Abstract
Activating mutations in the Kras gene are commonly found in some but not all epithelial cancers. In order to understand the susceptibility of different epithelial tissues to Kras-induced tumorigenesis, we introduced one of the most common Kras mutations, KrasG12D, broadly in epithelial tissues. We used a mouse model in which the G12D mutation is placed in the endogenous Kras locus controlled by inducible, Cre-mediated recombination in tissues expressing cytokeratin 19 including the oral cavity, GI tract, lungs, and ducts of the liver, kidney, and the pancreas. Introduction of the KrasG12D mutation in adult mouse tissues led to neoplastic changes in some but not all of these tissues. Notably, many hyperplasias, metaplasias and adenomas were observed in the oral cavity, stomach, colon and lungs, suggesting that exposure to products of the outside environment promotes KrasG12D-initiated tumorigenesis. However, environmental exposure did not consistently correlate with tumor formation, such as in the small intestine, suggesting that there are also intrinsic differences in susceptibility to Kras activation. The pancreas developed small numbers of mucinous metaplasias with characteristics of early stage pancreatic intraepithelial neoplasms (PanINs), supporting the hypothesis that pancreatic ducts have the potential to give rise pancreatic cancer.
Highlights
Cancer is thought to arise from a series of genetic and epigenetic changes that confer oncogenic properties on a cell and its descendents
Activating mutations in Kras are found in histologically normal tissues as well as in tumors [3] indicating that while these mutations naturally accumulate over the lifetime of an individual, they only rarely lead to tumor formation
We have recently developed a genetic tool that allows us to investigate the susceptibility of different epithelial tissues to KrasG12D-initiated tumorigenesis in adult mice
Summary
Cancer is thought to arise from a series of genetic and epigenetic changes that confer oncogenic properties on a cell and its descendents (reviewed in [1]). A number of oncogenes can contribute to cancer initiation or progression but none have been found to be sufficient for tumor formation. Other genes must be mutated, silenced or overexpressed, within the cell or its environment, for a tumor to form. Kras is a proto-oncogene that normally relays signals from a variety of transmembrane receptors to intracellular effectors that regulate processes such as proliferation, survival, and migration. While its activity is tightly regulated, somatic mutations occur that render its activity constitutive and thereby oncogenic (reviewed in [2]). Activating mutations in Kras are found in histologically normal tissues as well as in tumors [3] indicating that while these mutations naturally accumulate over the lifetime of an individual, they only rarely lead to tumor formation
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
