The side population of ovarian cancer cells defines a heterogeneous compartment exhibiting stem cell characteristics
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Maximilian Boesch1,2, Alain G. Zeimet3, Daniel Reimer3, Stefan Schmidt1, Guenther Gastl1, Walther Parson4, Franziska Spoeck1,2, Jiri Hatina5, Dominik Wolf1,6,*, Sieghart Sopper1,2,*
1 Internal Medicine V, Innsbruck Medical University, Innsbruck, Austria
2 Tyrolean Cancer Research Institute, Innsbruck, Austria
3 Department of Gynecology and Obstetrics, Innsbruck Medical University, Innsbruck, Austria
4 Institute of Legal Medicine, Innsbruck Medical University, Innsbruck, Austria
5 Department of Biology and Biomedical Centre, Faculty of Medicine Pilsen, Charles University Prague, Pilsen, Czech Republic
6 Medical Clinic III, Oncology, Hematology and Rheumatology, University Clinic Bonn (UKB), Bonn, Germany
* These authors contributed equally to this work
Sieghart Sopper, email:
Keywords: Cancer stem cell, cancer-initiating cell, side population, ABC drug transporter, epithelial ovarian cancer, tumor heterogeneity
Received: March 3, 2014 Accepted: May 30, 2014 Published: June 1, 2014
Cancer stem cells (CSC) are believed to be involved in tumor evasion of classical antitumor therapies and have thus become an attractive target for further improvement of anticancer strategies. However, the existence and identity of CSC are still a matter of controversy. In a systematic screen of 13 ovarian cancer cell lines we show that cells with stem cell properties are reliably detectable as a minor population, characterized by ABC transporter expression resulting in the side population (SP) phenotype. In different cell lines, either ABCG2 or ABCB1 was found to be responsible for this effect. Purified SP cells featured virtually all characteristics of bona fide CSC, including clonogenicity, asymmetric division and high tumorigenicity in vivo. Using in-depth phenotyping by multicolor flow cytometry, we found that among the investigated ovarian cancer cell lines the SP compartment exhibits tremendous heterogeneity and is composed of multiple phenotypically distinct subpopulations. Thus, our study confirms previous results showing that CSC are contained within the SP. However, the exact identity of the CSC is still disguised by the high complexity of the CSC-containing compartment. Further functional studies are needed to determine whether a single cellular subset can unambiguously be defined as CSC or whether multiple stem cell-like cells with different properties coexist. Moreover, the observed heterogeneity may reflect a high level of plasticity and likely influences tumor progression, escape from immune-surveillance and development of resistance to anticancer therapies and should therefore be considered in the development of new treatment strategies.
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