In vivo tumor growth of high-grade serous ovarian cancer cell lines
Introduction
Ovarian cancer (OC) is the fifth leading cause of cancer-related deaths among women in the US and the most lethal gynecologic malignancy [1]. The five-year survival rate has remained close to 25%, and all women are currently treated with the same approach consisting of surgical debulking followed by chemotherapy composed of paclitaxel and carboplatin [2]. Diagnosis of OC usually occurs after metastasis at stages II–IV, and this contributes to the poor survival [3]. Targeted therapies and better strategies for early detection would increase survival, but adequate model systems to study the disease remain a major challenge facing the gynecologic oncology research field [4], [5].
Ovarian cancer is a heterogeneous disease that includes at least five histotypes: clear cell, endometrioid, mucinous, low-grade serous, and high-grade serous tumors [6], [7]. Heterogeneity may be a result of the cell of origin that gives rise to different forms of the disease and reflects distinct molecular alterations associated with each histotype [8], [9], [10]. High-grade serous ovarian cancer (HGSOC), the most common and deadly form of the disease, is considered the “prototype” of epithelial OC, and the recent Cancer Genome Atlas Network analysis defined the landscape of deregulated pathways characterizing HGSOC [11]. Specifically, these tumors are classified based upon mutation of p53, BRCA1/2 mutation, somatic loss, or methylation, and a variety of protein markers including PAX8 and WT1. In addition, copy number variation is a hallmark of HGSOC and less commonly found in endometrioid, clear cell, and mucinous histotypes [12]. Recent genetic signatures from primary human tumors further divided HGSOC into four molecular groups, namely immunoreactive, proliferative, differentiated, and mesenchymal [13]. While these categories are well established in primary and recurrent HGSOC tumors, the ability to correlate genomic and molecular features with useful laboratory model systems is critical for the future development of new therapies, prevention strategies, and imaging studies [14].
Recent publications have characterized an expanded panel of OC cell lines at the genomic level, in 2-dimensional-cell culture (on plastic), and in regard to their in vitro response to chemotherapeutic drugs [15], [16], [17]. These reports further suggested that OC cell lines commonly used in the past (e.g., SKOV3, A2780) do not represent a good approximation of the HGSOC genotype and that a panel of recently described cell lines more closely resemble human serous tumor. However, several of the newly proposed models for HGSOC have never been characterized for the ability to form tumors in immune deficient mice, which is critical to study mechanisms of disease or therapeutic interventions in vivo. The goal of this study was to determine the tumorigenic ability of newly described HGSOC cell lines and the histologic characteristics of the xenografts derived from these cells.
Section snippets
Cell culture
All reagents were obtained from Life Technologies (Carlsbad, CA) unless otherwise indicated. OVCAR4 was obtained through Material Transfer Agreement (MTA) from the National Cancer Institute for the transfer of cell lines from the Division of Cancer Treatment and Diagnosis Tumor Repository. The DCTD Tumor Repository has maintained, since the early 1960s, a low temperature repository of transplantable tumor and tumor cell lines from various species. OVCAR4 were maintained in RPMI supplemented
Results
To assess which HGSOC cell lines recapitulate OC clinical features in vivo, xenograft assays and pathologic characterization of resulting tumors were performed. Kuramochi, OVSAHO, SNU118, COV362, and OVCAR4 were the top five most likely to be high-grade serous ovarian cancer according to the genomic data analysis published by Domcke et al. [17]. The same report identified CAOV3, OVCAR3, and OVCAR8 as possible representatives of high-grade serous cancer. Additionally, CAOV3, Kuramochi, OVCAR3,
Discussion
Validation and comprehensive characterization of genetically and phenotypically defined human cell models are essential for the success of biomedical research to treat and prevent ovarian carcinoma. The cellular models most commonly used in the literature, such as SKOV3 and A2780, have been questioned as being valid models of the most deadly and common OC histotype, high grade serous carcinoma [15], [17]. While a few very recent publications have provided invaluable characterization of the
Acknowledgments
The authors thank Sue Childress and Jay Pilrose for technical assistance. This work was supported in part by grants RSG-12-230-01-TBG from the American Cancer Society Illinois Division and DOD OCRP OC130046 (JEB), the Ovarian Cancer Research Foundation Liz Tilberis Scholar Award (MVB, JEB, and KCD), NIH/NCI grants CA109545 (MSS) and CA086984 (MSS), V Foundation and NIH/NCI CA182832 (DM and KPN), and NSF DGE1313583 (EL). We would like to acknowledge the generous donation from Adam Karpf of the
References (22)
- et al.
New perspectives in ovarian cancer treatment
Maturitas
(2014) - et al.
The role of targeted therapy in ovarian cancer
Eur. J. Cancer
(2011) - et al.
Coming into focus: the nonovarian origins of ovarian cancer
Ann. Oncol.
(2013) - et al.
Cancer statistics, 2014
CA Cancer J. Clin.
(2014) - et al.
Rethinking ovarian cancer: recommendations for improving outcomes
Nat. Rev. Cancer
(2011) - et al.
New strategies in the treatment of ovarian cancer: current clinical perspectives and future potential
Clin. Cancer Res.
(2013) The origin of ovarian carcinomas: a unifying hypothesis
Int. J. Gynecol. Pathol.
(2011)- et al.
The biology of ovarian cancer
Semin. Oncol.
(1998) The origin of ovarian cancers — hypotheses and controversies
Front. Biosci. (Schol. Ed.)
(2013)- et al.
Through the glass darkly: intraepithelial neoplasia, top-down differentiation, and the road to ovarian cancer
J. Pathol.
(2013)
Integrated genomic analyses of ovarian carcinoma
Nature
Cited by (142)
A quantitative MRI-based approach to estimate the permeation and retention of nanomedicines in tumors
2024, Journal of Controlled ReleaseLigand-installed polymeric nanocarriers for combination chemotherapy of EGFR-positive ovarian cancer
2023, Journal of Controlled Release