Targeted expression of oncogenic K-ras in intestinal epithelium causes spontaneous tumorigenesis in mice
Klaus-Peter Janssen1, Fatima el-Marjou, Daniel Pinto
1Cellular Morphogenesis and Signalisation, UMR144, Institut Curie, Paris, France.
Background & Aims:
Ras oncoproteins are mutated in about 50% of human colorectal cancers, but their precise role in tumor initiation or progression is still unclear.
Methods:
This study presents transgenic mice that express K-ras(V12G), the most frequent oncogenic mutation in human tumors, under control of the murine villin promoter in epithelial cells of the large and small intestine.
Results:
More than 80% of the transgenic animals displayed single or multiple intestinal lesions, ranging from aberrant crypt foci (ACF) to invasive adenocarcinomas. Expression of K-ras(V12G) caused activation of the MAP kinase cascade, and the tumors were frequently characterized by deregulated cellular proliferation. Unexpectedly, we obtained no evidence of inactivating mutations of the tumor suppressor gene Apc, the "gatekeeper" in colonic epithelial proliferation. However, spontaneous mutation of the tumor-suppressor gene p53, a frequent feature in the human disease, was found in 3 of 7 tumors that were tested.
Conclusions:
This animal model recapitulates the stages of tumor progression as well as a part of the genetic alterations found in human colorectal cancer. Furthermore, it indicates that activation of K-ras in concert with mutations in p53 may constitute a route to digestive tumor formation and growth, underlining the fact that the pathway to intestinal cancer is not necessarily a single road.
Insights
Activating K-ras mutations in intestinal epithelial cells of transgenic mice led to colorectal cancer development, mimicking human disease progression and genetic alterations. This model highlights K-ras activation and p53 mutations as key pathways in digestive tumor formation.
Area of Science:
- Oncology
- Gastroenterology
- Genetics
Background:
- Ras oncoproteins are frequently mutated in human colorectal cancers (CRCs), but their exact role in tumor development remains elusive.
- Understanding the molecular mechanisms driving CRC initiation and progression is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the role of oncogenic K-ras mutations in the development of colorectal cancer using a novel transgenic mouse model.
- To characterize the resulting tumors and their genetic alterations in comparison to human CRCs.
Main Methods:
- Generation of transgenic mice expressing the oncogenic K-ras(V12G) mutation in intestinal epithelial cells under the control of the villin promoter.
- Analysis of intestinal lesions, including aberrant crypt foci (ACF) and adenocarcinomas.
- Assessment of MAP kinase cascade activation, cellular proliferation, and mutations in tumor suppressor genes (Apc, p53).
Main Results:
- Over 80% of K-ras(V12G) transgenic mice developed intestinal lesions, ranging from ACF to invasive adenocarcinomas.
- K-ras(V12G) expression activated the MAP kinase pathway and led to deregulated cellular proliferation.
- No inactivating mutations in the Apc gene were observed, but spontaneous p53 mutations were detected in a subset of tumors.
Conclusions:
- The K-ras(V12G) transgenic mouse model effectively recapitulates key stages and genetic alterations of human colorectal cancer.
- Activation of K-ras, potentially in conjunction with p53 mutations, represents a significant pathway in digestive tumor formation and progression.
- This study underscores the diverse genetic routes leading to intestinal cancer.
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