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Identification and Characterization of Ovarian Cancer-Initiating Cells from Primary Human Tumors

¹ Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana; ² Department of Obstetrics Gynecology, Ren Ji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China; ³ Indiana University Simon Cancer Center; Departments of ⁴ Cellular and Integrative Physiology, ⁵ Medicine, and ⁶ Obstetrics Gynecology, Indiana University School of Medicine, Indianapolis, Indiana; ⁷ Department of Life Science and Institute of Molecular Biology, National Chung Cheng University, Ming-Hsiung, Chia-Yi, Taiwan, ROC; ⁸ Department of Obstetrics Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC; and ⁹ Division of Human Cancer Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio

Requests for reprints: Kenneth P. Nephew, Medical Sciences, 1001 East Third, Bloomington, IN 47405. Phone: 812-855-9445; Fax: 812-855-4436; E-mail: knephew{at}indiana.edu.

Key Words: ovarian cancer • cancer stem cells • drug resistance

The objective of this study was to identify and characterize a self-renewing subpopulation of human ovarian tumor cells (ovarian cancer-initiating cells, OCICs) fully capable of serial propagation of their original tumor phenotype in animals. Ovarian serous adenocarcinomas were disaggregated and subjected to growth conditions selective for self-renewing, nonadherent spheroids previously shown to derive from tissue stem cells. To affirm the existence of OCICs, xenoengraftment of as few as 100 dissociated spheroid cells allowed full recapitulation of the original tumor (grade 2/grade 3 serous adenocarcinoma), whereas >10⁵ unselected cells remained nontumorigenic. Stemness properties of OCICs (under stem cell–selective conditions) were further established by cell proliferation assays and reverse transcription–PCR, demonstrating enhanced chemoresistance to the ovarian cancer chemotherapeutics cisplatin or paclitaxel and up-regulation of stem cell markers (Bmi-1, stem cell factor, Notch-1, Nanog, nestin, ABCG2, and Oct-4) compared with parental tumor cells or OCICs under differentiating conditions. To identify an OCIC cell surface phenotype, spheroid immunostaining showed significant up-regulation of the hyaluronate receptor CD44 and stem cell factor receptor CD117 (c-kit), a tyrosine kinase oncoprotein. Similar to sphere-forming OCICs, injection of only 100 CD44⁺CD117⁺ cells could also serially propagate their original tumors, whereas 10⁵ CD44^–CD117^– cells remained nontumorigenic. Based on these findings, we assert that epithelial ovarian cancers derive from a subpopulation of CD44⁺CD117⁺ cells, thus representing a possible therapeutic target for this devastating disease. [Cancer Res 2008;68(11):4311–20]

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