Abstract
Human colorectal cancers are known to possess multiple mutations, though how these mutations interact in tumor development and progression has not been fully investigated. We have previously described the FCPIK3ca* murine colon cancer model, which expresses a constitutively activated phosphoinositide-3 kinase (PI3K) in the intestinal epithelium. The expression of this dominantly active form of PI3K results in hyperplasia and invasive mucinous adenocarcinomas. These cancers form via a non-canonical mechanism of tumor initiation that is mediated through activation of PI3K and not through aberrations in WNT signaling. Since the Adenomatous Polyposis Coli (APC) gene is mutated in the majority of human colon cancers and often occurs simultaneously with PIK3CA mutations, we sought to better understand the interaction between APC and PIK3CA mutations in the mammalian intestine. In this study, we have generated mice in which the expression of a constitutively active PI3K and the loss of APC occur simultaneously in the distal small intestine and colon. Here, we demonstrate that expression of a dominant active PI3K synergizes with loss of APC activity resulting in a dramatic change in tumor multiplicity, size, morphology and invasiveness. Activation of the PI3K pathway is not able to directly activate WNT signaling through the nuclear localization of CTNNB1 (β-catenin) in the absence of aberrant WNT signaling. Alterations at the transcriptional level, including increased CCND1, may be the etiology of synergy between these activated pathways.
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Acknowledgements
We thank Ella Ward and Jane Weeks in Experimental Pathology at the UW Carbone Cancer Center for their technical assistance. This project was supported by the Conquer Cancer Foundation of the American Society of Clinical Oncology through A Young Investigator Award (DAD); the National Cancer Institute of the US National Institutes of Health through T32 CA009614 (DAD), P50 CA095103 (Gastrointestinal Specialized Program of Research Excellence Grant, Vanderbilt Ingram Cancer Center), R01 CA123438 (RBH), P30 CA014520 (Core Grant, University of Wisconsin Carbone Cancer Center); and start-up funds (RBH) from the UW Division of Gastroenterology and Hepatology, the UW Department of Medicine, and the UW School of Medicine and Public Health.
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Dr Jamey Weichert is the founder of Cellectar, Inc. (Madison, WI), which holds the licensing rights to the CLR1404 technology, and therefore has a financial interest in this agent.
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DAD, AAL and RBH designed, performed and analyzed experiments, and wrote the manuscript. LN, CS, MM, DA and JB performed and analyzed experiments. MKW, LC and JW analyzed experiments. All authors discussed results and edited the manuscript.
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Deming, D., Leystra, A., Nettekoven, L. et al. PIK3CA and APC mutations are synergistic in the development of intestinal cancers. Oncogene 33, 2245–2254 (2014). https://doi.org/10.1038/onc.2013.167
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DOI: https://doi.org/10.1038/onc.2013.167
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