How dysregulated colonic crypt dynamics cause stem cell overpopulation and initiate colon cancer
How dysregulated colonic crypt dynamics cause stem cell overpopulation and initiate colon cancer
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DOI：
10.1158/0008-5472.can-07-2061
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发表时间：
2008-05-01
期刊：
影响因子：
11.2
通讯作者：
Runquist, Olaf A.
中科院分区：
文献类型：
--
作者：
Boman, Bruce M.;Fields, Jeremy Z.;Runquist, Olaf A.
基于对家族性腺瘤性息肉病(FAP)患者最早的结肠组织改变的研究，我们提出了一种假说，即由腺瘤性息肉病结肠(APC)突变引起的结直肠癌是由两种细胞机制的失调所介导的。一种是分化，这通常会降低结肠隐窝细胞能够增殖的比例(增殖分数)；另一种是细胞周期机制，同时增加了增殖细胞处于S期的可能性。在正常的隐窝中，位于隐窝底部的干细胞(SC)产生快速增殖的细胞，这些细胞在向隐窝向上迁移的过程中经历分化。我们对正常隐窝的模拟表明，这些转变是由调节增殖分数和S期概率的机制介导的。在FAP隐窝中，快速增殖的细胞群上移，如标记指数(LI；即S期细胞在隐窝中的分布)所示。我们对FAP的分析表明，这些转变之所以延迟，是因为增殖分数和S期的概率随隐窝水平的变化较慢。这导致增殖细胞群体的扩张，包括具有低频率的S期细胞的亚群。我们之前曾报道过，隐窝干细胞过多可以解释李氏移位。在这里，我们确定干细胞(或具有高硬度的细胞)是增殖细胞，处于S期的可能性很低。因此，控制增殖分数和S期概率的机制的失调解释了APC突变如何导致隐窝底部的SC过剩，使快速增殖的细胞群向上移动，并启动结肠肿瘤的发生。
Based on investigation of the earliest colonic tissue alteration in familial adenomatous polyposis (FAP) patients, we present the hypothesis that initiation of colorectal cancer by adenomatous polyposis coli (APC) mutation is mediated by dysregulation of two cellular mechanisms. One involves differentiation, which normally decreases the proportion (proliferative fraction) of colonic crypt cells that can proliferate; the other is a cell cycle mechanism that simultaneously increases the probability that proliferative cells are in S phase. In normal crypts, stem cells (SC) at the crypt bottom generate rapidly proliferating cells, which undergo differentiation while migrating up the crypt. Our modeling of normal crypts suggests that these transitions are mediated by mechanisms that regulate proliferative fraction and S-phase probability. In FAP crypts, the population of rapidly proliferating cells is shifted upwards, as indicated by the labeling index (LI; i.e., crypt distribution of cells in S phase). Our analysis of FAP indicates that these transitions are delayed because the proliferative fraction and S-phase probability change more slowly as a function of crypt level. This leads to expansion of the proliferative cell population, including a subpopulation that has a low frequency of S-phase cells. We previously reported that crypt SC overpopulation explains the LI shift. Here, we determine that SCs (or cells having high sternness) are proliferative cells with a low probability of being in S phase. Thus, dysregulation of mechanisms that control proliferative fraction and S-phase probability explains how APC mutations induce SC overpopulation at the crypt bottom, shift the rapidly proliferating cell population upwards, and initiate colon tumorigenesis.