Adrenocortical stem and progenitor cells: Implications for adrenocortical carcinoma

Abstract

The continuous centripetal repopulation of the adrenal cortex is consistent with a population of cells endowed with the stem/progenitor cell properties of self-renewal and pluripotency. The adrenocortical capsule and underlying undifferentiated cortical cells are emerging as critical components of the stem/progenitor cell niche. Recent genetic analysis has identified various signaling pathways including Sonic Hedgehog (Shh) and Wnt as crucial mediators of adrenocortical lineage and organ homeostasis. Shh expression is restricted to the peripheral cortical cells that express a paucity of steroidogenic genes but give rise to the underlying differentiated cells of the cortex. Wnt/β-catenin signaling maintains the undifferentiated state and adrenal fate of adrenocortical stem/progenitor cells, in part through induction of its target genes Dax1 and inhibin-α, respectively. The pathogenesis of ACC, a rare yet highly aggressive cancer with an extremely poor prognosis, is slowly emerging from studies of the stem/progenitor cells of the adrenal cortex coupled with the genetics of familial syndromes in which ACC occurs. The frequent observation of constitutive activation of Wnt signaling due to loss-of-function mutations in the tumor suppressor gene APC or gain-of-function mutation in β-catenin in both adenomas and carcinomas, suggests perhaps that the Wnt pathway serves an early or initiating insult in the oncogenic process. Loss of p53 might be predicted to cooperate with additional genetic insults such as IGF2 as both are the most common genetic abnormalities in malignant versus benign adrenocortical neoplasms. It is unclear whether other factors such as Pod1 and Pref1, which are implicated in stem/progenitor cell biology in the adrenal and/or other organs, are also implicated in the etiology of adrenocortical carcinoma. The rarity and heterogeneous presentation of ACC makes it difficult to identify the cellular origin and the molecular progression to cancer. A more complete understanding of adrenocortical stem/progenitor cell biology will invariably aid in characterization of the molecular details of ACC tumorigenesis and may offer new options for therapeutic intervention.

Fetal adrenal capsular cells serve as progenitor cells for steroidogenic and stromal adrenocortical cell lineages in M. musculus

“…Studies support the hypothesis that homeostatic maintenance of the adrenal cortex occurs through an inward centripetal displacement of cortical cells from the periphery of the gland (capsule or subcapsular region) toward the cortico-medullary boundary where apoptosis occurs (Simon and Hammer, 2012). In the mouse, adrenal enucleation (removal of the medulla and much of the cortex, leaving only the capsule and peripheral cortex) is followed by formation of new cells that spread out beneath the capsule and proliferate until regeneration is complete (Simon and Hammer, 2012). The repopulating cells are proposed to arise from the capsule or undifferentiated subcapsular cells (Schaberg, 1955).…”

“…The molecular mechanisms involved in this process are not well understood but the capsule has long been characterized as a simple structure that surrounds the gland. Studies support the hypothesis that homeostatic maintenance of the adrenal cortex occurs through an inward centripetal displacement of cortical cells from the periphery of the gland (capsule or subcapsular region) toward the cortico-medullary boundary where apoptosis occurs (Simon and Hammer, 2012). In the mouse, adrenal enucleation (removal of the medulla and much of the cortex, leaving only the capsule and peripheral cortex) is followed by formation of new cells that spread out beneath the capsule and proliferate until regeneration is complete (Simon and Hammer, 2012).…”

Transgenic GATA-4 expression induces adrenocortical tumorigenesis in C57Bl/6 mice

“…7). Stem/progenitor cells have been proposed to be the putative origin of neoplastic differentiation during adrenocortical tumorigenesis (Simon and Hammer, 2012).…”

“…In normal physiologic conditions, inhibin antagonizes TGFb2 signaling in the adrenal cortex by binding to the betaglycan co-receptor, required for efficient TGFb2 actions (Looyenga et al, 2010;Simon and Hammer, 2012). In Inha2/2 adrenals, due to the absence of Inha, TGFb2 could induce gonadlike transformation of adrenocortical progenitor cells (Looyenga et al, 2010;Simon and Hammer, 2012). However, in contrast to Inha2/2 mice, there is a gradual increase of Inha expression in our GDX TG mice, suggesting that other factor(s) than TGFb2 trigger the phenotype.…”

Adrenal cortical and chromaffin stem cells: Is there a common progeny related to stress adaptation?

“…Since Nestin expression can be related to malignancy and an undifferentiated state of the tumor this suggests that Nestin expression can be the consequence of a failure in certain key regulatory pathways in the stem cells (Krupkova et al, 2010). For example, adrenocortical tumors have been suggested to arise from a Wnt/β-catenin dysregulation (Simon and Hammer, 2012), which is not surprising as the activation of the Wnt/β-catenin pathway is crucial for adrenal development and homeostatic maintenance of the gland (Kim et al, 2008).…”