The cAMP pathway and the control of adrenocortical development and growth

Abstract

In the last 10 years, extensive studies showed that the cAMP pathway is deregulated in patients suffering from adrenocortical tumours, and particularly in primary pigmented nodular adrenocortical disease (PPNAD). Here we describe how evidence arising from the analysis of patients' data, mouse models and in vitro experiments, have shed light on the cAMP pathway as a central player in adrenal physiopathology. We also show how novel data generated from mouse models may point to new targets for potential therapies.

Fig. 1

Senescence-associated β-galactosidase staining in adrenals from 14-month-old females in WT and AdKO mice. C, cortex; XL, X-like zone; M, medulla; HE, βbars, 50 µm.

Fig. 2

Dysregulation of PKA-Wnt signalling pathways influences zonal identities and promotes tumours. Loss of RIα in adrenocortical cells (AdKO) leads to the resurgence, the expansion and the centrifugal differentiation of foetal-like cells that acquire fasciculata markers, concomitantly to an atrophy of fasciculata cells in the adult cortex. AdKO mice develop morbid hyperplasia causing ACTH-independent Cushing syndrome reminiscent of PPNAD in human (Sahut-Barnola et al., 2010). Constitutive activation of β-catenin in adrenocortical cells (ΔCat) leads to expansion of tumours that originate from both the outer cortex and the medullo-cortical boundary. There, tumourigenic cells expand centripetally and differentiate into ectopic glomerulosa to develop into Conn adenomas, at the expense of both fasciculata cells and medulla. Eventually, these benign adenomas may progress into carcinomas (Berthon et al., 2010). P, adult cortex progenitors; P?, hypothetical foetal cortex progenitors; Ca, capsule; G, Zona glomerulosa; F, Zona fasciculata; X, X-zone

Fig. 3

Cytb5 and 3βHSD expression in WT and AdKO adrenals. A–B, Immunodetection of 3βHSD (A) and Cytb5 (B) in female adrenals. In 18-month-old AdKO mice, full expansion of foetal-like cortex (low 3βHSD staining) is revealed. Remainings of the atrophic adult cortex, displaying higher 3βHSD staining, is delineated by dotted lines. C, Quantitative representation (RT-qPCR) of Cytb5 mRNA levels in adrenals of 12-month-old females. D, Levels of Cytb5 and 3βHSD were quantified by western blotting in adrenals of 12-month-old females. **P < 0,01. C, cortex; X_L, X-like zone; M, medulla; HE, haematoxylin and eosin; Scale bars, 50 µm.