Nature：肿瘤的发育

DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis

JIRINA BARTKOVA1, ZUZANA HOEJÍ1,5, KAREN KOED2, ALWIN KRÄMER1, FREDERIC TORT1, KARSTEN ZIEGER2, PER GULDBERG1, MAXWELL SEHESTED3, JAHN M. NESLAND4, CLAUDIA LUKAS1, TORBEN ØRNTOFT2, JIRI LUKAS1 & JIRI BARTEK1

During the evolution of cancer, the incipient tumour experiences 'oncogenic stress', which evokes a counter-response to eliminate such hazardous cells. However, the nature of this stress remains elusive, as does the inducible anti-cancer barrier that elicits growth arrest or cell death. Here we show that in clinical specimens from different stages of human tumours of the urinary bladder, breast, lung and colon, the early precursor lesions (but not normal tissues) commonly express markers of an activated DNA damage response. These include phosphorylated kinases ATM and Chk2, and phosphorylated histone H2AX and p53. Similar checkpoint responses were induced in cultured cells upon expression of different oncogenes that deregulate DNA replication. Together with genetic analyses, including a genome-wide assessment of allelic imbalances, our data indicate that early in tumorigenesis (before genomic instability and malignant conversion), human cells activate an ATR/ATM-regulated DNA damage response network that delays or prevents cancer. Mutations compromising this checkpoint, including defects in the ATM–Chk2–p53 pathway, might allow cell proliferation, survival, increased genomic instability and tumour progression

生物谷报道：两个小组在本期Nature上报告了他们的最新发现，这些发现有可能对我们关于癌症发育的观点产生重大影响。两个小组都对处在不同发育阶段的肿瘤（如膀胱癌、乳腺癌、结肠直肠癌、以及肺癌和皮肤癌等）进行了研究，寻找DNA受损响应的标志。而且，两个小组都发现，癌症发育早期阶段与一个主动的DNA受损响应和P53-依赖型细胞死亡有关。这表明，癌变事件所诱导的DNA受损响应是一种强有力的肿瘤抑制机制，而且也可以解释癌症前期病灶中P53突变的选择性压力。重要的是，DNA受损检查点的激发出现在染色体不稳定和恶变之前。

该文发表在Nature 434, 864 - 870 (14 April 2005)

本期封面所示为肺部增生中的53BP1病灶（绿颜色，指示DNA受损检查点的激发）。

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Nature：肿瘤的发育

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