{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T16:14:43Z","timestamp":1787242483310,"version":"build-2736575974"},"reference-count":48,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2019,6,25]],"date-time":"2019-06-25T00:00:00Z","timestamp":1561420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["OC130046"],"award-info":[{"award-number":["OC130046"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014008","name":"Ovarian Cancer Research Alliance","doi-asserted-by":"publisher","award":["543296"],"award-info":[{"award-number":["543296"]}],"id":[{"id":"10.13039\/100014008","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>High-grade serous ovarian cancer (HGSOC) can originate in the fallopian tube and then spread to the ovary. Our objective was to evaluate the role of multicellular tumor spheroids (MTS) in ovarian metastasis. By testing a panel of murine oviductal epithelial (MOE) cells with genetic alterations mimicking those seen in HGSOC, we found that loss of PTEN allowed MTS formation under ultra-low adhesion conditions. Confirming these results in vivo, MTS-like structures were observed in the oviducts of PAX8Cre\/+ PTENflox\/flox mice. MOE PTENshRNA cells could incorporate up to 25% wild type cells into MTS, while higher percentages of wild type cells resulted in a loss of MTS formation. MTS formation allowed MOE PTENshRNA cells to survive better under ultra-low adhesion conditions than control cells. MTS also attached to the ovarian stroma, as would be exposed during ovulation. Interestingly, MTS more robustly cleared monolayers of murine ovarian surface epithelia than murine ovarian fibroblasts. When xenografted into the ovarian bursa, OVCAR8 MTS were able to form tumors in the ovary at a similar rate as an equal number of OVCAR8 cells grown on traditional cell culture plastic. In conclusion, loss of a single gene (PTEN) allows the fallopian tube epithelia to form MTS, which survive better under ultra-low adhesion conditions, attach to the extracellular matrix exposed during ovulation, and colonize the ovary. These results suggest that MTS may contribute to seeding of the ovary in HGSOC patients.<\/jats:p>","DOI":"10.3390\/cancers11060884","type":"journal-article","created":{"date-parts":[[2019,6,25]],"date-time":"2019-06-25T10:52:31Z","timestamp":1561459951000},"page":"884","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Loss of PTEN in Fallopian Tube Epithelium Results in Multicellular Tumor Spheroid Formation and Metastasis to the Ovary"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5014-9311","authenticated-orcid":false,"given":"Matthew","family":"Dean","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Center for Biomolecular Science, University of Illinois at Chicago, Chicago, IL 60607, USA"},{"name":"Department of Animal Science, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Center for Biomolecular Science, University of Illinois at Chicago, Chicago, IL 60607, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tova M.","family":"Bergsten","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Center for Biomolecular Science, University of Illinois at Chicago, Chicago, IL 60607, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia R.","family":"Austin","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Center for Biomolecular Science, University of Illinois at Chicago, Chicago, IL 60607, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel D.","family":"Lantvit","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Center for Biomolecular Science, University of Illinois at Chicago, Chicago, IL 60607, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Russo","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Center for Biomolecular Science, University of Illinois at Chicago, Chicago, IL 60607, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna E.","family":"Burdette","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Center for Biomolecular Science, University of Illinois at Chicago, Chicago, IL 60607, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/S0090-8258(03)00365-2","article-title":"BRCA1\/2-related ovarian cancers are of tubal origin: A hypothesis","volume":"90","author":"Piek","year":"2003","journal-title":"Gynecol. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"12645","DOI":"10.1038\/ncomms12645","article-title":"Integrative proteomic profiling of ovarian cancer cell lines reveals precursor cell associated proteins and functional status","volume":"7","author":"Coscia","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1038\/s41467-017-00962-1","article-title":"High grade serous ovarian carcinomas originate in the fallopian tube","volume":"8","author":"Papp","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6116","DOI":"10.1158\/1078-0432.CCR-04-2509","article-title":"Patterns of gene expression in different histotypes of epithelial ovarian cancer correlate with those in normal fallopian tube, endometrium, and colon","volume":"11","author":"Marquez","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"dju410","DOI":"10.1093\/jnci\/dju410","article-title":"Ovarian cancer risk after salpingectomy: A nationwide population-based study","volume":"107","author":"Falconer","year":"2015","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1111\/aogs.12516","article-title":"Tubal ligation and salpingectomy and the risk of epithelial ovarian cancer and borderline ovarian tumors: A nationwide case-control study","volume":"94","author":"Madsen","year":"2015","journal-title":"Acta Obstet. Gynecol. Scand."