Activated wnt signaling in stroma contributes to development of pancreatic mucinous cystic neoplasms.
Activated wnt signaling in stroma contributes to development of pancreatic mucinous cystic neoplasms.
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DOI：
10.1053/j.gastro.2013.09.044
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发表时间：
2014-01
期刊：
影响因子：
29.4
通讯作者：
Lewis BC
中科院分区：
文献类型：
--
作者：
Sano M;Driscoll DR;De Jesus-Monge WE;Klimstra DS;Lewis BC
胰腺粘液性囊性肿瘤(MCN)是胰腺的一种囊性肿瘤，多见于女性，是胰腺导管腺癌的潜在先兆。MCNs主要发育于胰腺的体部和尾部，以粘液上皮和卵巢样上皮下基质的存在为特征。我们研究了Wnt信号在KRAS介导的小鼠胰腺肿瘤的发生和发展中的作用，以及在人MCN样本中Wnt的激活。LSL-KrasG12D、Ptf1a-cre小鼠与弹性酶-TVA小鼠杂交，以允许将复制能力强的禽肉瘤白血病病毒长端重复序列与剪接受体病毒一起编码的基因在出生后和散发性地导入胰腺腺泡细胞和腺泡细胞前体细胞。将表达WNT1的重复剪接受体病毒输送到这些小鼠的胰腺上皮细胞；组织病理学和免疫组织化学分析胰腺病变。我们分析了19例MCN患者Wnt信号通路中的因子水平。Wnt1在雌性小鼠胰腺腺泡细胞和腺泡细胞前体细胞中的表达导致胰体和尾部出现类似于MCN的单房性或多房性上皮性囊肿。囊性病变类似于MCN雌激素受体和孕激素受体阳性的卵巢样基质，但缺乏典型的粘液上皮。根据β-连环蛋白的核定位，激活的Wnt信号在间质中被检测到，但在囊上皮中没有检测到。在患者的β-catenin样本中，发现Wnt信号在卵巢样基质中被激活，这与在小鼠身上的发现一致。基于对小鼠和患者胰腺MCN样本的研究，规范的Wnt信号通路被激活，并促进卵巢样基质的发展，从而有助于MCNs的形成。
Pancreatic mucinous cystic neoplasm (MCN), a cystic tumor of the pancreas that develops most frequently in women, is a potential precursor to pancreatic ductal adenocarcinoma. MCNs develop primarily in the body and tail of the pancreas and are characterized by the presence of a mucinous epithelium and ovarian-like subepithelial stroma. We investigated the involvement of Wnt signaling in KRAS-mediated pancreatic tumorigenesis and development of MCN in mice, and Wnt activation in human MCN samples. LSL-KrasG12D, Ptf1a-cre mice were crossed with elastase-tva mice to allow for introduction of genes encoded by the replication-competent avian sarcoma-leukosis virus long-terminal repeat with splice acceptor viruses to pancreatic acinar cells and acinar cell progenitors, postnatally and sporadically. Repeat with splice acceptor viruses that expressed Wnt1 were delivered to the pancreatic epithelium of these mice; pancreatic lesions were analyzed by histopathology and immunohistochemical analyses. We analyzed levels of factors in Wnt signaling pathways in 19 MCN samples from patients. Expression of Wnt1 in the pancreatic acinar cells and acinar cell progenitors of female mice led to development of unilocular or multilocular epithelial cysts in the pancreas body and tail, similar to MCN. The cystic lesions resembled the estrogen receptor– and progesterone receptor–positive ovarian-like stroma of MCN, but lacked the typical mucinous epithelium. Activated Wnt signaling, based on nuclear localization of β-catenin, was detected in the stroma but not cyst epithelium. Wnt signaling to β-catenin was found to be activated in MCN samples from patients, within the ovarian-like stroma, consistent with the findings in mice. Based on studies of mice and pancreatic MCN samples from patients, the canonical Wnt signaling pathway becomes activated and promotes development of the ovarian-like stroma to contribute to formation of MCNs.
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DOI：
10.1126/science.1192149
发表时间：
2011-04-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Holm TM;Habashi JP;Doyle JJ;Bedja D;Chen Y;van Erp C;Lindsay ME;Kim D;Schoenhoff F;Cohn RD;Loeys BL;Thomas CJ;Patnaik S;Marugan JJ;Judge DP;Dietz HC
通讯作者：
Dietz HC
影响因子：
3.7
作者：
Pasca di Magliano M;Biankin AV;Heiser PW;Cano DA;Gutierrez PJ;Deramaudt T;Segara D;Dawson AC;Kench JG;Henshall SM;Sutherland RL;Dlugosz A;Rustgi AK;Hebrok M
通讯作者：
Hebrok M
影响因子：
64.8
作者：
Bhanot, P;Brink, M;Nusse, R
通讯作者：
Nusse, R
影响因子：
64.8
作者：
Hao, Huai-Xiang;Xie, Yang;Cong, Feng
通讯作者：
Cong, Feng
影响因子：
30.8
作者：
Kawaguchi, Y;Cooper, B;Wright, CVE
通讯作者：
Wright, CVE