Identification of ovarian high-grade serous carcinoma cell lines that show estrogen-sensitive growth as xenografts in immunocompromised mice

Alexis De Haven Brandon,Aitor Bermejo Arteagabeitia,Melanie Valenti,Albert Hallsworth,Balint Herodek,William Court,Vladimir Kirkin,Gary Box,Nicoll Matthews

doi:10.1038/s41598-020-67533-1

Alexis De Haven Brandon, Aitor Bermejo Arteagabeitia + Show 7 more

Open Access

https://doi.org/10.1038/s41598-020-67533-1

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Abstract

Ovarian cancer remains a significant challenge in women worldwide. Tumors of the high-grade serous carcinoma (HGSC) type represent the most common form of the disease. Development of new therapies for HGSC has been hampered by a paucity of preclinical models in which new drugs could be tested for target engagement and anti-tumor efficacy. Here, we systematically assessed in vivo growth of ovarian cancer cells, including six validated HGSC cell lines, in highly immunocompromised NSG mice by varying the injection site. We found that, with the exception of OVCAR3, HGSC cell lines COV318, COV362, KURAMOCHI, OVCAR4, and OVSAHO, generally demonstrate poor growth as either subcutaneous or intraperitoneal xenografts. Intrabursal injections performed with KURAMOCHI and COV362 cells did not improve tumor growth in vivo. Additional analysis revealed that OVSAHO and COV362 express moderate levels of estrogen receptor (ERα), which translated into improved growth of xenografts in the presence of 17β-Estradiol. Surprisingly, we also found that the growth of the widely used non-HGSC ovarian cell line SKOV3 could be significantly improved by estrogen supplementation. By describing successful establishment of estrogen-sensitive HGSC xenograft models, OVSAHO and COV362, this work will enable testing of novel therapies for this aggressive form of ovarian cancer.

Highlights

Ovarian cancer remains a significant challenge in women worldwide
On the other end of the spectrum were KURAMOCHI cells, which demonstrated only a partial tumor take (3 out of 5 sites) and an extremely long lag phase before producing small tumors; and COV318 and COV362, the two cell lines that failed to grow as subcutaneous xenografts in female NSG mice
In contrast to the published work that mostly used nude mice[22,32,33], we investigated the growth of ovarian cancer xenografts in the highly immunodeficient NSG mice

Summary

Introduction

Tumors of the high-grade serous carcinoma (HGSC) type represent the most common form of the disease. By describing successful establishment of estrogen-sensitive HGSC xenograft models, OVSAHO and COV362, this work will enable testing of novel therapies for this aggressive form of ovarian cancer. A subset of HGSC patients with BRCA1/2 mutations is treated with PARP inhibitors (olaparib, rucaparib, and niraparib), which were recently approved by Food and Drug Administration (FDA). Their use demonstrates the power of targeted therapy, which could significantly increase survival rates in women with ovarian cancer[11]. Development of new therapies for the HGSC has been hampered by scarcity of easy-to-use, high-fidelity preclinical tumor models

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