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"20500","DOI":"10.18632\/oncotarget.3985","article-title":"Tumorigenesis and peritoneal colonization from fallopian tube epithelium","volume":"21","author":"Eddie","year":"2015","journal-title":"Oncotarget"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1016\/j.ccr.2013.10.013","article-title":"Transformation of the fallopian tube secretory epithelium leads to high-grade serous ovarian cancer in Brca; Tp53; Pten models","volume":"24","author":"Perets","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1976","DOI":"10.1038\/s41388-017-0097-8","article-title":"PTEN loss in the fallopian tube induces hyperplasia and ovarian tumor formation","volume":"37","author":"Russo","year":"2018","journal-title":"Oncogene"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1158\/0008-5472.CAN-15-1382","article-title":"It\u2019s totally tubular\u2026riding the new wave of ovarian cancer research","volume":"76","author":"Perets","year":"2016","journal-title":"Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.canlet.2017.01.011","article-title":"Activin A stimulates migration of the fallopian tube epithelium, an origin of high-grade serous ovarian cancer, through non-canonical signaling","volume":"391","author":"Dean","year":"2017","journal-title":"Cancer Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6116","DOI":"10.1038\/srep06116","article-title":"Ovulation and extra-ovarian origin of ovarian cancer","volume":"4","author":"Sumi","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1021\/acscentsci.8b00405","article-title":"Imaging mass spectrometry reveals crosstalk between the fallopian tube and the ovary that drives primary metastasis of ovarian cancer","volume":"4","author":"Zink","year":"2018","journal-title":"ACS Cent. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1093\/carcin\/bgy170","article-title":"Exposure of the extracellular matrix and colonization of the ovary in metastasis of fallopian tube derived cancer","volume":"40","author":"Dean","year":"2019","journal-title":"Carcinogenesis"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neo.2014.12.004","article-title":"Spherical cancer models in tumor biology","volume":"17","author":"Weiswald","year":"2015","journal-title":"Neoplasia"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/S1040-8428(00)00077-9","article-title":"Spheroids and cell survival","volume":"36","author":"Bates","year":"2000","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.ygyno.2003.12.034","article-title":"Ovarian carcinoma ascites spheroids adhere to extracellular matrix components and mesothelial cell monolayers","volume":"93","author":"Burleson","year":"2004","journal-title":"Gynecol. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2071","DOI":"10.1016\/S0002-9440(10)63058-1","article-title":"\u03b21-integrins regulate the formation and adhesion of ovarian carcinoma multicellular spheroids","volume":"159","author":"Casey","year":"2001","journal-title":"Am. J. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1158\/2159-8274.CD-11-0010","article-title":"Ovarian cancer spheroids use myosin-generated force to clear the mesothelium","volume":"1","author":"Iwanicki","year":"2011","journal-title":"Cancer Discov."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5127","DOI":"10.1038\/s41388-018-0317-x","article-title":"Multicellular detachment generates metastatic spheroids during intra-abdominal dissemination in epithelial ovarian cancer","volume":"37","author":"Habyan","year":"2018","journal-title":"Oncogene"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1097\/PAS.0b013e318282da7f","article-title":"Fallopian tube intraluminal tumor spread from noninvasive precursor lesions: A novel metastatic route in early pelvic carcinogenesis","volume":"37","author":"Bijron","year":"2013","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_22","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_23","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1177\/2472555217697434","article-title":"3D models of the NCI60 cell lines for screening oncology compounds","volume":"22","author":"Selby","year":"2017","journal-title":"SLAS Discov. Adv. Life Sci. R D"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1002\/ijc.29528","article-title":"Mutant p53 expression in fallopian tube epithelium drives cell migration","volume":"137","author":"Quartuccio","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1242\/bio.2012653","article-title":"Spontaneous spheroid budding from monolayers: A potential contribution to ovarian cancer dissemination","volume":"1","author":"Pease","year":"2012","journal-title":"Biol. Open"},{"key":"ref_26","first-page":"255","article-title":"Ovarian surface epithelium: Biology, endocrinology, and pathology","volume":"22","author":"Auersperg","year":"2001","journal-title":"Endocr. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.trsl.2016.03.016","article-title":"New models of hematogenous ovarian cancer metastasis demonstrate preferential spread to the ovary and a requirement for the ovary for abdominal dissemination","volume":"175","author":"Coffman","year":"2016","journal-title":"Transl. