Colon Tumors with the Simultaneous Induction of Driver Mutations in APC, KRAS, and PIK3CA Still Progress through the Adenoma-to-carcinoma Sequence.
Colon Tumors with the Simultaneous Induction of Driver Mutations in APC, KRAS, and PIK3CA Still Progress through the Adenoma-to-carcinoma Sequence.
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DOI：
10.1158/1940-6207.capr-15-0003
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发表时间：
2015-10
期刊：
影响因子：
--
通讯作者：
Deming DA
中科院分区：
文献类型：
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作者：
Hadac JN;Leystra AA;Paul Olson TJ;Maher ME;Payne SN;Yueh AE;Schwartz AR;Albrecht DM;Clipson L;Pasch CA;Matkowskyj KA;Halberg RB;Deming DA
人类结直肠癌通常具有多个突变，包括每个肿瘤3-6个驱动突变。这些突变在肿瘤发生和发展过程中发生的时间仍然存在争议。更晚期的病变携带更多数量的驱动突变，表明结肠肿瘤可能通过肿瘤起始后突变的逐步积累从腺瘤进展为癌。然而，已经在结肠的正常外观上皮细胞中鉴定出与肿瘤进展有关的突变，这使得这些突变可能在肿瘤发生开始之前就存在。我们利用小鼠结肠癌模型来研究当肿瘤起始时存在多个突变时，肿瘤发生是否仍然通过腺瘤-癌序列发生。为了建立一个模型，其中肿瘤可以同时拥有突变的Apc，Kras，和Pik 3ca，我们开发了一种新的微创技术管理的腺病毒表达Cre重组酶的结肠的焦点区域。在这里，我们证明了这些额外的驱动突变在肿瘤发生时的存在，导致肿瘤多样性增加和浸润性腺癌进展率增加。这些癌症甚至可以转移到腹膜后淋巴结或肝脏。然而，尽管在起始时有多达三个伴随的驱动突变，这些肿瘤仍然通过腺瘤到癌的序列进行。
Human colorectal cancers often possess multiple mutations, including 3–6 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 prior to 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.