{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T18:48:14Z","timestamp":1767206894512,"version":"build-2238731810"},"reference-count":49,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,5,3]],"date-time":"2023-05-03T00:00:00Z","timestamp":1683072000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001528","name":"Wellington Medical Research Foundation","doi-asserted-by":"publisher","award":["2018\/291"],"award-info":[{"award-number":["2018\/291"]}],"id":[{"id":"10.13039\/501100001528","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Graci Foundation","award":["2018\/291"],"award-info":[{"award-number":["2018\/291"]}]},{"name":"Victoria University of Wellington Te Herenga Waka for Sarah Sczelecki\u2019s PhD scholarship","award":["2018\/291"],"award-info":[{"award-number":["2018\/291"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Cancers"],"abstract":"<jats:p>Ovarian cancer (OC) has the highest mortality rate of all gynaecological malignancies. The asymptomatic nature and limited understanding of early disease hamper research into early-stage OC. Therefore, there is an urgent need for models of early-stage OC to be characterised to improve the understanding of early neoplastic transformations. This study sought to validate a unique mouse model for early OC development. The homozygous Fanconi anaemia complementation group D2 knock-out mice (Fancd2\u2212\/\u2212) develop multiple ovarian tumour phenotypes in a sequential manner as they age. Using immunohistochemistry, our group previously identified purported initiating precursor cells, termed \u2018sex cords\u2019, that are hypothesised to progress into epithelial OC in this model. To validate this hypothesis, the sex cords, tubulostromal adenomas and equivalent controls were isolated using laser capture microdissection for downstream multiplexed gene expression analyses using the Genome Lab GeXP Genetic Analysis System. Principal component analysis and unbiased hierarchical clustering of the resultant expression data from approximately 90 OC-related genes determined that cells from the sex cords and late-stage tumours clustered together, confirming the identity of the precursor lesion in this model. This study, therefore, provides a novel model for the investigation of initiating neoplastic events that can accelerate progress in understanding early OC.<\/jats:p>","DOI":"10.3390\/cancers15092595","type":"journal-article","created":{"date-parts":[[2023,5,4]],"date-time":"2023-05-04T01:33:36Z","timestamp":1683164016000},"page":"2595","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Validation of a Precursor Lesion of Epithelial Ovarian Cancer in Fancd2-KO Mice"],"prefix":"10.3390","volume":"15","author":[{"given":"Sarah","family":"Sczelecki","sequence":"first","affiliation":[{"name":"The School of Biological Sciences, Te Herenga Waka Victoria University of Wellington, Wellington 6012, New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janet L.","family":"Pitman","sequence":"additional","affiliation":[{"name":"The School of Biological Sciences, Te Herenga Waka Victoria University of Wellington, Wellington 6012, New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"709","DOI":"10.2741\/S401","article-title":"The origin of ovarian cancers\u2014Hypotheses and controversies","volume":"5","author":"Auersperg","year":"2013","journal-title":"Front. Biosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/j.ajpath.2015.11.011","article-title":"The Dualistic Model of Ovarian Carcinogenesis: Revisited, Revised, and Expanded","volume":"186","author":"Kurman","year":"2016","journal-title":"Am. J. Pathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.2214\/AJR.15.15199","article-title":"Ovarian Cancer, the Revised FIGO Staging System, and the Role of Imaging","volume":"206","author":"Javadi","year":"2016","journal-title":"Am. J. Roentgenol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1002\/jcb.240590928","article-title":"Pathology of ovarian cancer precursors","volume":"59","author":"Scully","year":"1995","journal-title":"J. Cell. Biochem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1158\/0008-5472.CAN-03-3380","article-title":"A genetically defined model for human ovarian cancer","volume":"64","author":"Liu","year":"2004","journal-title":"Cancer Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"140","DOI":"10.4161\/cc.9.1.10264","article-title":"Induction of papillary carcinoma in human ovarian surface epithelial cells using combined genetic elements and peritoneal microenvironment","volume":"9","author":"Zheng","year":"2010","journal-title":"Cell Cycle"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1093\/carcin\/bgp007","article-title":"Oncogenic transformation of human ovarian surface epithelial cells with defined cellular oncogenes","volume":"30","author":"Sasaki","year":"2009","journal-title":"Carcinogenesis"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1158\/0008-5472.CAN-10-2550","article-title":"HMGA2 overexpression-induced ovarian surface epithelial transformation is mediated through regulation of EMT genes","volume":"71","author":"Wu","year":"2011","journal-title":"Cancer Res."