title: Impact of oviductal versus ovarian epithelial cell of origin on ovarian endometrioid carcinoma phenotype in the mouse.
abstract: Endometrioid carcinoma (EC) is a relatively indolent ovarian carcinoma subtype that is nonetheless deadly if detected late. Existing genetically engineered mouse models (GEMMs) of the disease, based on transformation of the ovarian surface epithelium (OSE), take advantage of known ovarian EC driver gene lesions, but do not fully recapitulate the disease features seen in patients. An EC model in which the Apc and Pten tumour suppressor genes are conditionally deleted in murine OSE yields tumours that are biologically more aggressive and significantly less differentiated than human ECs. Importantly, OSE is not currently thought to be the tissue of origin of most ovarian cancers, including ECs, suggesting that tumour initiation in Müllerian epithelium may produce tumours that more closely resemble their human tumour counterparts. We have developed Ovgp1-iCreERT2mice in which the Ovgp1 promoter controls expression of tamoxifen (TAM)-regulated Cre recombinase in oviductal epithelium - the murine equivalent of human Fallopian tube epithelium. Ovgp1-iCreERT2;Apcfl/fl;Ptenfl/flmice treated with TAM or injected with adenovirus expressing Cre into the ovarian bursa uniformly develop oviductal or ovarian ECs, respectively. On the basis of their morphology and global gene expression profiles, the oviduct-derived tumours more closely resemble human ovarian ECs than do OSE-derived tumours. Furthermore, mice with oviductal tumours survive much longer than their counterparts with ovarian tumours. The slow progression and late metastasis of oviductal tumours resembles the relatively indolent behaviour characteristic of so-called Type I ovarian carcinomas in humans, for which EC is a prototype. Our studies demonstrate the utility of Ovgp1-iCreERT2mice for manipulating genes of interest specifically in the oviductal epithelium, and establish that the cell of origin is an important consideration in mouse ovarian cancer GEMMs. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Wu
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Yali
authors.initials: Y
authors.lastname: Zhai
authors.affiliation: Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
authors.forename: Rork
authors.initials: R
authors.lastname: Kuick
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Karnezis
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Paloma
authors.initials: P
authors.lastname: Garcia
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Anum
authors.initials: A
authors.lastname: Naseem
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Tom C
authors.initials: TC
authors.lastname: Hu
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.|Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.|Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Fearon
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. kathcho@umich.edu.|Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA. kathcho@umich.edu.
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Cho
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000818:Animals; D030801:Animals, Genetically Modified; D018269:Carcinoma, Endometrioid / Q000235:genetics / Q000473:pathology; D000077216:Carcinoma, Ovarian Epithelial; D002454:Cell Differentiation; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000473:pathology; D004848:Epithelium / Q000473:pathology; D005187:Fallopian Tubes / Q000473:pathology; D005260:Female; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology; D010053:Ovary / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D013629:Tamoxifen / Q000378:metabolism
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D006023:Glycoproteins; C097024:Ovgp1 protein, mouse; C000613192:adenomatous polyposis coli protein, mouse; D013629:Tamoxifen; C045073:Cre recombinase; D019426:Integrases; D051059:PTEN Phosphohydrolase
keywords: Fallopian tube; cell of origin; endometrioid carcinoma; mouse ovarian cancer model; oviduct