Abstract
The development of genetically engineered models (GEM) of epithelial ovarian cancer (EOC) has been very successful, with well validated models representing high grade and low grade serous adenocarcinomas and endometrioid carcinoma (EC). Most of these models were developed using technologies intended to target the ovarian surface epithelium (OSE), the cell type long believed to be the origin of EOC. More recent evidence has highlighted what is likely a more prevalent role of the secretory cell of the fallopian tube in the ontogeny of EOC, however none of the GEM of EOC have demonstrated successful targeting of this important cell type.The precise technologies exploited to develop the existing GEM of EOC are varied and carry with them advantages and disadvantages. The use of tissue specific promoters to model disease has been very successful, but the lack of any truly specific OSE or oviductal secretory cell promoters makes the outcomes of these models quite unpredictable. Effecting genetic change by the administration of adenoviral vectors expressing Cre recombinase may alleviate the perceived need for tissue specific promoters, however the efficiencies of infection of different cell types is subject to numerous biological parameters that may lead to preferential targeting of certain cell populations.One important future avenue of GEM of EOC is the evaluation of the role of genetic modifiers. We have found that genetic background can lead to contrasting phenotypes in one model of ovarian cancer, and data from other laboratories have also hinted that the exact genetic background of the model may influence the resulting phenotype. The different genetic backgrounds may modify the biology of the tumors in a manner that will be relevant to human disease, but they may also be modifying parameters which impact the response of the host to the technologies employed to develop the model.
Highlights
A number of insightful reviews have summarized genetically engineered models (GEM) of epithelial ovarian cancer (EOC) [1,2,3,4,5,6,7,8,9]
The fundamental premise in the design of GEM of EOC is the development of tools or strategies to target genetic change to the presumed precursors of the disease
The origin of human EOC was presumed to be in the ovarian surface epithelium (OSE), or in the epithelial lining of inclusion cysts that had arisen from the OSE and the evidence supporting this has been extensively reviewed [10,11,12,13,14]
Summary
A number of insightful reviews have summarized GEM of EOC [1,2,3,4,5,6,7,8,9]. While targeting of OSE using the Amhr2-Cre transgenic to activate KrasG12D and to inactivate Pten resulted in low grade serous adenocarcinomas [51], similar activation/ inactivation of these genes induced following the intrabursal injection of Ad-CMV-Cre led to the development of ovarian endometrioid adenocarcinomas [76]. While both of these reports indicate tumors arising from the OSE, the two different strategies may target different subsets of cells on the ovarian surface. Strain differences may modulate parameters that influence the efficiency of viral infection, or subtly modify temporal patterns of promoter function
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