Ilary Ruscito1, Dan Cacsire Castillo-Tong2, Ignace Vergote3, Iulia Ignat4, Mandy Stanske5, Adriaan Vanderstichele3, Ram N Ganapathi6, Jacek Glajzer4, Hagen Kulbe4, Fabian Trillsch7, Alexander Mustea8, Caroline Kreuzinger2, Pierluigi Benedetti Panici9, Charlie Gourley10, Hani Gabra11, Mirjana Kessler12, Jalid Sehouli4, Silvia Darb-Esfahani5, Elena Ioana Braicu4. 1. Department of Gynecology, European Competence Center for Ovarian Cancer, Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany; Department of Gynecology, Obstetrics and Urology, Sapienza University of Rome, Rome, Italy; Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy. Electronic address: ilary.ruscito@uniroma1.it. 2. Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. 3. Division of Gynaecological Oncology, Leuven Cancer Institute, Department of Gynaecology and Obstetrics, Universitaire Ziekenhuizen Leuven, Katholieke Universiteit Leuven, Herestraat 49, B-3000 Leuven, Belgium. 4. Department of Gynecology, European Competence Center for Ovarian Cancer, Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany. 5. Institute of Pathology, Charite Medical University, Berlin, Campus Mitte, Germany. 6. Department of Cancer Pharmacology, Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, USA. 7. Department of Gynecology and Obstetrics, University of Munich, Marchioninistrasse 15, Munich, Germany; Department of Gynecology and Gynecologic Oncology, University Medical Center Hamburg-Eppendorf, Martinistr. 46, Hamburg, Germany. 8. Department of Gynecology and Obstetrics, University Medicine of Greifswald, Greifswald, Germany. 9. Department of Gynecology, Obstetrics and Urology, Sapienza University of Rome, Rome, Italy. 10. Nicola Murray Centre for Ovarian Cancer Research, University of Edinburgh Cancer Research UK Centre, MRC IGMM, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, UK. 11. Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, UK. 12. Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany.
Abstract
BACKGROUND: High-grade serous ovarian cancer (HGSOC) causes 80% of all ovarian cancer (OC) deaths. In this setting, the role of cancer stem-like cells (CSCs) is still unclear. In particular, the evolution of CSC biomarkers from primary (pOC) to recurrent (rOC) HGSOCs is unknown. Aim of this study was to investigate changes in CD133 and aldehyde dehydrogenase-1 (ALDH1) CSC biomarker expression in pOC and rOC HGSOCs. METHODS: Two-hundred and twenty-four pOC and rOC intrapatient paired tissue samples derived from 112 HGSOC patients were evaluated for CD133 and ALDH1 expression using immunohistochemistry (IHC); pOCs and rOCs were compared for CD133 and/or ALDH1 levels. Expression profiles were also correlated with patients' clinicopathological and survival data. RESULTS: Some 49.1% of the patient population (55/112) and 37.5% (42/112) pOCs were CD133+ and ALDH1+ respectively. CD133+ and ALDH1+ samples were detected in 33.9% (38/112) and 36.6% (41/112) rOCs. CD133/ALDH1 coexpression was observed in 23.2% (26/112) and 15.2% (17/112) of pOCs and rOCs respectively. Pairwise analysis showed a significant shift of CD133 staining from higher (pOCs) to lower expression levels (rOCs) (p < 0.0001). Furthermore, all CD133 + pOC patients were International Federation of Gynaecology and Obstetrics (FIGO)-stage III/IV (p < 0.0001) and had significantly worse progression-free interval (PFI) (p = 0.04) and overall survival (OS) (p = 0.02). On multivariate analysis, CD133/ALDH1 coexpression in pOCs was identified as independent prognostic factor for PFI (HR: 1.64; 95% CI: 1.03-2.60; p = 0.036) and OS (HR: 1.71; 95% CI: 1.01-2.88; p = 0.045). Analysis on 52 pts patients with known somatic BRCA status revealed that BRCA mutations did not influence CSC biomarker expression. CONCLUSIONS: The study showed that CD133/ALDH1 expression impacts HGSOC patients' survival and first suggests that CSCs might undergo phenotypic change during the disease course similarly to non stem-like cancer cells, providing also a first evidence that there is no correlation between CSCs and BRCA status.
BACKGROUND: High-grade serous ovarian cancer (HGSOC) causes 80% of all ovarian cancer (OC) deaths. In this setting, the role of cancer stem-like cells (CSCs) is still unclear. In particular, the evolution of CSC biomarkers from primary (pOC) to recurrent (rOC) HGSOCs is unknown. Aim of this study was to investigate changes in CD133 and aldehyde dehydrogenase-1 (ALDH1) CSC biomarker expression in pOC and rOC HGSOCs. METHODS: Two-hundred and twenty-four pOC and rOC intrapatient paired tissue samples derived from 112 HGSOC patients were evaluated for CD133 and ALDH1 expression using immunohistochemistry (IHC); pOCs and rOCs were compared for CD133 and/or ALDH1 levels. Expression profiles were also correlated with patients' clinicopathological and survival data. RESULTS: Some 49.1% of the patient population (55/112) and 37.5% (42/112) pOCs were CD133+ and ALDH1+ respectively. CD133+ and ALDH1+ samples were detected in 33.9% (38/112) and 36.6% (41/112) rOCs. CD133/ALDH1 coexpression was observed in 23.2% (26/112) and 15.2% (17/112) of pOCs and rOCs respectively. Pairwise analysis showed a significant shift of CD133 staining from higher (pOCs) to lower expression levels (rOCs) (p < 0.0001). Furthermore, all CD133 + pOC patients were International Federation of Gynaecology and Obstetrics (FIGO)-stage III/IV (p < 0.0001) and had significantly worse progression-free interval (PFI) (p = 0.04) and overall survival (OS) (p = 0.02). On multivariate analysis, CD133/ALDH1 coexpression in pOCs was identified as independent prognostic factor for PFI (HR: 1.64; 95% CI: 1.03-2.60; p = 0.036) and OS (HR: 1.71; 95% CI: 1.01-2.88; p = 0.045). Analysis on 52 pts patients with known somatic BRCA status revealed that BRCA mutations did not influence CSC biomarker expression. CONCLUSIONS: The study showed that CD133/ALDH1 expression impacts HGSOC patients' survival and first suggests that CSCs might undergo phenotypic change during the disease course similarly to non stem-like cancer cells, providing also a first evidence that there is no correlation between CSCs and BRCA status.