Telomere shortening and telomerase expression during multistage carcinogenesis of intraductal papillary mucinous neoplasms of the pancreas
Telomere shortening and telomerase expression during multistage carcinogenesis of intraductal papillary mucinous neoplasms of the pancreas
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DOI：
10.1007/s11605-007-0383-9
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发表时间：
2008-01-01
影响因子：
3.2
通讯作者：
Hiyama, Eiso
中科院分区：
文献类型：
--
作者：
Hashimoto, Yasushi;Murakami, Yoshiaki;Hiyama, Eiso
胰腺导管内乳头状粘液瘤（IPMN）越来越多地被认为是浸润性导管腺癌的前兆。端粒酶激活是对端粒危机的反应，随后端粒缩短被认为是大多数人类癌症发展的关键事件。本研究的目的是确定在组织学定义的IPMN进展背景下，该事件何时发生。我们分析了68个IPMN样本的端粒酶表达，并通过定量荧光原位杂交技术评估了17个IPMN患者的端粒长度，其中包括37个个体位点。胰腺导管腺癌（pdac, n=15）和慢性胰腺炎患者（n=10）的样本也进行了检查。37个IPMN基因座中有36个（97.3%）端粒明显缩短，平均端粒长度随着IPMN的进展而减少。值得注意的是，即使腺瘤IPMNs在14个病灶中也有7个显示端粒长度减少了50%。尽管端粒酶被激活，但从原位IPMN癌期到侵袭期，端粒明显缩短（P < 0.001；与交界性IPMN相比），表明端粒缩短到这个组织学级别的临界长度。上调的人类端粒酶逆转录酶表达可检测到，并随着癌症的发展逐渐增加，主要在交界性IPMN阶段观察到，然后在更晚期的组织病理学中观察到。进行性端粒缩短主要发生在端粒酶激活之前的早期IPMNs癌变过程中，从交界性到原位癌的进展是IPMNs癌变的关键阶段，在此阶段端粒功能障碍发生。
Intraductal papillary mucinous neoplasm (IPMN) of the pancreas has been increasingly identified as a precursor to infiltrating ductal adenocarcinoma. Telomerase activation in response to telomere crisis followed by telomere shortening is thought to be a crucial event in the development of most human cancers. The aim of this study was to determine when this event occurs in the context of histologically defined IPMN progression. We analyzed telomerase expression in 68 IPMN samples and assessed telomere length by quantitative fluorescence in situ hybridization in samples taken from 17 sequential IPMN patients that included 37 individual loci. Samples from pancreatic ductal adenocarcinomas (PDACs, n=15) and chronic pancreatitis patients (n=10) were also examined. Telomeres were significantly shortened in 36 (97.3%) of 37 IPMN loci, with average telomere length decreasing with IPMN progression. Notably, even adenoma IPMNs demonstrated a 50% reduction of telomere length in 7 of 14 foci examined. Marked telomere shortening was observed from the in situ IPMN carcinoma stage (P < 0.001; vs borderline IPMNs) through the invasive stage, although telomerase had been activated, indicating that telomeres had shortened to a critical length by this histological grade. Up-regulated human telomerase reverse transcriptase expression was detectable and increased gradually with cancer development and was primarily observed at the borderline IPMN stage and then in more advanced histopathologies. Progressive telomere shortening predominantly occurs during early IPMNs carcinogenesis before telomerase activation and progression from borderline to carcinoma in situ IPMNs is the critical stage of IPMNs carcinogenesis at which telomere dysfunction occurs.