Analysis of the role of Igf2 in adrenal tumour development in transgenic mouse models.

Adrenal cortical carcinomas (ACC) are rare but aggressive tumours associated with poor prognosis. The two most frequent alterations in ACC in patients are overexpression of the growth factor IGF2 and constitutive activation of Wnt/β-catenin signalling. Using a transgenic mouse model, we have previou...

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Autores principales:	Coralie Drelon, Annabel Berthon, Bruno Ragazzon, Frédérique Tissier, Roberto Bandiera, Isabelle Sahut-Barnola, Cyrille de Joussineau, Marie Batisse-Lignier, Anne-Marie Lefrançois-Martinez, Jérôme Bertherat, Antoine Martinez, Pierre Val
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8a5aa1d0e2864f478757abec9540e2e9
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spelling	oai:doaj.org-article:8a5aa1d0e2864f478757abec9540e2e92021-11-18T07:07:18ZAnalysis of the role of Igf2 in adrenal tumour development in transgenic mouse models.1932-620310.1371/journal.pone.0044171https://doaj.org/article/8a5aa1d0e2864f478757abec9540e2e92012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22952916/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Adrenal cortical carcinomas (ACC) are rare but aggressive tumours associated with poor prognosis. The two most frequent alterations in ACC in patients are overexpression of the growth factor IGF2 and constitutive activation of Wnt/β-catenin signalling. Using a transgenic mouse model, we have previously shown that constitutive active β-catenin is a bona fide adrenal oncogene. However, although all these mice developed benign adrenal hyperplasia, malignant progression was infrequent, suggesting that secondary genetic events were required for aggressive tumour development. In the present paper, we have tested IGF2 oncogenic properties by developing two distinct transgenic mouse models of Igf2 overexpression in the adrenal cortex. Our analysis shows that despite overexpression levels ranging from 7 (basal) to 87 (ACTH-induced) fold, Igf2 has no tumour initiating potential in the adrenal cortex. However, it induces aberrant accumulation of Gli1 and Pod1-positive progenitor cells, in a hedgehog-independent manner. We have also tested the hypothesis that Igf2 may cooperate with Wnt signalling by mating Igf2 overexpressing lines with mice that express constitutive active β-catenin in the adrenal cortex. We show that the combination of both alterations has no effect on tumour phenotype at stages when β-catenin-induced tumours are benign. However, there is a mild promoting effect at later stages, characterised by increased Weiss score and proliferation. Formation of malignant tumours is nonetheless a rare event, even when Igf2 expression is further increased by ACTH treatment. Altogether these experiments suggest that the growth factor IGF2 is a mild contributor to malignant adrenocortical tumourigenesis.Coralie DrelonAnnabel BerthonBruno RagazzonFrédérique TissierRoberto BandieraIsabelle Sahut-BarnolaCyrille de JoussineauMarie Batisse-LignierAnne-Marie Lefrançois-MartinezJérôme BertheratAntoine MartinezPierre ValPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 8, p e44171 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Coralie Drelon Annabel Berthon Bruno Ragazzon Frédérique Tissier Roberto Bandiera Isabelle Sahut-Barnola Cyrille de Joussineau Marie Batisse-Lignier Anne-Marie Lefrançois-Martinez Jérôme Bertherat Antoine Martinez Pierre Val Analysis of the role of Igf2 in adrenal tumour development in transgenic mouse models.
description	Adrenal cortical carcinomas (ACC) are rare but aggressive tumours associated with poor prognosis. The two most frequent alterations in ACC in patients are overexpression of the growth factor IGF2 and constitutive activation of Wnt/β-catenin signalling. Using a transgenic mouse model, we have previously shown that constitutive active β-catenin is a bona fide adrenal oncogene. However, although all these mice developed benign adrenal hyperplasia, malignant progression was infrequent, suggesting that secondary genetic events were required for aggressive tumour development. In the present paper, we have tested IGF2 oncogenic properties by developing two distinct transgenic mouse models of Igf2 overexpression in the adrenal cortex. Our analysis shows that despite overexpression levels ranging from 7 (basal) to 87 (ACTH-induced) fold, Igf2 has no tumour initiating potential in the adrenal cortex. However, it induces aberrant accumulation of Gli1 and Pod1-positive progenitor cells, in a hedgehog-independent manner. We have also tested the hypothesis that Igf2 may cooperate with Wnt signalling by mating Igf2 overexpressing lines with mice that express constitutive active β-catenin in the adrenal cortex. We show that the combination of both alterations has no effect on tumour phenotype at stages when β-catenin-induced tumours are benign. However, there is a mild promoting effect at later stages, characterised by increased Weiss score and proliferation. Formation of malignant tumours is nonetheless a rare event, even when Igf2 expression is further increased by ACTH treatment. Altogether these experiments suggest that the growth factor IGF2 is a mild contributor to malignant adrenocortical tumourigenesis.
format	article
author	Coralie Drelon Annabel Berthon Bruno Ragazzon Frédérique Tissier Roberto Bandiera Isabelle Sahut-Barnola Cyrille de Joussineau Marie Batisse-Lignier Anne-Marie Lefrançois-Martinez Jérôme Bertherat Antoine Martinez Pierre Val
author_facet	Coralie Drelon Annabel Berthon Bruno Ragazzon Frédérique Tissier Roberto Bandiera Isabelle Sahut-Barnola Cyrille de Joussineau Marie Batisse-Lignier Anne-Marie Lefrançois-Martinez Jérôme Bertherat Antoine Martinez Pierre Val
author_sort	Coralie Drelon
title	Analysis of the role of Igf2 in adrenal tumour development in transgenic mouse models.
title_short	Analysis of the role of Igf2 in adrenal tumour development in transgenic mouse models.
title_full	Analysis of the role of Igf2 in adrenal tumour development in transgenic mouse models.
title_fullStr	Analysis of the role of Igf2 in adrenal tumour development in transgenic mouse models.
title_full_unstemmed	Analysis of the role of Igf2 in adrenal tumour development in transgenic mouse models.
title_sort	analysis of the role of igf2 in adrenal tumour development in transgenic mouse models.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/8a5aa1d0e2864f478757abec9540e2e9
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Analysis of the role of Igf2 in adrenal tumour development in transgenic mouse models.

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