Yueh Alexander E, Payne Susan N, Leystra Alyssa A, Van De Hey Dana R, Foley Tyler M, Pasch Cheri A, Clipson Linda, Matkowskyj Kristina A, Deming Dustin A
Division of Hematology and Oncology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States of America.
University of Wisconsin Carbone Cancer Center, Madison, WI, United States of America.
PLoS One. 2016 Feb 10;11(2):e0148730. doi: 10.1371/journal.pone.0148730. eCollection 2016.
The phosphoinositide 3-kinase (PI3K) signaling pathway is critical for multiple important cellular functions, and is one of the most commonly altered pathways in human cancers. We previously developed a mouse model in which colon cancers were initiated by a dominant active PI3K p110-p85 fusion protein. In that model, well-differentiated mucinous adenocarcinomas developed within the colon and initiated through a non-canonical mechanism that is not dependent on WNT signaling. To assess the potential relevance of PI3K mutations in human cancers, we sought to determine if one of the common mutations in the human disease could also initiate similar colon cancers. Mice were generated expressing the Pik3caH1047R mutation, the analog of one of three human hotspot mutations in this gene. Mice expressing a constitutively active PI3K, as a result of this mutation, develop invasive adenocarcinomas strikingly similar to invasive adenocarcinomas found in human colon cancers. These tumors form without a polypoid intermediary and also lack nuclear CTNNB1 (β-catenin), indicating a non-canonical mechanism of tumor initiation mediated by the PI3K pathway. These cancers are sensitive to dual PI3K/mTOR inhibition indicating dependence on the PI3K pathway. The tumor tissue remaining after treatment demonstrated reduction in cellular proliferation and inhibition of PI3K signaling.
磷酸肌醇3激酶（PI3K）信号通路对多种重要的细胞功能至关重要，是人类癌症中最常发生改变的信号通路之一。我们之前构建了一种小鼠模型，其中结肠癌由显性激活的PI3K p110-p85融合蛋白引发。在该模型中，结肠内形成了高分化黏液腺癌，其通过一种不依赖WNT信号的非经典机制引发。为了评估PI3K突变在人类癌症中的潜在相关性，我们试图确定人类疾病中常见的突变之一是否也能引发类似的结肠癌。构建了表达Pik3caH1047R突变的小鼠，该突变是该基因三个人类热点突变之一的类似物。由于这种突变而表达组成型激活PI3K的小鼠会发生侵袭性腺癌，与人类结肠癌中发现的侵袭性腺癌惊人地相似。这些肿瘤在没有息肉样中间阶段的情况下形成，并且也缺乏核CTNNB1（β-连环蛋白），表明由PI3K途径介导的肿瘤起始的非经典机制。这些癌症对PI3K/mTOR双重抑制敏感，表明对PI3K途径有依赖性。治疗后剩余的肿瘤组织显示细胞增殖减少且PI3K信号受到抑制。
