Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray
Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray
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DOI：
10.1097/01.mp.0000086072.56290.fb
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发表时间：
2003-09-01
期刊：
影响因子：
7.5
通讯作者：
Hruban, RH
中科院分区：
文献类型：
--
作者：
Maitra, A;Adsay, NV;Hruban, RH
最近提出了胰腺癌的多步模型。在该模型中，明确定义的非侵入性导管病变被认为是浸润性癌症的前兆，并被归类为胰腺上皮内瘤变或PanIN。越来越多的证据表明PanIN代表胰腺导管上皮的真正肿瘤，在其向浸润性癌症的进展中积累组织学和遗传异常。我们有.构建了包含55个所有组织学分级的PanIN病变的组织微阵列，以进行胰腺癌进展模型的多组分分析。14个基因的蛋白质产物包含多种功能类别，如肿瘤抑制基因，（p53，Smad 4/Dpc 4），癌基因（β-连环蛋白），细胞周期抗原（p16，细胞周期蛋白D1），增殖抗原（Ki-67，拓扑异构酶H α）和上皮脱粘蛋白（MUC 1，MUC 2，MUC 5），以及通过全局微阵列表达分析描述为在浸润性胰腺癌中差异上调的“新”基因（间皮素、前列腺干细胞抗原、肌成束蛋白和14-3-3sigma）。目前研究的结果与先前发表的PanIN常规组织切片数据的比较表明，组织微阵列不仅是浸润性癌症的分子分析的有效平台，也是前驱病变的有效平台。此外，这项研究表明，PanIN的分子异常不是随机的，但通常可以分层为“早期”变化（例如，MUC 5和前列腺干细胞抗原的表达，或p16的缺失），“中间”变化（例如，细胞周期蛋白D1的表达），和“晚期”变化（例如，p53、增殖抗原、MUC 1、间皮素和14-3- 3 σ的表达，或Smad 4/Dpc 4的缺失）。使用高通量组织芯片为基础的方法来了解浸润性胰腺癌前驱病变的分子发病机制是设计合理的策略来早期检测这种致命肿瘤的有价值的辅助手段。
A multistep model for pancreatic adenocarcinoma has been proposed recently. In this model, well-defined, noninvasive ductal lesions are recognized as precursors of invasive cancer and have been classified under the nomenclature of pancreatic intra-epithelial neoplasia, or PanIN. Increasing evidence suggests that PanINs represent true neoplasms of the pancreatic ductal epithelium, accumulating histologic and genetic abnormalities in their progression toward invasive cancer. We have. constructed a tissue microarray containing 55 PanIN lesions of all histologic grades in order to perform a multicomponent analysis of the pancreatic adenocarcinoma progression model. The protein products of 14 genes encompassing a variety of functional classes, such as tumor suppressor genes (p53, Smad4/ Dpc4), oncogenes (beta-catenin), cell cycle antigens (p16, cyclin D1), proliferation antigens (Ki-67, topoisomerase H alpha), and epithelial apomucins (MUC1, MUC2, MUC5), as well as "novel" genes described as differentially up-regulated in invasive pancreas cancer by global microarray expression analysis (mesothelin, prostate stem cell antigen, fascin, and 14-3-3sigma,), were analyzed by immunohistochemistry on the PanIN tissue microarray. Comparison of the results from the current study with previously published data performed on routine histologic sections of PanINs demonstrates that tissue microarrays are a valid platform for molecular analysis not only of invasive cancers but of precursor lesions as well. In addition, this study demonstrates that molecular abnormalities in PanINs are not random but can usually be stratified into "early" changes (e.g., expression of MUC5 and prostate stem antigen, or loss of p16), "intermediate" changes (e.g., expression of cyclin D1), and "late" changes (e.g., expression of p53, proliferation antigens, MUC1, mesothelin, and 14-3-3sigma, or loss of Smad4/Dpc4). Understanding the molecular pathogenesis of precursor lesions of invasive pancreatic adenocarcinomas using a high-throughput tissue microarray-based approach is a valuable adjunct to designing rational strategies for early detection of this lethal neoplasm.