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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
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.
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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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