Elsevier

European Journal of Cancer

Volume 79, July 2017, Pages 214-225
European Journal of Cancer

Original Research
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

https://doi.org/10.1016/j.ejca.2017.04.016Get rights and content

Highlights

  • Cancer stem-like cells (CSCs) undergo phenotypic change during high-grade serous ovarian cancer (HGSOC) disease course.

  • CD133 + CSCs are significantly more represented in high-grade serous primary ovarian cancers (HGS pOCs) rather than paired recurrent ovarian cancers (rOCs).

  • CD133 positivity significantly correlates with International Federation of Gynaecology and Obstetrics (FIGO) III/IV stage and poor survival.

  • CD133/aldehyde-dehydrogenase-1 (ALDH1) coexpression in pOCs independently predicted poor progression-free interval (PFI)/overall survival (OS) in HGSOC patients.

  • Somatic BRCA mutations did not influence CD133 and/or ALDH1 expression in HGSOCs.

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.

Introduction

Ovarian cancer (OC) remains the most lethal gynaecological malignancy [1]. Advances in cancer genomics, epigenomics and proteomics have led to the understanding that OC is a heterogeneous group of different tumours displaying distinct phenotypes and aetiology [2], [3]. The current dichotomous OC classification [4], [5] groups these tumours in two distinct categories: Type I (low-grade serous–papillary, low-grade endometrioid, mucinous and clear cell carcinomas) and Type II (high-grade serous–papillary, high-grade endometrioid, carcinosarcomas and undifferentiated tumours). Type II OCs show a more aggressive biological behaviour, are diagnosed at advanced stage and are chromosomally highly unstable. Among them, high-grade serous OC (HGSOC) accounts for around 80% of all OC deaths [3]. The identification of predictive biomarkers is pivotal for designing new treatment strategies that would be able to reduce HGSOC-related mortality. In this context, the cancer stem-like cell (CSC) theory represents one model to investigate OC heterogeneity. This hypothesis, supported by increased evidence acquired in the last decade, proposes that, within OC tissues, a small population of cells has an increased capacity for self-renewal, tumorigenesis and differentiation [6]. In multiple experimental studies, CSCs have showed their propensity to increase potential of tumorigenesis, metastasis/ invasion, neoangiogenesis and chemoresistance [7], [8] and have been often correlated with a poor prognosis [9], [10], [11], [12], [13].

Several potential CSC markers have been identified in OC samples [14], [15]. Among them, aldehyde dehydrogenase-1 (ALDH1) and CD133 are currently the best characterised for ovarian CSCs. Their expression on the cell surface is associated with increased tumorigenesis and self-renewal capability [16], [17], [18]. Nevertheless, the clonal evolution of CSCs throughout the course of disease, from primary (pOC) to recurrent (rOC) OC, has not been elucidated yet, and information about the changes in CSC presence within the tumour after relapse is still lacking.

The aim of this study was to investigate the evolution of CSC biomarkers CD133 and ALDH1 expression in a large series of paired primary and recurrent HGSOCs.

Section snippets

Sample collection

A total of 224 paired samples from 112 HGSOC patients were collected during primary and secondary tumour debulking. Patients were included consecutively and have been treated between 1985 and 2013 through primary cytoreduction followed by platinum-based chemotherapy. Patients, retrospectively selected from the OCTIPS (Ovarian Cancer Therapy–Innovative Models Prolong Survival, Agreement No. 279113-2) Consortium database, were treated for both pOC and rOC in one of the European Gynaecological

Results

Primary and recurrent intrapatient paired tumour samples derived from 112 HGSOC patients were analysed for CD133 and ALDH1 expressions. Patients characteristics are listed in Table 1.

Immunohistochemistry staining showed that ALDH1 and CD133 proteins were localised to the cytoplasm (Fig. 1, Fig. 3).

Discussion

In the Era of Precision Medicine, huge steps have been taken in the understanding of HGSOC biology. In this tumour setting, the role of CSC and its clonal evolution during subsequent disease relapse has been relatively unexplored.

This study investigated the changes in CSC biomarkers CD133 and ALDH1 expression in primary and recurrent HGSOCs and showed that CD133 + CSCs are significantly more represented in pOCs rather than rOCs, whereas no significant changes in terms of ALDH1 expression levels

Role of the funding source

European Community's Seventh Framework Program supported this study under the grant agreement No. 279113-2 (OCTIPS).

Conflict of interest statement

All Authors declare no conflict of interest.

Acknowledgements

This work was supported by European Community's Seventh Framework Program under grant agreement No. 279113-2 (OCTIPS). The documentation of clinical and patient's data was managed with ‘AlcedisTRIAL the web based documentation system’ of Alcedis GmbH, Winchesterstr. 3, 35394 Giessen, Germany.

Elena Ioana Braicu, MD, PhD is participant in the BIH Charité Clinician Scientist Program funded by the Charité Universitätsmedizin Berlin and the Berlin Institute of Health.

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