Kras突变小鼠胰腺癌前病变PanIN细胞的生物学特性

背景与目的:胰腺腺管内上皮瘤(pancreatic intraepithelial neoplasia,PanIN)是近几年提出的新术语,目前对其缺乏足够认识.在首次建立小鼠PanIN细胞系的基础上探索Kras突变小鼠PanIN细胞的生物学特性.方法:通过免疫组化分析基因打靶KrasG12D突变小鼠PanIN组织,分离和建立LoxP-Stop-LoxP-KrasG12D;Pdx1-Cre产生的小鼠PanIN细胞系,鉴定其体外贴壁依赖性生长及在软琼脂半固体培养基中集落形成,对PanIN细胞中抑癌基因Tp53、Smad4、p16进行突变分析.结果:KrasG12D激活突变产生了各期小鼠胰腺癌前病变-胰腺腺管内上皮瘤(PanIN);PanIN细胞的胞浆和核中的磷酸化MAPK染色强阳性和高表达,EGFR、Her-2/Neu、和β-Catenin在PanIN细胞中也表现了高表达,Tp53在早期PanIN细胞和Smad4在各期PanIN细胞中的表达无异常;PanIN细胞在体外培养中的增殖速度与原发胰腺癌相似,并且能在软琼脂中形成光学显微镜下所见的集落,随着培养时间的延长而集落增大;PanIN细胞中除可检测到KrasG12D突变外无p16、Tp53、Smad4突变或缺失.结论:单纯Kras的激活突变足以启动PanIN,是胰腺癌发生的早期主要分子遗传学改变事件,PanIN细胞已在一定程度上具备了恶性转化的肿瘤细胞的生物学特性.

胰腺腺管内上皮瘤的分子遗传学研究进展

胰腺腺管内上皮瘤(pancreatic intraepithelial neoplasia,PanIN)是近几年提出的新术语,并被认为是胰腺癌的癌前病变,近年来随着PanIN转基因动物模型的建立,对其诸多方面的认识向前推进了一大步,尤其是对其分子生物学行为的认识也在逐渐深入,发现K-ras、p53、p16、Smad4等主要分子遗传学事件异常与PanIN及胰腺癌的恶性转化密切相关.为此深入研究胰腺癌癌前病变PanIN的分子遗传学事件异常是发现胰腺癌新肿瘤标志物及早期诊断,并终有效治疗或控制胰腺癌的关键,同时亦是近几年研究的热点与难点之一.本文从PanIN的起源、形态学变化和分子遗传学异常等方面做一简要概括.

BACKGROUND:?Ectopic?pancreatic?tissue?is?relatively?uncommon,?and?is?characterized?as?pancreatic?tissue?with?no?contact?with?the?normal?pancreas,?and?with?its?own?ductal?system?and?blood?supply.?It?is?usually?asymptomatic,?and?can?be?incidentally?diagnosed?by?conventional?imaging?studies. METHOD:?A? 69-year-old? woman? with? a? prior? history? of?bilateral?breast?carcinoma?presented?with?ectopic?pancreatic?intraepithelial?neoplasia?(PanIN)?that?was?identiifed?incidentally?in? the? small? bowel? during? an? oncological? resection? of? a?synchronous?primary?pancreatic?adenocarcinoma,?and?renal?cell?carcinoma. RESULTS:?The?patient?underwent?subtotal?pancreatectomy?with?splenectomy,?regional?lymphadenectomy,?radical?left?nephrectomy,?and?small?bowel?resection?with?primary?anastomosis?of?ectopic?PanIN-2.? She? had? an? uneventful? hospitalization? and? was?discharged?home?on?postoperative?day?7. CONCLUSIONS:?The?occurrence?of?ectopic?PanIN?is?extremely?unusual?with?only?few?cases?previously?reported?in?the?literature.?The?need?for?negative?margins?after?surgical?resection?of?ectopic?PanIN?lesions?remains?controversial.