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Induction of ovarian cancer by defined multiple genetic changes in a mouse model system
Sandra Orsulic1, Yi Li, Robert A Soslow
1Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. orsulics@mskcc.org
Abstract:
We have developed a mouse model for ovarian carcinoma by using an avian retroviral gene delivery technique for the introduction of multiple genes into somatic ovarian cells of adult mice. Ovarian cells from transgenic mice engineered to express the gene encoding the avian receptor TVA were efficiently infected in vitro with multiple vectors carrying coding sequences for oncogenes and marker genes. When target cells were derived from TVA transgenic mice deficient for p53, the addition of any two of the oncogenes c-myc, K-ras, and Akt were sufficient to induce ovarian tumor formation when infected cells were injected at subcutaneous, intraperitoneal, or ovarian sites. We demonstrated that the ovarian surface epithelium is the precursor tissue for these ovarian carcinomas, and that introduction of oncogenes causes phenotypic changes in the ovarian surface epithelial cells. The induced ovarian tumors in mice resembled human ovarian carcinomas in their rapid progression and intraperitoneal metastatic spread.
Insights
Researchers created a mouse model for ovarian carcinoma using avian retroviral gene delivery. Introducing specific oncogenes into p53-deficient ovarian cells induced tumors, mimicking human ovarian cancer progression and metastasis.
Area of Science:
- Oncology
- Genetics
- Animal Models
Background:
- Ovarian carcinoma is a significant health concern with complex genetic underpinnings.
- Developing accurate preclinical models is crucial for understanding disease mechanisms and testing therapies.
Purpose of the Study:
- To establish a novel mouse model for ovarian carcinoma using avian retroviral gene delivery.
- To investigate the oncogenes sufficient for inducing ovarian tumors in a p53-deficient background.
Main Methods:
- Utilized an avian retroviral gene delivery system to introduce multiple oncogenes (c-myc, K-ras, Akt) into somatic ovarian cells.
- Employed transgenic mice engineered to express the avian receptor TVA and deficient for p53.
- Injected modified ovarian cells into various sites (subcutaneous, intraperitoneal, ovarian) to assess tumor formation.
Main Results:
- Ovarian tumors were successfully induced in mice when specific combinations of oncogenes were introduced into p53-deficient ovarian cells.
- The ovarian surface epithelium was identified as the precursor tissue for the induced ovarian carcinomas.
- The induced tumors exhibited rapid progression and intraperitoneal metastatic spread, closely resembling human ovarian carcinomas.
Conclusions:
- The developed mouse model effectively recapitulates key features of human ovarian carcinoma, including tumorigenesis and metastasis.
- This model provides a valuable platform for studying ovarian cancer pathogenesis and for preclinical therapeutic evaluations.