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Adrenocortical Growth and Cancer

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Abstract

The adrenal gland consists of two distinct parts, the cortex and the medulla. Molecular mechanisms controlling differentiation and growth of the adrenal gland have been studied in detail using mouse models. Knowledge also came from investigations of genetic disorders altering adrenal development and/or function. During embryonic development, the adrenal cortex acquires a structural and functional zonation in which the adrenal cortex is divided into three different steroidogenic zones. Significant progress has been made in understanding adrenal zonation. Recent lineage tracing experiments have accumulated evidence for a centripetal differentiation of adrenocortical cells from the subcapsular area to the inner part of the adrenal cortex. Understanding of the mechanism of adrenocortical cancer (ACC) development was stimulated by knowledge of adrenal gland development. ACC is a rare cancer with a very poor overall prognosis. Abnormal activation of the Wnt/β‐catenin as well as the IGF2 signaling plays an important role in ACC development. Studies examining rare genetic syndromes responsible for familial ACT have played an important role in identifying genetic alterations in these tumors (like TP53 or CTNNB1 mutations as well as IGF2 overexpression). Recently, genomic analyses of ACT have shown gene expression profiles associated with malignancy as well as chromosomal and methylation alterations in ACT and exome sequencing allowed to describe the mutational landscape of these tumors. This progress leads to a new classification of these tumors, opening new perspectives for the diagnosis and prognostication of ACT. This review summarizes current knowledge of adrenocortical development, growth, and tumorigenesis. © 2015 American Physiological Society. Compr Physiol 5:293‐326, 2015.