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1530\/ERC-11-0107","article-title":"The impact of ovulation on fallopian tube epithelial cells: Evaluating three hypotheses connecting ovulation and serous ovarian cancer","volume":"18","author":"King","year":"2011","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1093\/carcin\/bgv132","article-title":"Mutagenic, surviving and tumorigenic effects of follicular fluid in the context of p53 loss: Initiation of fimbria","volume":"36","author":"Huang","year":"2015","journal-title":"Carcinogenesis"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1002\/path.2091","article-title":"A candidate precursor to serous carcinoma that originates in the distal fallopian tube","volume":"211","author":"Lee","year":"2007","journal-title":"J. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1002\/(SICI)1097-0215(20000115)85:2%3C160::AID-IJC2%3E3.0.CO;2-5","article-title":"Allelic imbalance and mutations of the PTEN gene in ovarian cancer","volume":"85","author":"Saito","year":"2000","journal-title":"Int. J. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"819","DOI":"10.3892\/ijmm_00000530","article-title":"MicroRNA-21 promotes the cell proliferation, invasion and migration abilities in ovarian epithelial carcinomas through inhibiting the expression of PTEN protein","volume":"26","author":"Lou","year":"2010","journal-title":"Int. J. Mol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1158\/0008-5472.CAN-07-2488","article-title":"MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN","volume":"68","author":"Yang","year":"2008","journal-title":"Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1038\/modpathol.2010.119","article-title":"High-grade fimbrial-ovarian carcinomas are unified by altered p53, PTEN and PAX2 expression","volume":"23","author":"Roh","year":"2010","journal-title":"Mod. Pathol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1186\/s13059-014-0526-8","article-title":"Combined image and genomic analysis of high-grade serous ovarian cancer reveals PTEN loss as a common driver event and prognostic classifier","volume":"15","author":"Martins","year":"2014","journal-title":"Genome Biol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Cancer Genome Atlas Research Network (2011). Integrated genomic analyses of ovarian carcinoma. Nature, 474, 609\u2013615.","DOI":"10.1038\/nature10166"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/nature03918","article-title":"Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis","volume":"436","author":"Chen","year":"2005","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1095\/biolreprod.109.081570","article-title":"Ovulation in the absence of the ovarian surface epithelium in the primate","volume":"82","author":"Wright","year":"2010","journal-title":"Biol. Reprod."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1093\/humrep\/der057","article-title":"Dynamics of the primate ovarian surface epithelium during the ovulatory menstrual cycle","volume":"26","author":"Wright","year":"2011","journal-title":"Hum. Reprod."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1093\/humrep\/des466","article-title":"Reproductive characteristics in relation to ovarian cancer risk by histologic pathways","volume":"28","author":"Merritt","year":"2013","journal-title":"Hum. Reprod."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"7547","DOI":"10.1073\/pnas.1017300108","article-title":"Modeling high-grade serous ovarian carcinogenesis from the fallopian tube","volume":"108","author":"Karst","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s13048-016-0213-3","article-title":"Genome-wide transcriptional regulation of estrogen receptor targets in fallopian tube cells and the role of selective estrogen receptor modulators","volume":"9","author":"Schipma","year":"2016","journal-title":"J. Ovarian Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"32785","DOI":"10.18632\/oncotarget.9051","article-title":"Loss of PAX8 in high-grade serous ovarian cancer reduces cell survival despite unique modes of action in the fallopian tube and ovarian surface epithelium","volume":"7","author":"Rodgers","year":"2016","journal-title":"Oncotarget"},{"key":"ref_44","first-page":"e3888","article-title":"In vitro mesothelial clearance assay that models the early steps of ovarian cancer metastasis","volume":"60","author":"Davidowitz","year":"2012","journal-title":"J. Vis. Exp."},{"key":"ref_45","first-page":"2804","article-title":"Alginate hydrogels for three-dimensional organ culture of ovaries and oviducts","volume":"52","author":"King","year":"2011","journal-title":"J. Vis. Exp."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1002\/gene.20008","article-title":"Tissue-specific expression of cre recombinase from the Pax8 locus","volume":"38","author":"Bouchard","year":"2004","journal-title":"Genesis"},{"key":"ref_47","first-page":"e53316","article-title":"Quantitation of intra-peritoneal ovarian cancer metastasis","volume":"113","author":"Lewellen","year":"2016","journal-title":"J. Vis. Exp."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.1158\/1535-7163.MCT-17-1195","article-title":"Phyllanthusmin derivatives induce apoptosis and reduce tumor burden in high-grade serous ovarian cancer by late-stage autophagy inhibition","volume":"17","author":"Young","year":"2018","journal-title":"Mol. Cancer Ther."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/6\/884\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:01:01Z","timestamp":1760187661000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/6\/884"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,25]]},"references-count":48,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2019,6]]}},"alternative-id":["cancers11060884"],"URL":"https:\/\/doi.org\/10.3390\/cancers11060884","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6,25]]}}}