},{"key":"ref_9","first-page":"1389","article-title":"Female mice chimeric for expression of the simian virus 40 TAg under control of the MISIIR promoter develop epithelial ovarian cancer","volume":"63","author":"Connolly","year":"2003","journal-title":"Cancer Res."},{"key":"ref_10","first-page":"3459","article-title":"Induction of carcinogenesis by concurrent inactivation of p53 and Rb1 in the mouse ovarian surface epithelium","volume":"63","author":"Choi","year":"2003","journal-title":"Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/S1535-6108(01)00002-2","article-title":"Induction of ovarian cancer by defined multiple genetic changes in a mouse model system","volume":"1","author":"Orsulic","year":"2002","journal-title":"Cancer Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/S0140-6736(71)92335-X","article-title":"Incessant ovulation\u2014A factor in ovarian neoplasia?","volume":"2","author":"Fathalla","year":"1971","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1093\/aje\/152.3.233","article-title":"Risk of ovarian cancer in relation to estrogen and progestin dose and use characteristics of oral contraceptives. SHARE Study Group. Steroid Hormones and Reproductions","volume":"152","author":"Ness","year":"2000","journal-title":"Am. J. Epidemiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1002\/path.1000","article-title":"Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer","volume":"195","author":"Piek","year":"2001","journal-title":"J. Pathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"viii28","DOI":"10.1093\/annonc\/mdt308","article-title":"Coming into focus: The nonovarian origins of ovarian cancer","volume":"24","author":"Dubeau","year":"2013","journal-title":"Ann. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5367","DOI":"10.1038\/s41467-019-13116-2","article-title":"Both fallopian tube and ovarian surface epithelium are cells-of-origin for high-grade serous ovarian carcinoma","volume":"10","author":"Zhang","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1387\/ijdb.120144jp","article-title":"The fate of granulosa cells following premature oocyte loss and the development of ovarian cancers","volume":"56","author":"Pitman","year":"2012","journal-title":"Int. J. Dev. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1095\/biolreprod66.4.1134","article-title":"Formation of ovarian follicles during fetal development in sheep","volume":"66","author":"Sawyer","year":"2002","journal-title":"Biol. Reprod."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1002\/path.1450","article-title":"FANCD2 protein is expressed in proliferating cells of human tissues that are cancer-prone in Fanconi anaemia","volume":"201","author":"Bier","year":"2003","journal-title":"J. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1093\/humupd\/dmm040","article-title":"Oocyte-secreted factors: Regulators of cumulus cell function and oocyte quality","volume":"14","author":"Gilchrist","year":"2008","journal-title":"Hum. Reprod. Update"},{"key":"ref_21","first-page":"936","article-title":"Phenotypes of the ovarian follicular basal lamina predict developmental competence of oocytes","volume":"24","author":"Morris","year":"2009","journal-title":"Hum. Reprod."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1095\/biolreprod46.6.1196","article-title":"Mouse oocytes promote proliferation of granulosa cells from preantral and antral follicles in vitro","volume":"46","author":"Vanderhyden","year":"1992","journal-title":"Biol. Reprod."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1006\/dbio.2001.0451","article-title":"Mouse oocyte mitogenic activity is developmentally coordinated throughout folliculogenesis and meiotic maturation","volume":"240","author":"Gilchrist","year":"2001","journal-title":"Dev. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1095\/biolreprod.114.121756","article-title":"Transcriptomic diversification of developing cumulus and mural granulosa cells in mouse ovarian follicles","volume":"92","author":"Wigglesworth","year":"2015","journal-title":"Biol. Reprod."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1095\/biolreprod.111.095208","article-title":"Temporal differences in granulosa cell specification in the ovary reflect distinct follicle fates in mice","volume":"86","author":"Mork","year":"2012","journal-title":"Biol. Reprod."},{"key":"ref_26","unstructured":"Gertrude Van Wagenen, M.E.S. (1965). Embryology of the Ovary and Testis: Homo Sapiens and Macaca Mulatta, Yale University Press."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1158\/2159-8290.CD-16-0607","article-title":"Genomics of Ovarian Cancer Progression Reveals Diverse Metastatic Trajectories Including Intraepithelial Metastasis to the Fallopian Tube","volume":"6","author":"Eckert","year":"2016","journal-title":"Cancer Discov."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1002\/path.3023","article-title":"TP53 mutations in serous tubal intraepithelial carcinoma and concurrent pelvic high-grade serous carcinoma\u2014Evidence supporting the clonal relationship of the two lesions","volume":"226","author":"Kuhn","year":"2012","journal-title":"J. