Plentz R R, Wiemann S U, Flemming P, Meier P N, Kubicka S, Kreipe H, Manns M P, Rudolph K L
Department of Gastroenterology, Hepatology, and Endocrinology, Medical School of Hannover, Germany.
Gut. 2003 Sep;52(9):1304-7. doi: 10.1136/gut.52.9.1304.
and aims: Chromosomal instability is one of the most consistent markers of sporadic colorectal cancer in humans. There is growing evidence that telomere shortening is one of the mechanisms leading to chromosomal instability and cancer initiation.
To test this hypothesis, the telomere length of colorectal epithelial cells and cells from connective tissue was determined at the adenoma-carcinoma transition at the cellular level by quantitative fluorescence in situ hybridisation.
Our study showed that the telomere fluorescence intensity of epithelial cells was significantly weaker at the earliest morphologically definable stage of carcinoma-high grade dysplasia with minimal invasive growth-compared with the surrounding adenoma. In contrast, cells from connective tissue had a similar telomere signal intensity at the carcinoma stage compared with the adenoma, and in turn cells from connective tissue had overall significantly stronger telomere fluorescence signals compared with epithelial cells.
These results demonstrate that short telomeres of epithelial cells characterise the adenoma-carcinoma transition during human colorectal carcinogenesis, suggesting that carcinomas arise from cells with critical short telomeres within the adenoma. Since the adenoma-carcinoma transition in colorectal cancer is characterised by an increase in chromosomal instability and anaphase bridges, our data support the hypothesis that short telomeres initiate colorectal cancer by induction of chromosomal instability.
染色体不稳定是人类散发性结直肠癌最一致的标志物之一。越来越多的证据表明，端粒缩短是导致染色体不稳定和癌症发生的机制之一。
为验证这一假设，通过定量荧光原位杂交在细胞水平上测定结直肠上皮细胞和结缔组织细胞在腺瘤-癌转变过程中的端粒长度。
我们的研究表明，与周围腺瘤相比，在癌的最早形态学可定义阶段——具有最小侵袭性生长的高级别发育异常阶段，上皮细胞的端粒荧光强度显著较弱。相比之下，结缔组织细胞在癌阶段的端粒信号强度与腺瘤阶段相似，而且与上皮细胞相比，结缔组织细胞的端粒荧光信号总体上显著更强。
这些结果表明，上皮细胞的短端粒是人类结直肠癌发生过程中腺瘤-癌转变的特征，提示癌起源于腺瘤内具有临界短端粒的细胞。由于结直肠癌中的腺瘤-癌转变以染色体不稳定性增加和后期桥为特征，我们的数据支持短端粒通过诱导染色体不稳定性引发结直肠癌这一假设。
