title: Establishment and Characterization of an In Vitro Model of Ovarian Cancer Stem-like Cells with an Enhanced Proliferative Capacity.
abstract: The establishment of cancer stem-like cell (CSC) culture systems may be instrumental in devising strategies to fight refractory cancers. Inhibition of the Rho kinase ROCK has been shown to favorably affect CSC spheroid cultures. In this study, we show how ROCK inhibition in human serous ovarian cancer (SOC) cells can help establish a CSC system, which illuminates cancer pathophysiology and its treatment in this setting. In the presence of a ROCK kinase inhibitor, spheroid cultures of SOC cells expressed characteristic CSC markers including ALDH1A1, CD133, and SOX2, along with differentiation and tumorigenic capabilities in mouse xenograft models of human SOC. High expression levels of ALDH, but not CD133, correlated with spheroid formation CSC marker expression and tumor forming capability. In clinical specimens of SOC, high levels of ALDH1A1 correlated with advanced stage and poor prognosis. Pharmacologic or genetic blockade of ALDH blocked cell proliferation and reduced expression of SOX2, the genetic ablation of which abolished spheroid formation, whereas SOX2 overexpression inhibited ALDH1A1 expression and blocked spheroid proliferation. Taken together, our findings illustrated a new method to culture human ovarian CSC, and they defined a reciprocal regulatory relationship between ALDH1A1 and SOX2, which impacts ovarian CSC proliferation and malignant progression.
authors.affiliation: Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. Division of Cancer Differentiation, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ishiguro
authors.affiliation: Division of Cancer Differentiation, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Sato
authors.affiliation: Division of Cancer Differentiation, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Ohata
authors.affiliation: Central Animal Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ikarashi
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Ryou-U
authors.initials: RU
authors.lastname: Takahashi
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ochiya
authors.affiliation: Department of Pathology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Department of Pathology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Tsuda
authors.affiliation: Department of Obstetrics and Gynecology, Kitasato University Hospital, Kanagawa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Onda
authors.affiliation: Department of Gynecology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Kato
authors.affiliation: Department of Gynecology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kasamatsu
authors.affiliation: Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Enomoto
authors.affiliation: Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakagama
authors.affiliation: Division of Cancer Differentiation, National Cancer Center Hospital, Tokyo, Japan. kojokamo@ncc.go.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Okamoto
mesh_terms: D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*