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1097\/01.pas.0000213335.40358.47","article-title":"Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship","volume":"31","author":"Kindelberger","year":"2007","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1038\/s41467-017-01217-9","article-title":"Molecular analysis of high-grade serous ovarian carcinoma with and without associated serous tubal intra-epithelial carcinoma","volume":"8","author":"Ducie","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1097\/PGP.0000000000000120","article-title":"Two types of ovarian cortical inclusion cysts: Proposed origin and possible role in ovarian serous carcinogenesis","volume":"34","author":"Banet","year":"2015","journal-title":"Int. J. Gynecol. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2021","DOI":"10.1101\/gad.1103403","article-title":"Epithelial cancer in Fanconi anemia complementation group D2 (Fancd2) knockout mice","volume":"17","author":"Houghtaling","year":"2003","journal-title":"Genes Dev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1158\/0008-5472.85.65.1","article-title":"Heterozygosity for p53 (Trp53+\/-) accelerates epithelial tumor formation in fanconi anemia complementation group D2 (Fancd2) knockout mice","volume":"65","author":"Houghtaling","year":"2005","journal-title":"Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"W566","DOI":"10.1093\/nar\/gkv468","article-title":"ClustVis: A web tool for visualizing clustering of multivariate data using Principal Component Analysis and heatmap","volume":"43","author":"Metsalu","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"20560","DOI":"10.1038\/s41598-020-76603-3","article-title":"VolcaNoseR is a web app for creating, exploring, labeling and sharing volcano plots","volume":"10","author":"Goedhart","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/ng1180","article-title":"PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes","volume":"34","author":"Mootha","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Mohr, U. (2001). International Classification of Rodent Tumors: The Mouse, Springer.","DOI":"10.1007\/978-3-662-07973-7"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/01926230490462075","article-title":"Mechanisms of hormone-mediated carcinogenesis of the ovary","volume":"32","author":"Capen","year":"2004","journal-title":"Toxicol. Pathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1002\/1097-0142(195811\/12)11:6<1226::AID-CNCR2820110619>3.0.CO;2-F","article-title":"Tumorigenesis in ovaries of mice after x irradiation","volume":"11","author":"Gutherie","year":"1958","journal-title":"Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1002\/ijc.2910040109","article-title":"Oocyte destruction and ovarian tumorigenesis after direct application of a chemical carcinogen (9, 0-dimethyl-1, 2-benzanthrene) to the mouse ovary","volume":"4","author":"Krarup","year":"1969","journal-title":"Int. J. Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/37987","article-title":"The mouse Dazla gene encodes a cytoplasmic protein essential for gametogenesis","volume":"389","author":"Ruggiu","year":"1997","journal-title":"Nature"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0021-9975(08)80236-8","article-title":"Incidence of tubulostromal adenoma of the ovary in aged germ cell-deficient mice","volume":"109","author":"Duncan","year":"1993","journal-title":"J. Comp. Pathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.mce.2015.05.022","article-title":"Lack of Rev7 function results in development of tubulostromal adenomas in mouse ovary","volume":"412","author":"Abbasi","year":"2015","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1038\/nm852","article-title":"Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors","volume":"9","author":"Taniguchi","year":"2003","journal-title":"Nat. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/77033","article-title":"Mutations in an oocyte-derived growth factor gene (BMP15) cause increased ovulation rate and infertility in a dosage-sensitive manner","volume":"25","author":"Galloway","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/1477-7827-1-67","article-title":"Animal models of ovarian cancer","volume":"1","author":"Vanderhyden","year":"2003","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1097\/PGP.0b013e3181f45f3e","article-title":"The origin of ovarian carcinomas: A unifying hypothesis","volume":"30","author":"Auersperg","year":"2011","journal-title":"Int. J. Gynecol. Pathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1111\/j.1432-0436.2008.00295.x","article-title":"MUC16 expression during embryogenesis, in adult tissues, and ovarian cancer in the mouse","volume":"76","author":"Wang","year":"2008","journal-title":"Differentiation"}],"updated-by":[{"DOI":"10.3390\/cancers17111869","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2023,5,3]],"date-time":"2023-05-03T00:00:00Z","timestamp":1683072000000}}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/9\/2595\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,3]],"date-time":"2025-08-03T14:07:53Z","timestamp":1754230073000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/9\/2595"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,3]]},"references-count":49,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["cancers15092595"],"URL":"https:\/\/doi.org\/10.3390\/cancers15092595","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,3]]}}}