title: Analysis of the role of Igf2 in adrenal tumour development in transgenic mouse models.
abstract: 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.
authors.affiliation: Clermont Université, Université Blaise Pascal, GReD, Clermont-Ferrand, France.
authors.forename: Coralie
authors.initials: C
authors.lastname: Drelon
authors.forename: Annabel
authors.initials: A
authors.lastname: Berthon
authors.forename: Bruno
authors.initials: B
authors.lastname: Ragazzon
authors.forename: Frédérique
authors.initials: F
authors.lastname: Tissier
authors.forename: Roberto
authors.initials: R
authors.lastname: Bandiera
authors.forename: Isabelle
authors.initials: I
authors.lastname: Sahut-Barnola
authors.forename: Cyrille
authors.initials: C
authors.lastname: de Joussineau
authors.forename: Marie
authors.initials: M
authors.lastname: Batisse-Lignier
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lefrançois-Martinez
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.forename: Antoine
authors.initials: A
authors.lastname: Martinez
authors.forename: Pierre
authors.initials: P
authors.lastname: Val
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000378:metabolism* / Q000473:pathology*; D000311:Adrenal Glands / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D051176:beta Catenin / Q000378:metabolism
chemical_list: C513121:IGF2 protein, mouse; D051176:beta Catenin; D007335:Insulin-Like Growth Factor II