Jackson Erica L, Olive Kenneth P, Tuveson David A, Bronson Roderick, Crowley Denise, Brown Michael, Jacks Tyler
Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02141, USA.
Cancer Res. 2005 Nov 15;65(22):10280-8. doi: 10.1158/0008-5472.CAN-05-2193.
We report a direct comparison of the differential effects of individual p53 mutations on lung tumor growth and progression, and the creation of a murine model of spontaneous advanced lung adenocarcinoma that closely recapitulates several aspects of advanced human pulmonary adenocarcinoma. We generated compound conditional knock-in mice with mutations in K-ras combined with one of three p53 alleles: a contact mutant, a structural mutant, or a null allele. p53 loss strongly promoted the progression of K-ras-induced lung adenocarcinomas, yielding a mouse model that is strikingly reminiscent of advanced human lung adenocarcinoma. The influence of p53 loss on malignant progression was observed as early as 6 weeks after tumor initiation. Furthermore, we found that the contact mutant p53R270H, but not the structural mutant p53R172H, acted in a partially dominant-negative fashion to promote K-ras-initiated lung adenocarcinomas. However, for both mutants, loss-of-heterozygosity occurred uniformly in advanced tumors, highlighting a residual tumor-suppressive function conferred by the remaining wild-type allele of p53. Finally, a subset of mice also developed sinonasal adenocarcinomas. In contrast to the lung tumors, expression of the point-mutant p53 alleles strongly promoted the development of sinonasal adenocarcinomas compared with simple loss-of-function, suggesting a tissue-specific gain-of-function.
我们报告了对单个p53突变对肺肿瘤生长和进展的差异影响的直接比较，并创建了一种自发晚期肺腺癌的小鼠模型，该模型紧密概括了晚期人类肺腺癌的几个方面。我们生成了携带K-ras突变并与三种p53等位基因之一组合的复合条件性敲入小鼠：一种接触突变体、一种结构突变体或一个无效等位基因。p53缺失强烈促进了K-ras诱导的肺腺癌的进展，产生了一种小鼠模型，该模型惊人地让人联想到晚期人类肺腺癌。早在肿瘤发生后6周就观察到了p53缺失对恶性进展的影响。此外，我们发现接触突变体p53R270H，但不是结构突变体p53R172H，以部分显性负性方式促进K-ras引发的肺腺癌。然而，对于这两种突变体，杂合性缺失在晚期肿瘤中均一致发生，突出了p53剩余野生型等位基因赋予的残余肿瘤抑制功能。最后，一部分小鼠还发生了鼻窦腺癌。与肺肿瘤相反，与简单的功能丧失相比，点突变p53等位基因的表达强烈促进了鼻窦腺癌的发展，表明存在组织特异性的功能获得。
