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Int. J. Mol. Sci. 2018, 19(9), 2547; https://doi.org/10.3390/ijms19092547

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

1
GROW—School for Oncology & Developmental Biology, Maastricht University, 6229HX Maastricht, The Netherlands
2
Department of Obstetrics and Gynaecology, Maastricht University Medical Centre, P. Debyelaan 25, 6229HX Maastricht, The Netherlands
3
Forendo Pharma Ltd., FI-20520 Turku, Finland
4
Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology and Turku Center for Disease Modeling (TCDM), University of Turku, FI-20520 Turku, Finland
5
Department of Pathology, Maastricht University Medical Centre, 6229HX Maastricht, The Netherlands
6
Department of Obstetrics and Gynaecology, Haukeland University Hospital, 5021 Bergen, Norway
7
Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway
8
Department of Radiology, Haukeland University Hospital, 5021 Bergen, Norway
9
Section for Radiology, Department of Clinical Medicine, University of Bergen, 5020 Bergen, Norway
10
School of Pharmacy, University of Eastern Finland, FI-80101 Kuopio, Finland
11
Department of Radiotherapy (MAASTRO), Maastricht University, 6229HX Maastricht, The Netherlands
ENITEC: European Network Individualized Treatment Endometrial Cancer (www.esgo.org/network/enitec; within the European Society of Gynaecological Oncology: www.esgo.org).
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 1 August 2018 / Revised: 19 August 2018 / Accepted: 22 August 2018 / Published: 28 August 2018
(This article belongs to the Special Issue Molecular Research of Endometrial Pathophysiology)
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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. View Full-Text
Keywords: endometrial cancer; orthotopic xenograft model; estrogen dependent; bioluminescence imaging; contrast-enhanced CT scan endometrial cancer; orthotopic xenograft model; estrogen dependent; bioluminescence imaging; contrast-enhanced CT scan
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Konings, G.F.; Saarinen, N.; Delvoux, B.; Kooreman, L.; Koskimies, P.; Krakstad, C.; Fasmer, K.E.; Haldorsen, I.S.; Zaffagnini, A.; Häkkinen, M.R.; Auriola, S.; Dubois, L.; Lieuwes, N.; Verhaegen, F.; Schyns, L.E.; Kruitwagen, R.F.; ENITEC Consortium; Xanthoulea, S.; Romano, A. Development of an Image-Guided Orthotopic Xenograft Mouse Model of Endometrial Cancer with Controllable Estrogen Exposure. Int. J. Mol. Sci. 2018, 19, 2547.

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