Gastrointestinal stem cells and cancer bridging - The molecular gap
Gastrointestinal stem cells and cancer bridging - The molecular gap
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DOI：
10.1385/scr:1:3:233
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发表时间：
2005-01-01
期刊：
影响因子：
--
通讯作者：
Wright, N. A.
中科院分区：
文献类型：
--
作者：
Leedham, S. J.;Thliveris, A. T.;Wright, N. A.
癌症被认为是一种涉及干细胞的疾病。消化道癌症发病率很高，部分原因是上皮细胞更新快和接触饮食毒素。对遗传性癌症综合征（包括女性腺瘤性息肉病（FAP））的研究取得了重大进展，包括腺瘤-癌序列。这种逐步进展的初始突变是在“看门人”肿瘤抑制基因腺瘤性结肠息肉病（APC）中。在FAP体细胞中，该基因的第二次命中是非随机事件，由种系突变的位置选择。在小鼠和人类中的广泛研究表明，隐窝是克隆单位，突变的干细胞可能会产生选择性优势，最终通过称为“小生境继承”的过程形成克隆隐窝种群。异常的隐窝病灶是由隐窝纵向分裂成两个子单位-隐窝分裂形成的。腺瘤的早期生长与两种主要理论有争议，“自上而下”和“自下而上”假说，试图解释肠中发育不良组织的扩散。最初的X染色体失活研究表明，结直肠肿瘤是单克隆的;然而，对罕见的XO/XY人类患者FAP和嵌合Min小鼠的研究表明，76%的腺瘤是多克隆的。通过引入纯合肿瘤抗性等位基因，已经实现了嵌合小鼠模型中肿瘤多样性的降低。该模型已被用于表明，相邻的启动隐窝之间的短程相互作用，而不是随机的息肉碰撞，是肿瘤多克隆性的原因。
Cancer is believed to be a disease involving stem cells. The digestive tract has a very high cancer prevalence partly owing to rapid epithelial cell turnover and exposure to dietary toxins. Work on the hereditary cancer syndromes including famalial adenomatous polyposis (FAP) has led to significant advances, including the adenoma-carcinoma sequence. The initial mutation involved in this stepwise progression is in the "gate-keeper" tumor suppressor gene adenomatous polyposis coli (APC). In FAP somatic, second hits in this gene are nonrandom events, selected for by the position of the germ-line mutation. Extensive work in both the mouse and human has shown that crypts are clonal units and mutated stem cells may develop a selective advantage, eventually forming a clonal crypt population by a process called "niche succession". Aberrant crypt foci are then formed by the longitudinal division of crypts into two daughter units-crypt fission. The early growth of adenomas is contentious with two main theories, the "top-down" and "bottom-up" hypotheses, attempting to explain the spread of dysplastic tissue in the bowel. Initial X chromosome inactivation studies suggested that colorectal tumors were monoclonal; however, work on a rare XO/XY human patient with FAP and chimeric Min mice showed that 76% of adenomas were polyclonal. A reduction in tumor multiplicity in the chimeric mouse model has been achieved by the introduction of a homozygous tumor resistance allele. This model has been used to suggest that short-range interaction between adjacent initiated crypts, not random polyp collision, is responsible for tumor polyclonality.