Impact of oviductal versus ovarian epithelial cell of origin on ovarian endometrioid carcinoma phenotype in the mouse

Rong Wu, Yali Zhai, Rork Kuick, Anthony Karnezis, Paloma Garcia, Anum Naseem, Tom C. Hu, Eric R. Fearon, Kathleen R. Cho

Research output: Contribution to journalArticle

19 Citations (Scopus)

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-iCreERT2 mice 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/fl mice 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-iCreERT2 mice 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.

Original languageEnglish (US)
Pages (from-to)341-351
Number of pages11
JournalJournal of Pathology
Volume240
Issue number3
DOIs
StatePublished - Nov 1 2016
Externally publishedYes

Fingerprint

Endometrioid Carcinoma
Epithelial Cells
Epithelium
Phenotype
Neoplasms
Tamoxifen
Ovarian Neoplasms
Carcinoma
Oviducts
Fallopian Tubes
Tumor Suppressor Genes
Transcriptome
Adenoviridae
Genes
Neoplasm Metastasis

Keywords

  • cell of origin
  • endometrioid carcinoma
  • Fallopian tube
  • mouse ovarian cancer model
  • oviduct

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Impact of oviductal versus ovarian epithelial cell of origin on ovarian endometrioid carcinoma phenotype in the mouse. / Wu, Rong; Zhai, Yali; Kuick, Rork; Karnezis, Anthony; Garcia, Paloma; Naseem, Anum; Hu, Tom C.; Fearon, Eric R.; Cho, Kathleen R.

In: Journal of Pathology, Vol. 240, No. 3, 01.11.2016, p. 341-351.

Research output: Contribution to journalArticle

Wu, Rong ; Zhai, Yali ; Kuick, Rork ; Karnezis, Anthony ; Garcia, Paloma ; Naseem, Anum ; Hu, Tom C. ; Fearon, Eric R. ; Cho, Kathleen R. / Impact of oviductal versus ovarian epithelial cell of origin on ovarian endometrioid carcinoma phenotype in the mouse. In: Journal of Pathology. 2016 ; Vol. 240, No. 3. pp. 341-351.
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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 M{\"u}llerian epithelium may produce tumours that more closely resemble their human tumour counterparts. We have developed Ovgp1-iCreERT2 mice 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/fl mice 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-iCreERT2 mice 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.",
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AU - Garcia, Paloma

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