Selective activation of p53-mediated tumour suppression in high-grade tumours.
Selective activation of p53-mediated tumour suppression in high-grade tumours.
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DOI：
10.1038/nature09526
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发表时间：
2010-11-25
期刊：
影响因子：
64.8
通讯作者：
Martins, Carla P.
中科院分区：
文献类型：
--
作者：
Junttila, Melissa R.;Karnezis, Anthony N.;Garcia, Daniel;Madriles, Francesc;Kortlever, Roderik M.;Rostker, Fanya;Swigart, Lamorna Brown;Pham, David M.;Seo, Youngho;Evan, Gerard I.;Martins, Carla P.
非小细胞肺癌（NSCLC）是全球癌症相关死亡的主要原因，总体5年生存率仅为10-15%。Ras通路的解除管制是非小细胞肺癌的常见标志，通常是通过直接激活Kras的突变。p53在非小细胞肺癌中也经常失活，由于致癌的Ras可能是p53的一个强有力的触发因素，似乎致癌的Ras信号在驱动p53的选择中起着主要和持久的作用。因此，p53的药物恢复是治疗这种疾病的一种有吸引力的治疗策略。在这里，我们模拟了由内源性Kras的散发性致癌激活引发的自发进化的非小细胞肺癌小鼠模型中p53恢复的可能治疗效果。令人惊讶的是，尽管p53修复确实导致高级别肿瘤的相对比例显著降低，但它未能诱导已建立的肿瘤显著消退。这是由于p53仅在每个肿瘤中更具侵袭性的肿瘤细胞中选择性激活。这种p53的选择性激活与Ras信号强度的显著上调和致癌信号传感器p19ARF的诱导相关。我们的数据表明，p53介导的肿瘤抑制只有在致癌Ras信号通量超过临界阈值时才会被触发。重要的是，低水平致癌Kras无法参与p53揭示了p53抑制早期肿瘤进化的能力和治疗性p53恢复根除癌症的有效性的内在局限性。
Non-small cell lung carcinoma (NSCLC) is the leading cause of cancer-related death worldwide, with an overall 5-year survival rate of only 10–15%. Deregulation of the Ras pathway is a frequent hallmark of NSCLC, often through mutations that directly activate Kras. p53 is also frequently inactivated in NSCLC and, since oncogenic Ras can be a potent trigger of p53, it seems likely that oncogenic Ras signalling plays a major and persistent part in driving the selection against p53. Hence, pharmacological restoration of p53 is an appealing therapeutic strategy for treating this disease. Here, we model the likely therapeutic impact of p53 restoration in a spontaneously evolving mouse model of NSCLC initiated by sporadic oncogenic activation of endogenous Kras. Surprisingly, p53 restoration failed to induce significant regression of established tumours although it did result in a significant decrease in the relative proportion of tumours classed as high grade. This is due to selective activation of p53 only in the more aggressive tumour cells within each tumour. Such selective activation of p53 correlates with marked up regulation in Ras signal intensity and induction of the oncogenic signalling sensor p19ARF . Our data indicate that p53-mediated tumour suppression is triggered only when oncogenic Ras signal flux exceeds a critical threshold. Importantly, the failure of low-level oncogenic Kras to engage p53 reveals inherent limits in the capacity of p53 to restrain early tumour evolution and to the efficacy of therapeutic p53 restoration to eradicate cancers.
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