@article{38abd15c41294416b42baafc17c33b5f,
title = "Loss of PTEN in Fallopian Tube Epithelium Results in Multicellular Tumor Spheroid Formation and Metastasis to the Ovary",
abstract = "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.",
keywords = "Cancer, Fallopian tube, Metastasis, Ovary, Oviduct, PTEN, Spheroid",
author = "Dean, {Matthew Jordan} and Vivian Jin and Bergsten, {Tova M.} and Austin, {Julia R.} and Lantvit, {Daniel D.} and Angela Russo and Burdette, {Joanna E.}",
note = "Funding Information: Funding: This work was funded by NIH UG3 ES029073, CA240301, and the Department of Defense grant OC130046 to J.E. Burdette and the Ovarian Cancer Research Fund Alliance grant 543296 to M. Dean. J.R. Austin was supported by T32 AT007533, which was awarded by the Office of the Director, National Institutes of Health (OD) and the National Center for Complementary and Integrative Health (NCCIH). The cytokeratin 8 antibody was developed by Drs. Philippe Brulet and Rolf Kemler and was obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the National Institute of Child Health and Human Development and maintained by the University of Iowa, Department of Biological Sciences, Iowa City, IA, 52242. Funding Information: This work was funded by NIH UG3 ES029073, CA240301, and the Department of Defense grant OC130046 to J.E. Burdette and the Ovarian Cancer Research Fund Alliance grant 543296 to M. Dean. J.R. Austin was supported by T32 AT007533, which was awarded by the Office of the Director, National Institutes of Health (OD) and the National Center for Complementary and Integrative Health (NCCIH). The cytokeratin 8 antibody was developed by Drs. Philippe Brulet and Rolf Kemler and was obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the National Institute of Child Health and Human Development and maintained by the University of Iowa, Department of Biological Sciences, Iowa City, IA, 52242. Publisher Copyright: {\textcopyright} 2019 by the authors. Licensee MDPI, Basel, Switzerland.",
year = "2019",
month = jun,
day = "25",
doi = "10.3390/cancers11060884",
language = "English (US)",
volume = "11",
journal = "Cancers",
issn = "2072-6694",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "6",
}