Development of an Image-Guided Orthotopic Xenograft Mouse Model of Endometrial Cancer with Controllable Estrogen Exposure.

Gonda Konings,Andrea Romano,Frank Verhaegen,Kristine Fasmer,Natasja Lieuwes,Bert Delvoux,Pasi Koskimies,Merja Häkkinen,Loes Kooreman,Roy Kruitwagen,Camilla Krakstad,Seppo Auriola,Amina Zaffagnini,Sofia Xanthoulea,Niina Saarinen,Lotte Schyns,Ingfrid Haldorsen,Enitec Consortium ,Ludwig Dubois

doi:10.3390/ijms19092547

Abstract

Endometrial cancer (EC) is the most common gynaecological malignancy in Western society and the majority of cases are estrogen dependent. While endocrine drugs proved to be of insufficient therapeutic value in the past, recent clinical research shows promising results by using combinational regimens and pre-clinical studies and identified potential novel endocrine targets. Relevant pre-clinical models can accelerate research in this area. In the present study we describe an orthotopic and estrogen dependent xenograft mouse model of EC. Tumours were induced in one uterine horn of female athymic nude mice using the well-differentiated human endometrial adenocarcinoma Ishikawa cell line—modified to express the luciferase gene for bioluminescence imaging (BLI). BLI and contrast-enhanced computed-tomograph (CE-CT) were used to measure non-invasive tumour growth. Controlled estrogen exposure was achieved by the use of MedRod implants releasing 1.5 μg/d of 17β-estradiol (E2) in ovariectomized mice. Stable E2 serum concentration was demonstrated by LC-MS/MS. Induced tumours were E2 responsive as increased tumour growth was observed in the presence of E2 but not placebo, assessed by BLI, CE-CT, and tumour weight at sacrifice. Metastatic spread was assessed macroscopically by BLI and histology and was seen in the peritoneal cavity, in the lymphovascular space, and in the thoracic cavity. In conclusion, we developed an orthotopic xenograft mouse model of EC that exhibits the most relevant features of human disease, regarding metastatic spread and estrogen dependency. This model offers an easy to manipulate estrogen dosage (by simply adjusting the MedRod implant length), image-guided monitoring of tumour growth, and objectively measurable endpoints (including tumour weight). This is an excellent in vivo tool to further explore endocrine drug regimens and novel endocrine drug targets for EC.

Highlights

Endometrial cancer (EC) is the most common gynaecological malignancy in the Western world with over 60,000 new cases estimated in 2017 (U.S.; https://seer.cancer.gov)
In this study we describe the development of an orthotopic endometrial cancer (EC) mouse model where estrogen exposure was controlled and estrogen dependent tumour growth was measured
A novel MedRod delivery system was used in which subcutaneous implants provided a constant release of 17β-estradiol (E2) after ovariectomy (OVX)

Summary

Introduction

Endometrial cancer (EC) is the most common gynaecological malignancy in the Western world with over 60,000 new cases estimated in 2017 (U.S.; https://seer.cancer.gov). About 70% of ECs are diagnosed at an early stage and are treated with surgery and with selected cases receiving adjuvant chemo/radio therapy. About 25% of EC patients will develop recurrent diseases. In patients with recurrent EC, and in EC cases with primary advanced stage and distant metastatic disease, treatment options are limited. The y consist of aggressive chemotherapy, which yields low efficacy, poor patient prognosis, and is accompanied by significant side effects [1,2]. The re is a need for additional treatment possibilities

Methods

Results

Conclusion