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Cited by 406Ovarian cancer diagnosis and treatmentCancer Cells and MetastasisOvarian function and disorders

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Ovarian Cancer Cell Line Panel (OCCP): Clinical Importance of In Vitro Morphological Subtypes

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Beaufort, Corine M., Helmijr, Jean C. A., Piskorz, Anna M., Hoogstraat, Marlous, Ruigrok-Ritstier, Kirsten, Besselink, Nicolle, Murtaza, Muhammed, van IJcken, Wilfred F. J., Heine, Anouk A. J., Smid, Marcel, Koudijs, Marco J., Brenton, James D., Berns, Els M. J. J., Helleman, Jozien·2014·PLoS ONE
DOI 10.1371/journal.pone.0103988PMC PMC4167545
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Abstract

Epithelial ovarian cancer is a highly heterogeneous disease and remains the most lethal gynaecological malignancy in the Western world. Therapeutic approaches need to account for inter-patient and intra-tumoural heterogeneity and detailed characterization of in vitro models representing the different histological and molecular ovarian cancer subtypes is critical to enable reliable preclinical testing. There are approximately 100 publicly available ovarian cancer cell lines but their cellular and molecular characteristics are largely undescribed. We have characterized 39 ovarian cancer cell lines under uniform conditions for growth characteristics, mRNA/microRNA expression, exon sequencing, drug response for clinically-relevant therapeutics and collated all available information on the original clinical features and site of origin. We tested for statistical associations between the cellular and molecular features of the lines and clinical features. Of the 39 ovarian cancer cell lines, 14 were assigned as high-grade serous, four serous-type, one low-grade serous and 20 non-serous type. Three morphological subtypes: Epithelial (n = 21), Round (n = 7) and Spindle (n = 12) were identified that showed distinct biological and molecular characteristics, including overexpression of cell movement and migration-associated genes in the Spindle subtype. Comparison with the original clinical data showed association of the spindle-like tumours with metastasis, advanced stage, suboptimal debulking and poor prognosis. In addition, the expression profiles of Spindle, Round and Epithelial morphologies clustered with the previously described C1-stromal, C5-mesenchymal and C4 ovarian subtype expression profiles respectively. Comprehensive profiling of 39 ovarian cancer cell lines under controlled, uniform conditions demonstrates clinically relevant cellular and genomic characteristics. This data provides a rational basis for selecting models to develop specific treatment approaches for histological and molecular subtypes of ovarian cancer.

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Crossref · 10.1371/journal.pone.0103988

