Hadac Jamie N, Leystra Alyssa A, Paul Olson Terrah J, Maher Molly E, Payne Susan N, Yueh Alexander E, Schwartz Alexander R, Albrecht Dawn M, Clipson Linda, Pasch Cheri A, Matkowskyj Kristina A, Halberg Richard B, Deming Dustin A
Department of Oncology, University of Wisconsin, Madison, Wisconsin.
Division of General Surgery, Department of Surgery, University of Wisconsin, Madison, Wisconsin.
Cancer Prev Res (Phila). 2015 Oct;8(10):952-61. doi: 10.1158/1940-6207.CAPR-15-0003. Epub 2015 Aug 14.
Human colorectal cancers often possess multiple mutations, including three to six driver mutations per tumor. The timing of when these mutations occur during tumor development and progression continues to be debated. More advanced lesions carry a greater number of driver mutations, indicating that colon tumors might progress from adenomas to carcinomas through the stepwise accumulation of mutations following tumor initiation. However, mutations that have been implicated in tumor progression have been identified in normal-appearing epithelial cells of the colon, leaving the possibility that these mutations might be present before the initiation of tumorigenesis. We utilized mouse models of colon cancer to investigate whether tumorigenesis still occurs through the adenoma-to-carcinoma sequence when multiple mutations are present at the time of tumor initiation. To create a model in which tumors could concomitantly possess mutations in Apc, Kras, and Pik3ca, we developed a novel minimally invasive technique to administer an adenovirus expressing Cre recombinase to a focal region of the colon. Here, we demonstrate that the presence of these additional driver mutations at the time of tumor initiation results in increased tumor multiplicity and an increased rate of progression to invasive adenocarcinomas. These cancers can even metastasize to retroperitoneal lymph nodes or the liver. However, despite having as many as three concomitant driver mutations at the time of initiation, these tumors still proceed through the adenoma-to-carcinoma sequence.
人类结直肠癌通常具有多个突变，每个肿瘤包含三到六个驱动突变。这些突变在肿瘤发生和发展过程中出现的时间仍存在争议。更晚期的病变携带更多的驱动突变，这表明结肠肿瘤可能在肿瘤起始后通过突变的逐步积累从腺瘤发展为癌。然而，在外观正常的结肠上皮细胞中已鉴定出与肿瘤进展相关的突变，这使得这些突变可能在肿瘤发生起始之前就已存在。我们利用结肠癌小鼠模型来研究当肿瘤起始时存在多个突变时，肿瘤发生是否仍通过腺瘤到癌的序列进行。为了创建一个肿瘤可同时在Apc、Kras和Pik3ca中具有突变的模型，我们开发了一种新型微创技术，将表达Cre重组酶的腺病毒施用于结肠的一个局部区域。在此，我们证明肿瘤起始时这些额外驱动突变的存在会导致肿瘤 multiplicity增加以及进展为浸润性腺癌的速率增加。这些癌症甚至可转移至腹膜后淋巴结或肝脏。然而，尽管在起始时多达三个驱动突变同时存在，这些肿瘤仍通过腺瘤到癌的序列发展。