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Figure 1. Figure 1. Comparison of fetal and adult adrenal. (A) Fetal adrenal gland histology. The fetal gland is composed of two types of tissue, the fetal zone and the definitive zone. The fetal zone constitutes more than 80% of the fetal gland. Under the capsule lies the definitive zone. (B) Adult adrenal gland histology. The adult adrenal is constituted by two distinct tissues, the outer cortex and the inner medulla. These two tissues have different cellular origin and produce corticosteroid and catecholamines, respectively. The cortex is composed of three distinct cell layers: the glomerulosa, fasciculata and reticularis. The adrenal gland is encapsulated. Originally published, with permission, by Nat Rev Endocrinol ().
Figure 2. Figure 2. Steroidogenic pathways in human adult adrenal cortex. The adrenal cortex produces zone‐specific steroids due to specific steroidogenic enzyme expression. There are three distinct steroids: mineralocorticoids produced by zona glomerulosa, glucocorticoids synthesized by zona fasciculata, and androgen produced by zona reticularis. Cholesterol, which is the common precursor, is internalized by StAR protein in the inner mitochondrial membrane. Abbreviations: CYP11B2, aldosterone synthase; CYP17, 17‐hydroxylase, CYP17, 17,20‐lyase; CYP11B1, 11β‐hydroxylase; DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; HSD3B2, type II 3β‐hydroxysteroid dehydrogenase; CYP11A1, cholesterol side‐chain cleveage; CYP21, 21‐hydroxylase; 17βHSD, 17β‐hydroxysteroid dehydrogenase; p450Aro, aromatase; StAR, steroidogenic acute regulatory protein; CS, corticosterone; DOC, deoxycortisol; DOCS, deoxycorticosterone; 18OHCS, 18‐hydroxylase corticosterone.
Figure 3. Figure 3. Development of adrenal gland from urogenital ridge to adult adrenal. (A) Transversal section of an embryo at four weeks in human or at embryonic day nine in mouse. (B) (1) The urogenital ridge corresponds to longitudinal elevation of the intermediate mesoderm. (2) The adrenogonadal primordium (AGP) is formed by condensation of coelomic epithelium and/or intermediate mesoderm. AGP separates into adrenal primordium and gonadal primordium in which germ cells accumulate. (3) Fetal adrenal is localized cranial to the kidney. (4) The adult adrenal gland is formed by fetal adrenal proliferation and differentiation in steroidogenic cells and by migration of chromaffin cells inner the cortex. Factors involved in each step have been annotated. (C) Adrenal gland organogenesis in human and mouse. At the eighth week of gestation in humans (E10.5 in mice), the adrenal primordial/fetal zone (grey cells) derives from the AGP. At the ninth week of gestation in humans (E11.5‐12.5 in mice), chromaffin cells (red cells) colonize the inner layer of the fetal cortex to form the future medulla. At 14.5 days in mice, there is an encapsulation of the fetal zone by mesenchymal cells (blue cells) followed by the formation of definitive cells (orange cells). There is a proliferation of the fetal zone until the birth. At birth, the adrenal cortex undergoes profound structural modification: the definitive zone begins to differentiate in zona fasciculata (yellow cells) and zona glomerulosa (orange cells). The fetal zone regresses after birth in humans, while in mice the fetal zone persists until puberty for males and the first pregnancy in females. In humans, at the age of 6 to 8 years, the zona reticularis (green cells) is formed. Abbreviation: E, embryonic day. Adapted, with permission, from ().
Figure 4. Figure 4. Model of adrenal development. Subcapsular progenitor cells (dark grey) give rise to definitive adrenal cells by centripedal differentiation (major pathway) based on works by (). Some alternative pathways could participate or are activated to maintain the zona fasciculata in certain conditions. Blue: capsular cells; dark‐gray: progenitor cells; orange: zona glomerulosa cells; yellow: zona fasciculata cells; light‐gray: X‐zone cells; white: medulla cells.
Figure 5. Figure 5. Alterations of 11p15 locus and IGF2 overexpression in ACC. The imprinted 11p15 locus contains the CDKN1C (p57kip2), IGF2, and H19 genes. In a normal adrenal (on the left), only the paternal allele of the IGF2 gene is expressed, whereas only the maternal alleles of CDKN1C and H19 are expressed. Paternal isodisomy is usually observed in adrenal cancers (on the right) with loss of the maternal allele at 11p15. This leads to the overexpression of IGF2 and decreased expression of CDKN1C and H19.
Figure 6. Figure 6. The Wnt signaling pathway. Left: In the absence of Wnt ligand, β‐catenin is low, owing to degradation by the ubiquitin‐proteasome system after phosphorylation by the GSK3β‐APC‐AXIN‐WTX complex. Right: Stimulation by Wnt ligand leads to the inactivation of the degradation complex, which leads to the stabilization of β‐catenin in the cytoplasm. After translocation to the nucleus, β‐catenin stimulates expression of target genes after interaction with TCF/LEF. Mutations of β‐catenin abolish phosphorylation of β‐catenin, which leads to its accumulation by preventing its degradation by the ubiquitin‐proteasome system.


Figure 1. Comparison of fetal and adult adrenal. (A) Fetal adrenal gland histology. The fetal gland is composed of two types of tissue, the fetal zone and the definitive zone. The fetal zone constitutes more than 80% of the fetal gland. Under the capsule lies the definitive zone. (B) Adult adrenal gland histology. The adult adrenal is constituted by two distinct tissues, the outer cortex and the inner medulla. These two tissues have different cellular origin and produce corticosteroid and catecholamines, respectively. The cortex is composed of three distinct cell layers: the glomerulosa, fasciculata and reticularis. The adrenal gland is encapsulated. Originally published, with permission, by Nat Rev Endocrinol ().


Figure 2. Steroidogenic pathways in human adult adrenal cortex. The adrenal cortex produces zone‐specific steroids due to specific steroidogenic enzyme expression. There are three distinct steroids: mineralocorticoids produced by zona glomerulosa, glucocorticoids synthesized by zona fasciculata, and androgen produced by zona reticularis. Cholesterol, which is the common precursor, is internalized by StAR protein in the inner mitochondrial membrane. Abbreviations: CYP11B2, aldosterone synthase; CYP17, 17‐hydroxylase, CYP17, 17,20‐lyase; CYP11B1, 11β‐hydroxylase; DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; HSD3B2, type II 3β‐hydroxysteroid dehydrogenase; CYP11A1, cholesterol side‐chain cleveage; CYP21, 21‐hydroxylase; 17βHSD, 17β‐hydroxysteroid dehydrogenase; p450Aro, aromatase; StAR, steroidogenic acute regulatory protein; CS, corticosterone; DOC, deoxycortisol; DOCS, deoxycorticosterone; 18OHCS, 18‐hydroxylase corticosterone.


