Caldwell Christine M, Green Rebecca A, Kaplan Kenneth B
Section of Molecular and Cell Biology, University of California, Davis, Davis, CA 95616, USA.
J Cell Biol. 2007 Sep 24;178(7):1109-20. doi: 10.1083/jcb.200703186.
Previous research has proposed that genomic instability contributes to cancer progression, with its initiation linked to tetraploid cell formation (Duesberg, P., and R. Li. 2003. Cell Cycle. 2:202-210; Ganem, N.J., Z. Storchova, and D. Pellman. 2007. Curr. Opin. Genet. Dev. 17:157-162). However, there is little direct evidence linking cancer-causing mutations with such events, and it remains controversial whether genomic instability is a cause or an effect of cancer. In this study, we show that adenomatous polyposis coli (APC) mutations found in human colorectal cancers dominantly inhibit cytokinesis by preventing mitotic spindle anchoring at the anaphase cortex and, thus, blocking initiation of the cytokinetic furrow. We find that dividing crypt cells in the small intestines of APC(Min/+) mice exhibit similar mitotic defects, including misoriented spindles and misaligned chromosomes. These defects are observed in normal crypt cells with wild-type levels of beta-catenin and, importantly, are associated with tetraploid genotypes. We provide direct evidence that the dominant activity of APC mutants induces aneuploidy in vivo. Our data support a model whereby tetraploid cells represent a first step in the onset of genomic instability and colorectal cancer.
先前的研究表明，基因组不稳定促进癌症进展，其起始与四倍体细胞形成有关（杜斯伯格，P.，和R. 李。2003年。《细胞周期》。2：202 - 210；加内姆，N.J.，Z. 斯托乔娃，和D. 佩尔曼。2007年。《当代遗传学与发育学观点》。17：157 - 162）。然而，几乎没有直接证据将致癌突变与此类事件联系起来，并且基因组不稳定是癌症的原因还是结果仍存在争议。在本研究中，我们表明在人类结直肠癌中发现的腺瘤性息肉病大肠杆菌（APC）突变通过阻止有丝分裂纺锤体在后期皮质处锚定，从而阻断胞质分裂沟的起始，进而主要抑制胞质分裂。我们发现APC(Min/+)小鼠小肠中正在分裂的隐窝细胞表现出类似的有丝分裂缺陷，包括纺锤体方向错误和染色体排列错误。在具有野生型β-连环蛋白水平的正常隐窝细胞中观察到这些缺陷，并且重要的是，这些缺陷与四倍体基因型相关。我们提供了直接证据表明APC突变体的显性活性在体内诱导非整倍体。我们的数据支持一种模型，即四倍体细胞代表基因组不稳定和结直肠癌发生的第一步。
