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Development of keratoacanthomas and squamous cell carcinomas in transgenic rabbits with targeted expression of EJras
1Department of Comparative Medicine, Jake Gittlen Cancer Research Institute, Hershey, Pennsylvania, USA.
Abstract:
Activated ras genes have been frequently identified in both benign and malignant human tumors, including keratoacanthoma and squamous cell carcinoma. In this study, we developed two lines of transgenic rabbits in which the expression of EJras has been specifically targeted to the rabbit epidermal keratinocytes, using the upstream regulatory region of cottontail rabbit papillomavirus. All of the F1 transgenic progenies developed multiple keratoacanthomas at about 3 days after birth. The rabbits developed an average of 20 tumors, which usually reached the size of approximately 1 cm in diameter and then spontaneously regressed in about 2 months, similar to keratoacanthoma regression in humans. In addition, up to 18% of the rabbits then developed squamous cell carcinoma at about 5 months of age. The expression of EJras was detectable in all of the keratoacanthomas and squamous cell carcinomas. These results strongly support the involvement of the ras oncogene in both the initiation and regression of keratoacanthoma, and in the development of squamous cell carcinomas. These novel transgenic rabbits, with their consistent tumorigenic phenotype at an early age, high similarity to the human lesions, and easy accessibility for examination, manipulation, biopsy, and treatment, should provide a unique model system for studying ras activation-related tumor initiation, regression, and progression, and for evaluating antitumor therapies.
Insights
Transgenic rabbits expressing EJras developed keratoacanthomas and squamous cell carcinomas, mirroring human skin tumors. This new model aids research into ras oncogene-driven tumor development and regression.
Area of Science:
- Oncology
- Genetics
- Dermatology
Background:
- Activated ras genes are common in human tumors like keratoacanthoma and squamous cell carcinoma.
- The role of ras oncogenes in tumor initiation and progression is well-established.
- A suitable animal model is needed to study ras-driven tumorigenesis.
Purpose of the Study:
- To create a transgenic rabbit model for studying ras oncogene activation in skin tumors.
- To investigate the role of EJras in the development and regression of keratoacanthoma and squamous cell carcinoma.
- To establish a novel preclinical model for evaluating anti-tumor therapies.
Main Methods:
- Developed transgenic rabbits with EJras expression targeted to epidermal keratinocytes using cottontail rabbit papillomavirus regulatory elements.
- Monitored F1 transgenic progenies for tumor development, characteristics, and regression.
- Analyzed EJras expression in developed tumors (keratoacanthomas and squamous cell carcinomas).
Main Results:
- All F1 transgenic rabbits developed multiple keratoacanthomas within 3 days of birth.
- Tumors averaged 20 per rabbit, reached ~1 cm, and spontaneously regressed in ~2 months.
- 18% of rabbits subsequently developed squamous cell carcinoma by 5 months of age, with detectable EJras expression.
Conclusions:
- EJras involvement in keratoacanthoma initiation and regression is strongly supported.
- Ras oncogene activation is implicated in squamous cell carcinoma development.
- These transgenic rabbits offer a valuable model for studying ras-related tumors and testing therapies.
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