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Updated: Aug 29, 2026
A Genetically Engineered Mouse Model of Sporadic Colorectal Cancer
Published on: July 6, 2017
'Designer' tumors in mice
Katerina Politi1, Ana Kljuic, Matthias Szabolcs
1Department of Genetics and Development, Columbia University, New York, NY 10032, USA.
Abstract:
We have developed and tested successfully a general method based on Cre-mediated recombination that can be used for ubiquitous or tissue-specific expression of protein products, including tumor-inducing oncoproteins. Depending on the specificity of a chosen promoter driving cre expression, tumors develop by design in bitransgenic mouse progeny derived by crossing Cre-producing mice with partners carrying a dormant oncogenic transgene (targeted into the 3' noncoding region of the cytoplasmic beta-actin locus) that becomes functional after excision of a 'floxed' DNA segment. To provide proof-of-principle, we have used as models transgenes encoding the polyomavirus middle T antigen (PVMT) and the T antigens of the SV40 early region (SVER). Cre-dependent activation of widespread SVER expression resulted in hyperplasias or invasive tumors affecting particular visceral smooth muscles, whereas Cre-dependent, mammary gland-specific expression of PVMT-induced adenocarcinomas, according to plan. Unexpectedly, we also encountered spontaneous (Cre-independent) oncogene expression occurring as a rare event, which simulates the initiation of sporadic tumors and leads to PVMT-induced hemangiomas and mammary carcinomas or SVER-induced disseminated sarcomas, thus, revealing particular tissue susceptibilities to the actions of these oncoproteins.
Insights
A novel Cre-mediated recombination method enables controlled oncoprotein expression for tumor development studies. This system allows for tissue-specific tumor induction in mice, aiding cancer research.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Cancer research often requires precise control over oncogene activation.
- Existing methods may lack the specificity needed for targeted tumor induction.
Purpose of the Study:
- To develop and validate a versatile Cre-lox system for inducible and tissue-specific oncogene expression.
- To model tumor development using specific oncoproteins like polyomavirus middle T antigen (PVMT) and SV40 early region T antigens (SVER).
Main Methods:
- Utilized Cre-mediated recombination to control the expression of dormant oncogenic transgenes.
- Generated bitransgenic mice by crossing Cre-producing lines with mice carrying floxed oncogenes.
- Employed specific promoters to drive Cre expression for tissue-specific oncogene activation.
Main Results:
- Successfully induced tumors in specific tissues, including mammary gland adenocarcinomas (PVMT) and visceral smooth muscle hyperplasias/tumors (SVER).
- Demonstrated the feasibility of designing tumors by controlling oncogene expression.
- Observed rare, spontaneous Cre-independent oncogene activation, revealing tissue susceptibilities.
Conclusions:
- The developed Cre-lox system provides a powerful tool for studying oncogenesis with spatiotemporal control.
- This method facilitates the investigation of specific oncoproteins' roles in tumor initiation and progression.
- Unexpected findings highlight the complexity of oncogene action and tissue-specific responses.
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