Differential roles of telomere attrition in type I and II endometrial carcinogenesis
Differential roles of telomere attrition in type I and II endometrial carcinogenesis
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DOI：
10.2353/ajpath.2008.071179
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发表时间：
2008-08-01
影响因子：
6
通讯作者：
Castrillon, Diego H.
中科院分区：
文献类型：
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作者：
Akbay, Esra A.;Contreras, Cristina M.;Castrillon, Diego H.
子宫内膜癌通常分为两大类肿瘤，I型（TI）和II型（TII），具有不同的流行病学/临床特征和遗传改变。由于端粒磨损似乎会引发某些癌症的基因组不稳定性，我们通过分析两种肿瘤类型中的端粒和端粒状态的其他标志物来探讨端粒功能障碍在子宫内膜癌中的作用。我们描述了一种新的方法，端粒显色原位杂交，这使我们能够检测细胞与短端粒相对于控制（基质）细胞在同一组织切片。使用这种方法，我们发现两种类型的肿瘤细胞都有短端粒。然而，只有TII肿瘤与相邻的形态正常上皮中的关键端粒缩短显著相关，表明端粒缩短有助于TII而不是TI肿瘤的发生。为了探讨这一假设，我们分析了小鼠端粒短，并记录了独特的子宫内膜病变，在组织学上类似于TII浆液性癌的原位前体，这些病变尚未观察到以前在TI小鼠模型的子宫内膜癌。基于这一点和以前的研究，我们提出了一个模型，端粒磨损有助于启动TII和TI子宫内膜癌的进展。
Endometrial cancer has been generally categorized into two broad groups of tumors, type I (TI) and type II (TII), with distinct epidemiological/clinical features and genetic alterations. Because telomere attrition appears to trigger genomic instability in certain cancers, we explored the role of telomere dysfunction in endometrial cancer by analyzing telomeres and other markers of telomere status in both tumor types. We describe a new method, telomere chromogenic in situ hybridization, which permitted us to detect cells with short telomeres relative to control (stromal) cells within the same tissue section. Using this method, we found that both types of tumor cells had short telomeres. However, only TII tumors were significantly associated with critical telomere shortening in adjacent, morphologically normal epithelium, suggesting that telomere shortening contributes to the initiation of TII but not TI tumors. To explore this hypothesis, we analyzed mice with critically short telomeres and documented distinctive endometrial lesions that histologically resembled the in situ precursor of TII serous carcinomas; these lesions have not been observed previously in TI mouse models of endometrial cancer. Based on this and previous studies, we propose a model in which telomere attrition contributes to the initiation of TII and progression of TI endometrial cancers.