Restoration of p53 function leads to tumour regression in vivo
Restoration of p53 function leads to tumour regression in vivo
复制标题
DOI：
10.1038/nature05541
复制
发表时间：
2007-02-08
期刊：
影响因子：
64.8
通讯作者：
Jacks, Tyler
中科院分区：
文献类型：
--
作者：
Ventura, Andrea;Kirsch, David G.;Jacks, Tyler
肿瘤发生是一个多步骤的过程，需要癌基因的激活和肿瘤抑制基因的失活（1）。人类癌症的小鼠模型最近证明，肿瘤维持通常需要持续表达显性作用的癌基因（例如Hras、Kras和Myc）（2-5）;这种表型被称为癌基因成瘾（6）。通过开发特异性抑制癌蛋白（如BCR-ABL、c-KIT和EGFR）功能的活性抗癌药物，这一概念已得到临床验证（7-10）。因此，识别肿瘤维持所需的其他基因突变可能会为新的癌症疗法提供临床有用的靶点。尽管p53功能丧失是人类癌症的共同特征（11），但尚不清楚肿瘤维持是否需要持续灭活该或其他肿瘤抑制途径。为了探索这个问题，我们开发了一种基于Cre-loxP的策略来暂时控制体内肿瘤抑制基因的表达。在这里，我们表明，恢复内源性p53的表达，导致小鼠的原发性淋巴瘤和肉瘤的消退，而不影响正常组织。肿瘤消退的机制取决于肿瘤的类型，p53恢复的主要结果是淋巴瘤中的细胞凋亡和肉瘤中细胞生长的抑制以及细胞衰老的特征。这些结果支持通过药理学再激活p53来治疗人类癌症的努力。
Tumorigenesis is a multi-step process that requires activation of oncogenes and inactivation of tumour suppressor genes(1). Mouse models of human cancers have recently demonstrated that continuous expression of a dominantly acting oncogene ( for example, Hras, Kras and Myc) is often required for tumour maintenance(2-5); this phenotype is referred to as oncogene addiction(6). This concept has received clinical validation by the development of active anticancer drugs that specifically inhibit the function of oncoproteins such as BCR-ABL, c-KIT and EGFR(7-10). Identifying additional gene mutations that are required for tumour maintenance may therefore yield clinically useful targets for new cancer therapies. Although loss of p53 function is a common feature of human cancers(11), it is not known whether sustained inactivation of this or other tumour suppressor pathways is required for tumour maintenance. To explore this issue, we developed a Cre-loxP-based strategy to temporally control tumour suppressor gene expression in vivo. Here we show that restoring endogenous p53 expression leads to regression of autochthonous lymphomas and sarcomas in mice without affecting normal tissues. The mechanism responsible for tumour regression is dependent on the tumour type, with the main consequence of p53 restoration being apoptosis in lymphomas and suppression of cell growth with features of cellular senescence in sarcomas. These results support efforts to treat human cancers by way of pharmacological reactivation of p53.