Stage-specific sensitivity to p53 restoration during lung cancer progression.
Stage-specific sensitivity to p53 restoration during lung cancer progression.
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肿瘤发生是一个多步骤的过程，是关键癌基因和肿瘤抑制通路突变顺序积累的结果。以这些潜在的基因异常为靶点的个性化癌症治疗，前提是肿瘤抑制基因的持续失活和癌基因的激活在晚期癌症中是必不可少的。P53肿瘤抑制通路的突变在人类癌症中很常见，对有缺陷的P53通路的药物再激活的重大努力正在进行中。在这里，我们表明，在已建立的小鼠肺癌中，P53的恢复会导致显着但不完全的肿瘤细胞丢失，特别是在恶性腺癌中，而在腺瘤中不是。我们将MAPK信号的扩增定义为恶性进展的关键决定因素，也是Arf肿瘤抑制基因表达的刺激因子。在这种情况下，对P53修复的反应严重依赖于Arf的表达。我们认为，P53不仅通过抑制导致肿瘤进展的改变的获得来限制恶性进展，而且在P53修复的背景下，还响应于更多的致癌信号来介导肿瘤的退化。我们的观察还强调，p53通路不是由低水平的癌基因活性参与的，而低水平的癌基因活性足以满足肺癌发展的早期阶段。这些数据表明，由于肿瘤细胞群体的分期异质性，恢复在肿瘤进展中重要的途径，而不是启动，可能会导致肿瘤的不完全消退。
Tumourigenesis is a multistep process that results from the sequential accumulation of mutations in key oncogene and tumour suppressor pathways. Personalized cancer therapy that is based on targeting these underlying genetic abnormalities presupposes that sustained inactivation of tumour suppressors and activation of oncogenes is essential in advanced cancers. Mutations in the p53 tumour-suppressor pathway are common in human cancer and significant efforts toward pharmaceutical reactivation of defective p53 pathways are underway. Here we show that restoration of p53 in established murine lung tumours leads to significant but incomplete tumour cell loss specifically in malignant adenocarcinomas but not in adenomas. We define amplification of MAPK signaling as a critical determinant of malignant progression and also a stimulator of Arf tumour-suppressor expression. The response to p53 restoration in this context is critically dependent on the expression of Arf. We propose that p53 not only limits malignant progression by suppressing the acquisition of alterations that lead to tumour progression, but also, in the context of p53 restoration, responds to increased oncogenic signaling to mediate tumor regression. Our observations also underscore that the p53 pathway is not engaged by low levels of oncogene activity that are sufficient for early stages of lung tumour development. These data suggest that restoration of pathways important in tumour progression, as opposed to initiation, may lead to incomplete tumour regression due to the stage-heterogeneity of tumour cell populations.
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影响因子：
64.5
作者：
BREMNER, R;BALMAIN, A
通讯作者：
BALMAIN, A
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
30.8
作者：
Haigis, Kevin M.;Kendall, Krystle R.;Jacks, Tyler
通讯作者：
Jacks, Tyler
DOI：
10.1073/pnas.1004796107
发表时间：
2010-06-01
影响因子：
11.1
作者：
Young, Nathan P.;Jacks, Tyler
通讯作者：
Jacks, Tyler
影响因子：
64.5
作者：
Serrano, M;Lin, AW;Lowe, SW
通讯作者：
Lowe, SW