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Development of an Image-Guided Orthotopic Xenograft Mouse Model of Endometrial Cancer with Controllable Estrogen Exposure
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...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165149/ https://www.ncbi.nlm.nih.gov/pubmed/30154339 http://dx.doi.org/10.3390/ijms19092547 |
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author | Konings, Gonda FJ Saarinen, Niina Delvoux, Bert Kooreman, Loes Koskimies, Pasi Krakstad, Camilla Fasmer, Kristine E. Haldorsen, Ingfrid S. Zaffagnini, Amina Häkkinen, Merja R. Auriola, Seppo Dubois, Ludwig Lieuwes, Natasja Verhaegen, Frank Schyns, Lotte EJR Kruitwagen, Roy FPM Xanthoulea, Sofia Romano, Andrea |
author_facet | Konings, Gonda FJ Saarinen, Niina Delvoux, Bert Kooreman, Loes Koskimies, Pasi Krakstad, Camilla Fasmer, Kristine E. Haldorsen, Ingfrid S. Zaffagnini, Amina Häkkinen, Merja R. Auriola, Seppo Dubois, Ludwig Lieuwes, Natasja Verhaegen, Frank Schyns, Lotte EJR Kruitwagen, Roy FPM Xanthoulea, Sofia Romano, Andrea |
author_sort | Konings, Gonda FJ |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6165149 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-61651492018-10-10 Development of an Image-Guided Orthotopic Xenograft Mouse Model of Endometrial Cancer with Controllable Estrogen Exposure Konings, Gonda FJ Saarinen, Niina Delvoux, Bert Kooreman, Loes Koskimies, Pasi Krakstad, Camilla Fasmer, Kristine E. Haldorsen, Ingfrid S. Zaffagnini, Amina Häkkinen, Merja R. Auriola, Seppo Dubois, Ludwig Lieuwes, Natasja Verhaegen, Frank Schyns, Lotte EJR Kruitwagen, Roy FPM Xanthoulea, Sofia Romano, Andrea Int J Mol Sci Article 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. MDPI 2018-08-28 /pmc/articles/PMC6165149/ /pubmed/30154339 http://dx.doi.org/10.3390/ijms19092547 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Konings, Gonda FJ Saarinen, Niina Delvoux, Bert Kooreman, Loes Koskimies, Pasi Krakstad, Camilla Fasmer, Kristine E. Haldorsen, Ingfrid S. Zaffagnini, Amina Häkkinen, Merja R. Auriola, Seppo Dubois, Ludwig Lieuwes, Natasja Verhaegen, Frank Schyns, Lotte EJR Kruitwagen, Roy FPM Xanthoulea, Sofia Romano, Andrea Development of an Image-Guided Orthotopic Xenograft Mouse Model of Endometrial Cancer with Controllable Estrogen Exposure |
title | Development of an Image-Guided Orthotopic Xenograft Mouse Model of Endometrial Cancer with Controllable Estrogen Exposure |
title_full | Development of an Image-Guided Orthotopic Xenograft Mouse Model of Endometrial Cancer with Controllable Estrogen Exposure |
title_fullStr | Development of an Image-Guided Orthotopic Xenograft Mouse Model of Endometrial Cancer with Controllable Estrogen Exposure |
title_full_unstemmed | Development of an Image-Guided Orthotopic Xenograft Mouse Model of Endometrial Cancer with Controllable Estrogen Exposure |
title_short | Development of an Image-Guided Orthotopic Xenograft Mouse Model of Endometrial Cancer with Controllable Estrogen Exposure |
title_sort | development of an image-guided orthotopic xenograft mouse model of endometrial cancer with controllable estrogen exposure |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165149/ https://www.ncbi.nlm.nih.gov/pubmed/30154339 http://dx.doi.org/10.3390/ijms19092547 |
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