Figure 3. Development of adrenal gland from urogenital ridge to adult adrenal. (A) Transversal section of an embryo at four weeks in human or at embryonic day nine in mouse. (B) (1) The urogenital ridge corresponds to longitudinal elevation of the intermediate mesoderm. (2) The adrenogonadal primordium (AGP) is formed by condensation of coelomic epithelium and/or intermediate mesoderm. AGP separates into adrenal primordium and gonadal primordium in which germ cells accumulate. (3) Fetal adrenal is localized cranial to the kidney. (4) The adult adrenal gland is formed by fetal adrenal proliferation and differentiation in steroidogenic cells and by migration of chromaffin cells inner the cortex. Factors involved in each step have been annotated. (C) Adrenal gland organogenesis in human and mouse. At the eighth week of gestation in humans (E10.5 in mice), the adrenal primordial/fetal zone (grey cells) derives from the AGP. At the ninth week of gestation in humans (E11.5‐12.5 in mice), chromaffin cells (red cells) colonize the inner layer of the fetal cortex to form the future medulla. At 14.5 days in mice, there is an encapsulation of the fetal zone by mesenchymal cells (blue cells) followed by the formation of definitive cells (orange cells). There is a proliferation of the fetal zone until the birth. At birth, the adrenal cortex undergoes profound structural modification: the definitive zone begins to differentiate in zona fasciculata (yellow cells) and zona glomerulosa (orange cells). The fetal zone regresses after birth in humans, while in mice the fetal zone persists until puberty for males and the first pregnancy in females. In humans, at the age of 6 to 8 years, the zona reticularis (green cells) is formed. Abbreviation: E, embryonic day. Adapted, with permission, from ().


Figure 4. Model of adrenal development. Subcapsular progenitor cells (dark grey) give rise to definitive adrenal cells by centripedal differentiation (major pathway) based on works by (). Some alternative pathways could participate or are activated to maintain the zona fasciculata in certain conditions. Blue: capsular cells; dark‐gray: progenitor cells; orange: zona glomerulosa cells; yellow: zona fasciculata cells; light‐gray: X‐zone cells; white: medulla cells.


Figure 5. Alterations of 11p15 locus and IGF2 overexpression in ACC. The imprinted 11p15 locus contains the CDKN1C (p57kip2), IGF2, and H19 genes. In a normal adrenal (on the left), only the paternal allele of the IGF2 gene is expressed, whereas only the maternal alleles of CDKN1C and H19 are expressed. Paternal isodisomy is usually observed in adrenal cancers (on the right) with loss of the maternal allele at 11p15. This leads to the overexpression of IGF2 and decreased expression of CDKN1C and H19.


Figure 6. The Wnt signaling pathway. Left: In the absence of Wnt ligand, β‐catenin is low, owing to degradation by the ubiquitin‐proteasome system after phosphorylation by the GSK3β‐APC‐AXIN‐WTX complex. Right: Stimulation by Wnt ligand leads to the inactivation of the degradation complex, which leads to the stabilization of β‐catenin in the cytoplasm. After translocation to the nucleus, β‐catenin stimulates expression of target genes after interaction with TCF/LEF. Mutations of β‐catenin abolish phosphorylation of β‐catenin, which leads to its accumulation by preventing its degradation by the ubiquitin‐proteasome system.
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Lucile Lefèvre, Jérôme Bertherat, Bruno Ragazzon. Adrenocortical Growth and Cancer. Compr Physiol 2014, 5: 293-326. doi: 10.1002/cphy.c140010