Review
Adrenocortical stem and progenitor cells: Implications for adrenocortical carcinoma

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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.

Highlights

► A population of stem/progenitor cells centripetally repopulates the adrenal cortex. ► Recent data suggest a dual fetal and capsular origin of the adult adrenal cortex. ► Stem/progenitor cell fate is regulated in part by Wnt-activated Dax1 and inhibin-α. ► Activated β-catenin and elevated IGF2 are implicated in adrenal tumorigenesis. ► Stem/progenitor cell-like and/or fetal adrenal-like alterations contribute to ACC.

Introduction

A cancer cell represents a genetically altered cell that has acquired pro-growth, anti-apoptotic properties, avoidance of immune detection, and/or a variety of other properties that delineates it from its tissue of origin (for a review of the hallmarks of cancer see (Hanahan and Weinberg, 2011). While signaling and transcription pathways are shared between cell types, it is a unique combinatorial code of gene expression that defines both a normal and malignant cell as tissue-specific (i.e. an adrenal chromaffin cell and a pheochromocytoma cell derived from an adrenal medullary cell) (Harari and Inabnet, 2011). Therefore, an understanding of the normal development and homeostasis of an organ is essential for the molecular characterization of most cancer types.

Adrenocortical tumors (ACT) are common with benign adrenocortical adenomas (ACA) present in about 3–7% of the population (Fassnacht et al., 2011, Giordano, 2010). Malignant adrenocortical carcinomas (ACC) are rare, accounting for only 0.2% of cancer cases reported annually (Fassnacht et al., 2011, Giordano, 2010). The adrenal gland contains stem/progenitor cells that are responsible for the centripetal repopulation of the adult cortex (Kim et al., 2009). Many of the factors that are proving to play a role in the homeostatic growth of the adrenal gland also appear to be significant in adrenocortical tumorigenesis (see Table 1). Specifically, adrenocortical stem/progenitor biology is proving to be at the crossroads of normal gland maintenance and oncogenic transformation.

Section snippets

Development of the adrenal gland

The adrenal gland is two distinct endocrine organs that have separate embryological origins and physiologic functions; the mesoderm-derived cortex secretes steroid hormones while the neural crest-derived medulla secretes catecholamines (Else and Hammer, 2005). Formation of the adrenal gland occurs in several distinct developmental events (Else and Hammer, 2005, Kim and Hammer, 2007). During the 4th week of gestation in humans (E9.0 in mice), proliferation of mesoderm-derived cells of the

Establishment of the stem cell niche

The adrenal capsule has recently been proposed to serve as a stem cell niche/residence for adult adrenocortical stem/progenitor cells that reside within and/or underneath the capsule (Kim et al., 2009, Wood and Hammer, 2011). As such, the formation of the multicellular capsule and its role in the transition from a fetal to adult cortex and ultimately in the homeostatic maintenance of the adult gland has become a critical area of current research. While most histologic studies describe the

Homeostatic maintenance

Replenishment of damaged or dying cells is essential for organ homeostasis, implying the existence of adult tissue stem/progenitor cells, which have since been implicated in most tissues and/or organs including bone marrow, skin, liver, small intestine and many others. Historically, the adrenal gland has been shown to also possess regenerative properties in a variety of model systems including growth of rat adrenal explants, enucleation of rat adrenals and subsequent regrowth of a functional

Steroidogenic factor 1 in normal and neoplastic adrenocortical growth

The expression of the orphan nuclear receptor Sf1 defines the adrenogonadal lineages during development as evidenced by gonadal and adrenal aplasia in Sf1 knockout mice and patients with loss-of-function mutations in the Sf1 gene. While emerging data indicate that Sf1(−), Gli(+) capsular cells become Sf1(+) cells of the underlying cortex during development (Fig. 2), the role of Sf1 in homeostatic proliferation of the adult gland has been delineated in other studies. The compensatory growth of

IGF signaling pathway

The insulin-like growth factor signaling pathway has been implicated in the growth of numerous tissue types and its dysregulation is a frequent occurrence in cancer (Ryan and Goss, 2008). IGF2 is normally expressed at high levels in the developing fetal adrenal where it is considered the primary mitogen for early growth of the developing gland (Ilvesmaki et al., 1993, Mesiano et al., 1993). IGF2 expression drops dramatically at birth coincident with fetal zone regression and appears to be

P53

The TP53 gene, which encodes the versatile p53 protein, is the most frequently mutated gene in all cancers with a frequency of ∼50% thus aptly earning its nickname “the guardian of the genome” (Vousden and Prives, 2009). p53 modulates the expression of an impressive array of genes (∼100 have been identified as direct p53 targets) to ultimately engage in a variety of functions (cell cycle inhibition, DNA repair, apoptosis, and senescence) aimed at protecting against the propagation of harmful

Concluding remarks

The current body of literature supports the hypothesis that stem/progenitor cells reside within the capsule/subcapsule of the adrenal. A great deal of work remains to fully characterize these cells, their lineage relationships and the coincident signaling and transcription pathways involved in organ homeostasis. However, since the turnover rate of the adrenal gland is relatively slow, defining adrenocortical lineages in vivo is relatively time consuming. Similarly, due to the rarity of ACC and

Acknowledgements

This work was supported by National Institutes of Health RO1 Grant CA134606. The authors would like to thank the members of the Hammer laboratory for their invaluable insight and help in preparation of this manuscript.

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