探索原发性至复发性高级别浆液性卵巢癌（HGSOC）中CD133/醛脱氢酶-1（ALDH1）阳性癌症干细胞样细胞的克隆进化。卵巢癌治疗创新模型延长生存期（OCTIPS）联盟的一项研究。
Exploring the clonal evolution of CD133/aldehyde-dehydrogenase-1 (ALDH1)-positive cancer stem-like cells from primary to recurrent high-grade serous ovarian cancer (HGSOC). A study of the Ovarian Cancer Therapy-Innovative Models Prolong Survival (OCTIPS) Consortium.
作者信息
Ruscito Ilary, Cacsire Castillo-Tong Dan, Vergote Ignace, Ignat Iulia, Stanske Mandy, Vanderstichele Adriaan, Ganapathi Ram N, Glajzer Jacek, Kulbe Hagen, Trillsch Fabian, Mustea Alexander, Kreuzinger Caroline, Benedetti Panici Pierluigi, Gourley Charlie, Gabra Hani, Kessler Mirjana, Sehouli Jalid, Darb-Esfahani Silvia, Braicu Elena Ioana
机构信息
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.
Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
出版信息
Eur J Cancer. 2017 Jul;79:214-225. doi: 10.1016/j.ejca.2017.04.016. Epub 2017 May 16.
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.
背景
高级别浆液性卵巢癌（HGSOC）导致了所有卵巢癌（OC）死亡病例的80%。在这种情况下，癌症干细胞样细胞（CSCs）的作用仍不清楚。特别是，CSC生物标志物从原发性（pOC）到复发性（rOC）HGSOC的演变尚不清楚。本研究的目的是调查原发性和复发性HGSOC中CD133和醛脱氢酶-1（ALDH1）CSC生物标志物表达的变化。
方法
使用免疫组织化学（IHC）对来自112例HGSOC患者的224份原发性和复发性患者配对组织样本进行CD133和ALDH1表达评估；比较原发性和复发性样本的CD133和/或ALDH1水平。表达谱还与患者的临床病理和生存数据相关。
结果
约49.1%的患者群体（55/112）和37.5%（42/！12）的原发性样本分别为CD133阳性和ALDH1阳性。在33.9%（38/112）和36.6%（41/112）的复发性样本中检测到CD133阳性和ALDH1阳性样本。原发性和复发性样本中CD133/ALDH1共表达分别为23.2%（26/112）和15.2%（17/112）。成对分析显示CD133染色从较高水平（原发性样本）显著转变为较低表达水平（复发性样本）（p < 0.0001）。此外，所有CD133阳性原发性患者均为国际妇产科联盟（FIGO）III/IV期（p < 0.0001），无进展生存期（PFI）（p = 0.04）和总生存期（OS）（p = 0.02）显著更差。多变量分析显示，原发性样本中CD133/ALDH1共表达被确定为PFI（HR：1.64；95% CI：1.03 - 2.60；p = 0.036）和OS（HR：1.71；95% CI：1.01 - 2.88；p = 0.045）的独立预后因素。对52例已知体细胞BRCA状态的患者分析显示，BRCA突变不影响CSC生物标志物表达。
结论
该研究表明CD133/ALDH1表达影响HGSOC患者的生存，首次表明CSCs可能在病程中与非干细胞样癌细胞类似地发生表型变化，也首次证明CSCs与BRCA状态之间没有相关性。
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