤维细胞中 ZEB1 表达高与预后不良相关。淋巴结比率大于 0.10 也与预后不良趋势相关。与作为上皮间质转化诱导剂的作用一致，癌细胞中的 ZEB1 表达与波形蛋白表达呈正相关，与 E-钙黏蛋白表达呈负相关。多变量分析表明，基质 ZEB1 表达分级是切除后生存的唯一独立因素。
我们的数据表明，癌细胞和基质成纤维细胞中的 ZEB1 表达是 PDAC 的强预后因素。首次发现基质 ZEB1 表达是 PDAC 切除后生存的独立预测因子。这一观察结果表明，靶向 ZEB1 及其下游途径的治疗方法可能同时针对癌细胞和支持性癌相关成纤维细胞。
