Induction of ovarian cancer by defined multiple genetic changes in a mouse model system

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.

Models of ovarian cancer metastasis: Murine models

“…It remains to be determined whether such models will have a superior predictive value over xenograft models in pre-clinical trials and drug discovery applications. Contacting the authors [2,[16][17][18] …”

“…Rodent ( Fig. 1) and human OSE cell lines with defined genetic alterations have also been generated by in vitro transformation of normal OSE [2][3][4]. The relevance of cell lines as models of metastatic disease is limited because of the fact that in vitro conditions do not adequately mimic physiological processes involved in the induction and maintenance of a metastatic phenotype.…”

“…Orsulic et al [2] developed a model in which a defined set of genetic alterations can be introduced specifically into mouse OSE cells through an avian retroviral gene delivery system ex vivo. In this model, p53 deficient mice are engineered to express the avian tumor virus A (TVA) receptor exclusively in epithelial cells.…”

“…All of the genetically engineered mouse models described above have the potential for being valuable models of metastatic ovarian cancer. The avian retroviral gene delivery technique described by Orsulic et al is particularly useful for the analysis of different combinations of multiple genetic alterations and their collaboration in tumor initiation and progression [2] aswell asfor testing pathway-targeting therapies [19]. An important advantage of the MISIIR-TAg model is the short latency of metastatic disease because of germline expression of the transgene.…”

“…Genetically engineered mice are not only more useful for the identification of individual genes and signaling pathways involved in the regulation of cancer dissemination, but can also serve as valuable models for the development of pathway-targeted therapies and investigation into tumor-host interactions and anti-tumor immune mechanisms. There are still some technical problems that need to be addressed, such as the complexity of surgical procedures [2,17,18] and the premature development of malignant disease [16]. The use of mouse models for drug testing will also require concurrent development of imaging techniques for monitoring tumor response to the drug.…”