Identification and manipulation of biliary metaplasia in pancreatic tumors.
Identification and manipulation of biliary metaplasia in pancreatic tumors.
复制标题
DOI：
10.1053/j.gastro.2013.08.053
复制
发表时间：
2014-01
期刊：
影响因子：
29.4
通讯作者：
Crawford HC
中科院分区：
文献类型：
--
作者：
Delgiorno KE;Hall JC;Takeuchi KK;Pan FC;Halbrook CJ;Washington MK;Olive KP;Spence JR;Sipos B;Wright CV;Wells JM;Crawford HC
化生组织通常具有发育相关组织的特征。胰腺化生导管通常与胰腺炎和胰腺导管腺癌有关。簇状细胞是一种化学感觉细胞，通过效应器分子对细胞外环境中的信号做出反应。正常小鼠胰腺中缺少簇状细胞，这种细胞常见于胆道。使用簇状细胞的异常外观作为指标，我们测试胰腺化生是否代表转分化为胆汁表型，以及这对胰腺肿瘤的发生有什么影响。我们分析了在表达Kras激活形式的小鼠(KrasLSL−G12D/+；Ptf1aCre/+小鼠)中发展起来的胰腺组织和肿瘤。对来自小鼠的正常胆管、胰管和肿瘤相关化生组织进行了簇状细胞和胆管祖细胞标记物的分析，包括SOX17，一种调节胆管发育的转录因子。我们还分析了单独表达转基因SOX17(ROSAtTa/+；Ptf1CreerTM/+；Teto-SOX17)或与激活的Kras一起表达(ROSAtTa/+；Ptf1a CreerTM/+；Teto-SOX17；KrasLSL−G12D；+)的小鼠的胰腺组织。丛状细胞常见于胰腺化生区域，在肿瘤进展过程中逐渐减少，在浸润性肿瘤中不存在。对小鼠胰胆管系统的分析显示，胆管中有簇状细胞，但正常的胰管中没有。胆汁标志物分析显示SOX17在胰腺化生和肿瘤中的表达。胰腺特异的SOX17过表达导致导管上皮化生、炎症和胶原沉积。与只表达KrasG12D的小鼠相比，高表达SOX17和KrasG12D的小鼠有更大程度的组织转化。对人胰腺组织阵列的免疫荧光分析显示，化生和早期肿瘤中存在簇状细胞，以及SOX17的表达，这与胆汁表型一致。KrasG12D和SOX17在小鼠中的表达诱导了含有簇状细胞的胆管表型的化生组织的发展。簇状细胞表达许多可以改变微环境的致癌因子。SOX17的表达可诱导小鼠胰腺炎并促进KrasG12D诱导的小鼠肿瘤形成。
Metaplasias often have characteristics of developmentally related tissues. Pancreatic metaplastic ducts are usually associated with pancreatitis and pancreatic ductal adenocarcinoma. The tuft cell is a chemosensory cell that responds to signals in the extracellular environment via effector molecules. Commonly found in the biliary tract, tuft cells are absent from normal murine pancreas. Using the aberrant appearance of tuft cells as an indicator, we tested if pancreatic metaplasia represents transdifferentiation to a biliary phenotype and what effect this has on pancreatic tumorigenesis. We analyzed pancreatic tissue and tumors that developed in mice that express an activated form of Kras (KrasLSL−G12D/+;Ptf1aCre/+ mice). Normal bile duct, pancreatic duct, and tumor-associated metaplasias from the mice were analyzed for tuft cell and biliary progenitor markers, including SOX17, a transcription factor that regulates biliary development. We also analyzed pancreatic tissues from mice expressing transgenic SOX17 alone (ROSAtTa/+;Ptf1 CreERTM/+;tetO-SOX17) or along with activated Kras (ROSAtT a/+;Ptf1a CreERTM/+;tetO-SOX17;KrasLSL−G12D;+). Tuft cells were frequently found in areas of pancreatic metaplasia, decreased throughout tumor progression, and were absent from invasive tumors. Analysis of the pancreatobiliary ductal systems of mice revealed tuft cells in the biliary tract, but not the normal pancreatic duct. Analysis for biliary markers revealed expression of SOX17 in pancreatic metaplasia and tumors. Pancreas-specific overexpression of SOX17 led to ductal metaplasia along with inflammation and collagen deposition. Mice that overexpressed SOX17 along with KrasG12D had a greater degree of transformed tissue compared with mice expressing only KrasG12D. Immunofluorescence analysis of human pancreatic tissue arrays revealed the presence of tuft cells in metaplasia and early-stage tumors, along with SOX17 expression, consistent with a biliary phenotype. Expression of KrasG12D and SOX17 in mice induces development of metaplasias with a biliary phenotype, containing tuft cells. Tuft cells express a number of tumorigenic factors that can alter the microenvironment. Expression of SOX17 induces pancreatitis and promotes KrasG12D-induced tumorigenesis in mice.
登录
查看更多内容
胃簇细胞表达DCLK1并在增生中膨胀。
影响因子：
2.3
作者：
Saqui-Salces, Milena;Keeley, Theresa M.;Grosse, Ann S.;Qiao, Xiaotan T.;El-Zaatari, Mohamad;Gumucio, Deborah L.;Samuelson, Linda C.;Merchant, Juanita L.
通讯作者：
Merchant, Juanita L.
影响因子：
1.5
作者：
Cuttler, Anne S.;LeClair, Renee J.;Stohn, J. Patrizia;Wang, Qiaozeng;Sorenson, Christine M.;Liaw, Lucy;Lindner, Volkhard
通讯作者：
Lindner, Volkhard
影响因子：
2.5
作者：
Bezencon, C.;Fuerholz, A.;Damak, S.
通讯作者：
Damak, S.
影响因子：
29.4
作者：
Bombardelli, Lorenzo;Carpenter, Eileen S.;Crawford, Howard C.
通讯作者：
Crawford, Howard C.
影响因子：
30.8
作者：
Kawaguchi, Y;Cooper, B;Wright, CVE
通讯作者：
Wright, CVE