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Figures

Figure 1 Overview of the presented data, results and in silico clinical translation. STR short tandem repeat, MSI microsatellite instability, PFS progression-free survival.
Figure 1 Overview of the presented data, results and in silico clinical translation. STR short tandem repeat, MSI microsatellite instability, PFS progression-free survival.CC BY · PubMed Central
Figure 2 Overview of the cell line characteristics. Morphology: E Epithelial, R Round, S Spindle, Histology & Putative Histology: S serous, HGS high-grade serous, LGS low-grade serous, E endometrioid, C clear cell, Mx mixed, M mucinous. Origin: A ascites, T tumour tissue, TM tissue from metastasis, TO ovarian tumour tissue, P pleural effusion. Time: P primary disease, R relapsed disease, CR at clinical resistance. Platinum treated: U untreated, P platinum-based treatment, O other chemotherapy, R radiotherapy. Protein markers: bright red no expression (signal –to-noise ratio <5), light red low expression (signal –to-noise ratio 5–20), light green expression (signal –to-noise ratio 20–200), bright green high expression (signal –to-noise ratio >200), grey not determined. Therapy response: green to red scale sensitive to resistant. Doubling time: green less than one day, yellow 1–2days, orange >2days. MSI microsatellite instability. Gene mutations: dark blue identified by at least two methods, light blue identified by one method, light red identified with one method BUT not with second method. Gene amplification: orange amplified (2–3x SD above the median), red highly amplified (>3x SD above the median). The WNT/bCatenin pathway (WNT/bCAT) and homologous recombination repair (HRR) columns show the number of mutated genes in these pathways.
Figure 2 Overview of the cell line characteristics. Morphology: E Epithelial, R Round, S Spindle, Histology & Putative Histology: S serous, HGS high-grade serous, LGS low-grade serous, E endometrioid, C clear cell, Mx mixed, M mucinous. Origin: A ascites, T tumour tissue, TM tissue from metastasis, TO ovarian tumour tissue, P pleural effusion. Time: P primary disease, R relapsed disease, CR at clinical resistance. Platinum treated: U untreated, P platinum-based treatment, O other chemotherapy, R radiotherapy. Protein markers: bright red no expression (signal –to-noise ratio <5), light red low expression (signal –to-noise ratio 5–20), light green expression (signal –to-noise ratio 20–200), bright green high expression (signal –to-noise ratio >200), grey not determined. Therapy response: green to red scale sensitive to resistant. Doubling time: green less than one day, yellow 1–2days, orange >2days. MSI microsatellite instability. Gene mutations: dark blue identified by at least two methods, light blue identified by one method, light red identified with one method BUT not with second method. Gene amplification: orange amplified (2–3x SD above the median), red highly amplified (>3x SD above the median). The WNT/bCatenin pathway (WNT/bCAT) and homologous recombination repair (HRR) columns show the number of mutated genes in these pathways.CC BY · PubMed Central
Figure 3 Box-plot of the concentration of drug causing 50% growth inhibition (GI50) for all 39 cell lines and eight therapeutics. The whiskers extend to 1.5 times the height of the box (i.e. 25th percentile to median and median to 75th percentile) or, if there is no value in that range, to the minimum or maximum values.
Figure 3 Box-plot of the concentration of drug causing 50% growth inhibition (GI50) for all 39 cell lines and eight therapeutics. The whiskers extend to 1.5 times the height of the box (i.e. 25th percentile to median and median to 75th percentile) or, if there is no value in that range, to the minimum or maximum values.CC BY · PubMed Central
Figure 4 Volcano plot with the correlation between the GI50 values for Cisplatin (A&C) and Paclitaxel (B&D) and the expression of each mRNA (A&B) or microRNA (C&D). X-axes spearman correlation, Y-axes -Log of the p-value.
Figure 4 Volcano plot with the correlation between the GI50 values for Cisplatin (A&C) and Paclitaxel (B&D) and the expression of each mRNA (A&B) or microRNA (C&D). X-axes spearman correlation, Y-axes -Log of the p-value.CC BY · PubMed Central
Figure 5 Hierarchical clustering based on the expression of the 1141 genes and 18 microRNAs differentially expressed between the three morphological subtypes. Histology & Putative Histology: S serous, HGS high-grade serous, LGS low-grade serous, E endometrioid, C clear cell, Mx mixed, M mucinous, Morphology: E Epithelial, R Round, S Spindle, Red colour high expression, Green colour low expression.
Figure 5 Hierarchical clustering based on the expression of the 1141 genes and 18 microRNAs differentially expressed between the three morphological subtypes. Histology & Putative Histology: S serous, HGS high-grade serous, LGS low-grade serous, E endometrioid, C clear cell, Mx mixed, M mucinous, Morphology: E Epithelial, R Round, S Spindle, Red colour high expression, Green colour low expression.CC BY · PubMed Central
Figure 6 Hierarchical clustering of 26 cell lines and 267 ovarian carcinomas based on the expression of the 1141 morphological subtypes-associated genes (A) and the association with progression-free survival (B). The diseases and functions associated with gene clusters A-D are shown together with the p-value and the number of genes associated (#). Red colour high expression, Green colour low expression.
Figure 6 Hierarchical clustering of 26 cell lines and 267 ovarian carcinomas based on the expression of the 1141 morphological subtypes-associated genes (A) and the association with progression-free survival (B). The diseases and functions associated with gene clusters A-D are shown together with the p-value and the number of genes associated (#). Red colour high expression, Green colour low expression.CC BY · PubMed Central

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Metadata

Authors
Beaufort, C. M., Helmijr, J. C. A., Piskorz, A. M., Hoogstraat, M., Ruigrok-Ritstier, K., Besselink, N., Murtaza, M., van IJcken, W. F. J., Heine, A. A. J., Smid, M., Koudijs, M. J., Brenton, J. D., Berns, E. M. J. J., & Helleman, J.
Affiliations
  • Erasmus MC Cancer Institute (NL)
  • University of Cambridge (GB)
  • University Medical Center Utrecht (NL)
Corresponding author
Berns, Els M. J. J.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2014-09-17
Volume
9
Issue
9
Pages
e103988
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0103988
PMC
PMC4167545
OpenAlex
W2015030879
Cited by
403
References
89
Citations by year
2026: 15 · 2025: 24 · 2024: 30 · 2023: 48 · 2022: 38 · 2021: 54 · 2020: 52 · 2019: 41 · 2018: 27 · 2017: 28 · 2016: 25 · 2015: 21
FWCI
29.95
Type
journal article
Language
en
Update notices
correction (2015-03-23)
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • RePub (Erasmus University Rotterdam) (submittedVersion)
Funders
  • Cancer Research UK (15601)
  • Universitair Medisch Centrum Utrecht
Topics
  • Health Sciences › Medicine › Oncology › Ovarian cancer diagnosis and treatment
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
Keywords
epithelial ovarian cancer, ovarian cancer cell lines, morphological subtypes, high-grade serous carcinoma, low-grade serous carcinoma, tumor heterogeneity, metastasis, prognosis, drug response, preclinical models
MeSH terms
Carcinoma, Ovarian Epithelial, Female, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Gene Expression Regulation, Neoplastic, MicroRNAs

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