隐藏干细胞作为肠癌的细胞来源
Nick Barker1, Rachel A Ridgway, Johan H van Es
1Hubrecht Institute for Developmental Biology and Stem Cell Research, Uppsalalaan 8, 3584CT Utrecht & University Medical Centre Utrecht, Netherlands.
Nature
|December 19, 2008
概括
肠癌是由细菌腺多样性肠杆菌 (APC) 的突变引起的. 在长寿肠道干细胞中删除APC迅速触发瘤生长,而在短暂细胞中删除则不会. 这突显了干细胞在肠道瘤中发挥的关键作用.
科学领域:
- 胃肠病学 胃肠病学
- 在瘤学瘤学.
- 分子生物学分子生物学
背景情况:
- 肠癌的发病包括Wnt通路激活突变,特别是在大肠腺瘤多样性肠杆菌 (APC) 中.
- 确定肠道癌的精确细胞来源一直是一个重大挑战.
- Lgr5 (含G蛋白结合受体5的氨酸丰富重复) 标志着长寿的肠干细胞.
研究的目的:
- 为了确定由APC突变驱动的肠道瘤的起源细胞.
- 研究肠道干细胞与在早期瘤发育中的过渡增强细胞之间的作用.
- 为了阐明早期腺瘤的干细胞层次.
主要方法:
- 利用一种可诱导他莫西芬的Cre复合酶小鼠模型,准Lgr5表达性肠干细胞.
- 诱导大肠腺瘤多样性肠杆菌 (APC) 基因缺失,特别是在肠道干细胞中.
- 在干细胞中APC删除后的瘤发育的比较与过渡放大细胞.
主要成果:
- 在Lgr5+肠干细胞中删除APC导致了快速转变,并在几天内形成了微腺瘤.
- 来自干细胞的小腺瘤不受阻碍地生长,在3-5周内发展为宏观腺瘤.
- 在过渡放大细胞中的APC删除导致微腺瘤生长停滞,大型腺瘤很少见.
结论:
- 干细胞特异性APC损失足以启动逐渐增长的肠道瘤.
- 在早期的瘤病变中保持了干细胞/原始细胞等级.
- 原始细胞对于肠道瘤的持续生长和进展至关重要.
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