Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia
Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia
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DOI：
10.1016/s0002-9440(10)64432-x
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发表时间：
2002-11-01
影响因子：
6
通讯作者：
Maitra, A
中科院分区：
文献类型：
--
作者：
van Heek, NT;Meeker, AK;Maitra, A
最近提出了胰腺导管腺癌的多步骤癌变模型。在这个模型中，胰腺导管中的非侵袭性前体病变积累了癌症相关基因的基因改变，最终导致浸润性癌症的发展。这些前驱病变的命名被标准化为胰腺上皮内瘤变或泛宁。尽管对侵袭性胰腺癌的生物学认识有了很大的进步，但对胰腺导管上皮中促进其进展为癌症的起始遗传事件知之甚少。端粒是染色体末端的独特结构，在细胞分裂过程中防止染色体断裂-融合-桥周期。严重缩短的端粒可导致染色体不稳定，这是大多数人类上皮性癌症的必要条件。尽管已有证据表明侵袭性胰腺癌存在端粒功能障碍，但在非侵袭性前体病变的背景下，这一现象的发生还没有被阐明。我们在档案标本中使用了一种最近描述的原位杂交技术(Meeker AK，Gage NVR，Hicks JL，Simon I，Coffman Jr，Platz EX，3月GE，De Matzo AM：端粒长度评估：结合端粒荧光原位杂交和免疫染色。美国病理学杂志2002,160：1259-1268)，用于评估包含各种非侵袭性胰腺导管病变的组织微阵列中的端粒长度。其中包括82个组织学分级的Panin病变(24个Panin-1A，23个Panin-1B，24个Panin-2和11个Panin-3)，这些病变是从胰腺切除标本中选择的，无论是腺癌还是慢性胰腺炎。将Panin病变的端粒荧光强度与邻近正常胰腺导管上皮和腺泡(62/82个病变)或间质成纤维细胞和朗格汉斯胰岛(20/82个病变，24%)进行比较。与邻近的正常结构相比，82个PAIN中有79个(96%)端粒信号显著减少。值得注意的是，即使是最早被认为是前驱病变的Panin-1A，在所检查的23个病灶中，有21个(91%)的端粒荧光强度显著降低。在慢性胰腺炎中，所有的PAIN病变都观察到端粒信号的减少，而萎缩性和炎症性导管病变保持了正常的端粒长度。Panin皮损的端粒荧光强度与Ki-67定量标记指数和拓扑异构酶Ha表达的增殖性无关。因此，端粒缩短是迄今为止在胰腺癌进展模型中发现的最常见的早期遗传异常。端粒可能是维持染色体完整性的重要门卫，从而维持胰腺导管上皮的正常细胞生理。胰腺癌中端粒长度的关键缩短；可能使这些非侵袭性导管病变积累进行性染色体异常并发展为浸润性癌阶段。
A multistep model of carcinogenesis has recently been proposed for pancreatic ductal adenocarcinomas. In this model, noninvasive precursor lesions in the pancreatic ductules accumulate genetic alterations in cancer-associated genes eventually leading to the development of an invasive cancer. The nomenclature for these precursor lesions has been standardized as pancreatic intraepithelial neoplasia or PanIN. Despite the substantial advances made in understanding the biology of invasive pancreatic adenocarcinomas, little is known about the initiating genetic events in the pancreatic ductal epithelium that facilitates its progression to cancer. Telomeres; are distinctive structures at the ends of chromosomes that protect against chromosomal breakage-fusion-bridge cycles in dividing cells. Critically shortened telomeres can cause chromosomal instability, a sine qua non of most human epithelial cancers. Although evidence for telomeric dysfunction has been demonstrated in invasive pancreatic cancer, the onset of this phenomenon has not been elucidated in the context of noninvasive precursor lesions. We used a recently described in situ hybridization technique in archival samples (Meeker AK, Gage NVR, Hicks JL, Simon I, Coffman JR, Platz EX, March GE, De Matzo AM: Telomere length assessment in human archival tissues: combined telomere fluorescence in situ hybridization and immunostaining. American journal of Pathology 2002, 160:1259-1268) for assessment of telomere length in tissue microarrays containing a variety of noninvasive pancreatic ductal lesions. These included 82 PanIN lesions of all histological grades (24 PanIN-1A, 23 PanIN-1B, 24 PanIN-2, and 11 PanIN-3) that were selected from pancreatectomy specimens for either adenocarcinoma or chronic pancreatitis. Telomere fluorescence intensities in PanIN lesions were compared with adjacent normal pancreatic ductal epithelium and acini (62 of 82 lesions, 76%), or with stromal fibroblasts and islets of Langerhans (20 of 82 lesions, 24%). Telomere signals were strikingly reduced in 79 (96%) of 82 PanINs compared to adjacent normal structures. Notably, even PanIN-1A, the earliest putative precursor lesion, demonstrated a dramatic reduction of telomere fluorescence intensity in 21 (91%) of 23 foci examined. In chronic pancreatitis, reduction of telomere signal was observed in all PanIN lesions, whereas atrophic and inflammatory ductal lesions retained normal telomere length. Telomere fluorescence intensity in PanIN lesions did not correlate with proliferation measured by quantitative Ki-67-labeling index or topoisomerase Ha expression. Thus, telomere shortening is by far the most common early genetic abnormality recognized to date in the progression model of pancreatic adenocarcinomas. Telomeres may be an essential gatekeeper for maintaining chromosomal integrity, and thus, normal cellular physiology in pancreatic ductal epithelium. A critical shortening of telomere length in PanINs; may predispose these noninvasive ductal lesions to accumulate progressive chromosomal abnormalities and to develop toward the stage of invasive carcinoma.