Institute for Experimental Medicine, Group Inflammatory Carcinogenesis, UKSH Campus Kiel, Kiel, Germany.
Institute of Immunology, UKSH Campus Kiel, Kiel, Germany.
PLoS One. 2014 May 5;9(5):e94357. doi: 10.1371/journal.pone.0094357. eCollection 2014.
Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive stroma being also present in chronic pancreatitis (CP). Using immunohistochemistry, the stroma of CP and PDAC was comprehensively analyzed and correlated with epithelial/carcinoma-related alterations and clinicopathological patient characteristics. While there were no significant differences between CP and PDAC regarding the distribution of CD3+ T cells and α-SMA+ fibroblasts, proportions of CD4+ and CD8+ T cells were significantly lower and numbers of CD25+(CD4+) and FoxP3+(CD4+) regulatory T cells were greater in PDAC compared with CP. Macrophages were more prevalent in CP, but localized more closely to carcinoma cells in PDAC, as were γδ-T cells. Duct-related FoxP3 and L1CAM expression increased from CP to PDAC, while vimentin expression was similarly abundant in both diseases. Moreover, stromal and epithelial compartments of well-differentiated tumors and CPs shared considerable similarities, while moderately and poorly differentiated tumors significantly differed from CP tissues. Analysis of 27 parameters within each pancreatic disease revealed a significant correlation of i) CD4+ and FoxP3+CD4+ T cells with FoxP3 expression in PDAC cells, ii) α-SMA+ fibroblasts with L1CAM expression and proliferation in PDAC cells, iii) CD3 and CD8 expression with γδ-TCR expression in both pancreatic diseases and iv) CD68+ and CD163+ macrophages with vimentin expression in PDAC cells. High expression of FoxP3, vimentin and L1CAM in PDAC cells as well as a tumor-related localization of macrophages each tended to correlate with higher tumor grade. Multivariate survival analysis revealed a younger age at time of surgery as a positive prognostic marker for PDAC patients with the most frequently operated disease stage T3N1M0. Overall this study identified several interrelationships between stroma and epithelial/carcinoma cells in PDACs but also in CP, which in light of previous experimental data strongly support the view that the inflammatory stroma contributes to malignancy-associated alterations already in precursor cells during CP.
胰腺导管腺癌（PDAC）的一个特征是存在广泛的基质，这种基质也存在于慢性胰腺炎（CP）中。使用免疫组织化学，全面分析 CP 和 PDAC 的基质，并将其与上皮/癌相关的改变以及临床病理患者特征相关联。虽然 CP 和 PDAC 之间在 CD3+T 细胞和 α-SMA+成纤维细胞的分布方面没有显著差异，但 PDAC 中 CD4+和 CD8+T 细胞的比例显著较低，CD25+（CD4+）和 FoxP3+（CD4+）调节性 T 细胞的数量较多。CP 中巨噬细胞更为普遍，但在 PDAC 中更接近癌细，γδ-T 细胞也是如此。与 CP 相比，PDAC 中与导管相关的 FoxP3 和 L1CAM 表达增加，而波形蛋白在两种疾病中的表达相似。此外，分化良好的肿瘤和 CP 的基质和上皮成分具有相当大的相似性，而中度和低度分化的肿瘤与 CP 组织有显著差异。对每种胰腺疾病的 27 个参数进行分析，结果表明：i）PDAC 细胞中的 FoxP3 和 FoxP3+CD4+T 细胞之间存在显著相关性，ii）α-SMA+成纤维细胞与 PDAC 细胞中的 L1CAM 表达和增殖之间存在显著相关性，iii）两种胰腺疾病中的 CD3 和 CD8 表达与 γδ-TCR 表达之间存在显著相关性，iv）PDAC 细胞中的 CD68+和 CD163+巨噬细胞与 vimentin 表达之间存在显著相关性。PDAC 细胞中 FoxP3、波形蛋白和 L1CAM 的高表达以及巨噬细胞的肿瘤相关定位均倾向于与更高的肿瘤分级相关。多变量生存分析显示，手术时年龄较小是 PDAC 患者的一个阳性预后标志物，这些患者最常进行的手术疾病分期为 T3N1M0。总的来说，这项研究确定了 PDAC 中基质和上皮/癌细胞之间的几种相互关系，也确定了 CP 中的相互关系，这些关系结合以前的实验数据，强烈支持了这样一种观点，即炎症性基质在 CP 中就已经在祖细胞中导致了与恶性相关的改变。
