Cancer Cell:端粒损伤介导四倍体形成促发癌变

6月12日，Cancer Cell杂志报道了关于端粒失调与异常核型细胞产生及肿瘤发生之间关系的最新研究。

人类亚四倍体核型肿瘤细胞被认为起源于四倍体前体细胞，但形成四倍体的起因尚不明了。此前，有研究证实，小鼠细胞核内复制伴有持续的端粒功能失调和全基因组范围的DNA损伤。

本研究发现，在人类成纤维细胞和乳房上皮细胞端粒危机时，伴有核内复制和有丝分裂失调。研究者还发现p53和Rb可抑制四倍体形成。利用可诱导系统造成短期端粒破坏，研究者发现端粒驱动的四倍体形成加强了小鼠细胞的癌性转化。遗传导致的肿瘤，类似于人类实体瘤，演变出亚四倍体核型。这些数据证实，特别短的端粒诱导了端粒驱动的四倍体形成。这在癌性损伤早期具有促进肿瘤发生的潜能。（生物谷bioon.com）

doi:10.1016/j.cell.2011.10.017
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Telomere-Driven Tetraploidization Occurs in Human Cells Undergoing Crisis and Promotes Transformation of Mouse Cells

Teresa Davoli, Titia de Lange

Human cancers with a subtetraploid karyotype are thought to originate from tetraploid precursors, but the cause of tetraploidization is unknown. We previously documented endoreduplication in mouse cells with persistent telomere dysfunction or genome-wide DNA damage. We now report that endoreduplication and mitotic failure occur during telomere crisis in human fibroblasts and mammary epithelial cells and document the role of p53 and Rb in repressing tetraploidization. Using an inducible system to generate transient telomere damage, we show that telomere-driven tetraploidization enhances the tumorigenic transformation of mouse cells. Similar to human solid cancers, the resulting tumors evolved subtetraploid karyotypes. These data establish that telomere-driven tetraploidization is induced by critically short telomeres and has the potential to promote tumorigenesis in early cancerous lesions.