Hubrecht Institute, KNAW & University Medical Center Utrecht, Utrecht, the Netherlands.
EMBO Rep. 2014 Jan;15(1):62-9. doi: 10.1002/embr.201337799. Epub 2013 Dec 15.
The concept of 'field cancerization' describes the clonal expansion of genetically altered, but morphologically normal cells that predisposes a tissue to cancer development. Here, we demonstrate that biased stem cell competition in the mouse small intestine can initiate the expansion of such clones. We quantitatively analyze how the activation of oncogenic K-ras in individual Lgr5(+) stem cells accelerates their cell division rate and creates a biased drift towards crypt clonality. K-ras mutant crypts then clonally expand within the epithelium through enhanced crypt fission, which distributes the existing Paneth cell niche over the two new crypts. Thus, an unequal competition between wild-type and mutant intestinal stem cells initiates a biased drift that leads to the clonal expansion of crypts carrying oncogenic mutations.
“ 肿瘤异质性 ” 这一概念描述了具有遗传改变但形态正常的细胞的克隆扩增，这使得组织易于发生癌症发展。在这里，我们证明了小鼠小肠中偏向性的干细胞竞争可以启动这种克隆的扩增。我们定量分析了致癌基因 K-ras 在单个 Lgr5(+)干细胞中的激活如何加速其细胞分裂率，并导致向隐窝克隆性的偏向性漂移。然后，K-ras 突变隐窝通过增强隐窝分裂在上皮内进行克隆性扩增，从而将现有的 Paneth 细胞龛分配到两个新的隐窝上。因此，野生型和突变型肠干细胞之间的不平衡竞争引发了偏向性漂移，导致携带致癌突变的隐窝发生克隆性扩增。
