Review paper: origin and molecular pathology of adrenocortical neoplasms

Abstract

Neoplastic adrenocortical lesions are common in humans and several species of domestic animals. Although there are unanswered questions about the origin and evolution of adrenocortical neoplasms, analysis of human tumor specimens and animal models indicates that adrenocortical tumorigenesis involves both genetic and epigenetic alterations. Chromosomal changes accumulate during tumor progression, and aberrant telomere function is one of the key mechanisms underlying chromosome instability during this process. Epigenetic changes serve to expand the size of the uncommitted adrenal progenitor population, modulate their phenotypic plasticity (i.e., responsiveness to extracellular signals), and increase the likelihood of subsequent genetic alterations. Analyses of heritable and spontaneous types of human adrenocortical tumors documented alterations in either cell surface receptors or their downstream effectors that impact neoplastic transformation. Many of the mutations associated with benign human adrenocortical tumors result in dysregulated cyclic adenosine monophosphate signaling, whereas key factors and/or signaling pathways associated with adrenocortical carcinomas include dysregulated expression of the IGF2 gene cluster, activation of the Wnt/beta-catenin pathway, and inactivation of the p53 tumor suppressor. A better understanding of the factors and signaling pathways involved in adrenal tumorigenesis is necessary to develop targeted pharmacologic and genetic therapies.

Fig. 1

Steroid hormone biosynthetic pathways. All steroidogenic cells share the capacity to mobilize and cleave cholesterol. The repertoire of enzymes distal to P450scc determines the steroidogenic capacity of a given cell. Note that P450c17 has both 17α-hydroxylase and 17,20-lyase activities. Cyt b₅ selectively enhances the 17,20-lyase activity of P450c17 through allosteric effects. Abbreviations: 3β-HSD, 3β-hydroxysteroid dehydrogenase; 17β-HSD, 17β-hydroxysteroid dehydrogenase; cyt b₅, cytochrome b₅; DOC, deoxycorticosterone; DHEA, dehydroepiandrosterone; P450aldo, aldosterone synthase; P450c11, cytochrome P450 11β-hydroxylase; P450c17, cytochrome P450 17α-hydroxylase/17,20-lyase; P450c21, cytochrome P450 21-hydroxylase.

Fig. 2

Differentiation of multipotential subcapsular adrenocortical progenitors into corticoid-producing or gonadal-like cells. See the accompanying text for details. Abbreviations: ACTH, adrenocorticotropic hormone; GDX, gonadectomy; LH, luteinizing hormone; LHR, LH receptor; MC2R, melanocortin-2 receptor (ACTH receptor); Sf1, steroidogenic factor 1.