Aldosterone-Producing Adenoma Formation in the Adrenal Cortex Involves Expression of Stem/Progenitor Cell Markers

Abstract

Aldosterone producing adenoma (APA) is the most common form of surgically curable hypertension. To further understand mechanisms involved in APA formation, we investigated the expression of molecules linked to adrenal stem/precursor cells [β-catenin, Sonic hedgehog (Shh), CD56], and nuclear receptors that play key roles in adrenocortical development and function steroidogenic factor 1, dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1) in six control adrenal glands and 14 adrenals with APA and compared their expression with that of specific markers of zona glomerulosa (ZG) [CYP11B2, Disabled 2 (Dab2)]. Both Dab2 and CD56 were expressed in ZG. Although Dab2 associates uniquely with differentiated ZG cells and its expression is lost when cells transdifferentiate to zona fasciculata (ZF) cells, CD56 was also expressed in ZF and in aldosterone-producing cell clusters, confirming that these structures possess an intermediate phenotype between ZG and ZF cells. Shh was barely detectable in cells located to the outer part of the ZG in the control adrenal; in contrast, its expression was detected in the entire APA and was dramatically increased in the hyperplastic peritumoral ZG. Transcriptome profiling revealed differential expression of components of Shh signaling pathway in a subgroup of APA. Similarly, Wnt/β-catenin signaling was activated in the majority of APA as well as in the entire peritumoral adrenal cortex; however, no mutation was identified in the CTNNB1 gene that could account for β-catenin activation. Our data suggest that both APA and adjacent ZG present characteristics of stem/precursor cells; the reexpression of genes involved in fetal adrenal development could underlie excessive ZG cell proliferation and APA formation.

Integrating Genetics and Genomics in Primary Aldosteronism

“…This is supported by 2 subsequent transcriptome analyses performed in our laboratory on 123 APA samples and 11 control adrenals, which showed a subgroup structure that could reflect distinct pathogenic mechanisms and which was confirmed by functional pathological investigations. 40,41 Nevertheless, CYP11B2 expression appears to be consistently increased, although to variable extent, among APA samples, with low expression of CYP11B2 in APA being a rare finding. 42 …”

“…Recently, we have shown that activation of ␤-catenin occurs in approximately two thirds of APAs. 41 However, ␤-catenin activation status was not associated with any biological or clinical parameters. Moreover, the sequencing of exons 3 and 5 of the CTNNB1 gene in tumor DNA from 41 patients did not show mutations that could account for ␤-catenin activation.…”

An update on novel mechanisms of primary aldosteronism

“…Nevertheless, despite their morphological appearance, ZF-like cells still express markers of the ZG cells such as CYP11B2, DAB2, or CD56, suggesting that adenoma cells derive from ZG (Boulkroun et al 2010(Boulkroun et al , 2011. In different studies, mutational status of the tumor has been shown to be correlated with its cellular composition and size: KCNJ5 mutations were associated with large ZF-like APA, while ATP1A1 and CACNA1D mutations were associated with small ZG-like APA, suggesting that adenoma size is associated with cellular composition (Azizan et al 2012, Dekkers et al 2014.…”

“…Our actual knowledge does not allow explanation of the mechanisms involved in APA formation and their histological variability. Different hypotheses have been formulated: i) if APA derive from ZG cells, the ZF-like phenotype would be due to greater metabolic activity or induction of lipid uptake (Boulkroun et al 2010(Boulkroun et al , 2011; ii) if APA derive from ZF cells, AS expression would be due to the presence of a somatic mutation in identified or not yet identified genes (Azizan et al 2012(Azizan et al , 2013; iii) APA derive from aldosteroneproducing cell clusters (APCCs; Nishimoto et al 2010). APCCs are AS-positive cell clusters of cuneiform or trapezoid shape located in the ZG and outer ZF that were reported recently in addition to the conventional adrenal cortex zonation (Nishimoto et al 2010).…”

“…One potential mechanism could be the activation of the WNT/b-catenin pathway. Indeed, it has been shown that this pathway is activated in w70% of APA (Boulkroun et al 2011, Berthon et al 2014), that in rare cases somatic activating mutations of CTNN1B, coding for b-catenin, have been described in APA (Azizan et al 2013, Scholl et al 2013 and that constitutive b-catenin activation in the adrenal cortex induces ectopic ZG differentiation and dedifferentiation of the orthotopic ZF, resulting in hyperaldosteronism in 10-month-old mice (Berthon et al 2010). However some of these mice develop malignant characteristics, such as uncontrolled neovascularization and local invasion, a phenotype rarely observed in patients with PA (Berthon et al 2010); it is possible that the levels of b-catenin dosage play a role in the development of specific types of tumors within the adrenal cortex (Berthon et al 2014).…”