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igf_and_growth_programs_in_acc

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IGF and Growth Programs in ACC

Molecular Biology and Tumor Evolution

IGF and related growth programs in adrenocortical carcinoma (ACC) refer to a set of recurrent molecular abnormalities involving the insulin-like growth factor axis, adrenal developmental regulators, and downstream networks that govern proliferation, survival, differentiation, and cellular metabolism.123 Within ACC biology, these programs help explain how malignant adrenal cortical cells retain partial steroidogenic lineage features while acquiring fetal-like growth signaling, dedifferentiation, and relative independence from normal trophic control.456

Among these abnormalities, IGF2 overexpression is one of the most consistent molecular findings in ACC and is usually linked to dysregulation of the imprinted 11p15 region rather than to a simple activating mutation.78 However, available data also indicate that IGF2 excess alone is unlikely to be sufficient for malignant transformation. ACC appears to arise through cooperation among IGF-axis activation, TP53 pathway disruption, Wnt/β-catenin signaling, copy-number imbalance, epigenetic change, and altered adrenal lineage control.91011

The evidence base is substantial but uneven. Most human data derive from retrospective tumor series, expression profiling studies, and integrated genomic analyses of relatively small cohorts, while functional interpretation relies heavily on a limited number of model systems, especially H295/H295R cells.121314 As a result, many reported pathways are biologically plausible and recurrent at the group level, but fewer are established as universal drivers or clinically actionable dependencies. In current practice, these growth programs contribute more to biologic classification, prognostic research, and target discovery than to routine frontline diagnosis or standard treatment selection.215

Biological Context

ACC develops in an organ whose normal function depends on tightly coordinated endocrine, developmental, and steroidogenic signaling. Early experimental work showed that malignant adrenocortical tissue can exhibit loss of normal ACTH responsiveness, ectopic receptor signaling, and abnormal control of steroidogenesis, indicating that carcinoma involves both proliferative activation and disruption of usual adrenal regulatory programs.161718 Clonality and cytogenetic studies later placed these abnormalities within a multistep neoplastic framework characterized by monoclonal growth and progressively increasing genomic complexity.192021

A reliable conclusion is that ACC is not defined by a single molecular pathway. Instead, it appears to combine preserved adrenal lineage traits with progressive dedifferentiation, proliferative autonomy, and chromosomal instability.222324 The practical implication is that molecular growth markers can support biologic interpretation and research stratification, but they do not replace histopathology, endocrine evaluation, and staging in clinical diagnosis.

Major Growth Programs

IGF2, IGF1R, and downstream signaling

IGF2 overexpression is the most reproducible growth-program abnormality in ACC and is much more characteristic of carcinoma than benign adrenal tissue or adenoma.252627 This pattern is commonly associated with 11p15 dysregulation, including maternal allele loss, copy-neutral imbalance, and altered imprinting architecture.7288 Many tumors also show increased IGF1R expression, supporting activation of MAPK and PI3K/AKT/mTOR-linked proliferative signaling.2915

What appears relatively reliable is that the IGF axis is central to ACC biology at the cohort level. What remains less reliable is the assumption that IGF2 abundance alone predicts aggressiveness, prognosis, or a uniquely targetable dependency, because some tumors with lower IGF2 expression appear to rely on alternative growth circuits.303132 Clinically, this makes IGF2 more useful as a recurring biologic feature than as a stand-alone biomarker for treatment selection.

Developmental and lineage-regulatory programs

Beyond receptor signaling, ACC frequently shows distortion of adrenal developmental circuitry, especially pathways centered on SF-1 and Wnt/β-catenin.62333 SF-1–related transcriptional activity may be amplified by loss of repressors such as POD1/TCF21, while Wnt pathway activation is recurrent in genomic and experimental studies and may cooperate with IGF2 during progression toward carcinoma.34359

Other developmental pathways, including JAG1-associated Notch signaling and Sonic Hedgehog-related crosstalk, have been implicated in subsets of ACC.363738 These observations are most reliable as evidence of network-level dysregulation rather than proof that any single developmental pathway independently drives most tumors. Their main practical role is to refine models of tumor state and to support combination-targeting hypotheses in translational research.

Loss of growth-suppressive signaling

ACC may also progress through loss of inhibitory signals, not only through activation of growth-promoting ones. Reduced BMP pathway activity, altered TGF-β/SMAD signaling, and disruption of activin-inhibin biology have each been associated with increased proliferation, impaired apoptosis, or altered steroidogenic regulation in tissue studies and cell models.39404142

This literature is biologically coherent but less mature than the evidence for IGF2. The practical implication is that impaired growth restraint may be a major component of ACC pathogenesis, which helps explain why blockade of a single activated pathway may not be sufficient in preclinical or translational settings.

Heterogeneity and Cooperative Biology

These major pathways are best understood within a broader pattern of molecular heterogeneity. Integrated profiling studies consistently identify ACC subgroups that differ in copy-number burden, methylation state, cell-cycle activation, steroid phenotype, and prognosis.24314 Across these classes, recurrent themes include IGF2 dysregulation, TP53 pathway abnormality, Wnt pathway alteration, and widespread chromosomal imbalance rather than a uniform molecular architecture.211

This context helps explain why IGF2 is common but not fully explanatory. Experimental models suggest that Wnt activation may contribute earlier to hyperplasia or adenoma formation, whereas IGF2 may accelerate progression in cooperation with other lesions rather than act as a solitary initiating event.910 Pediatric adrenocortical tumors also show prominent IGF-pathway involvement, but the surrounding biology may differ, particularly through stronger links to TP53 abnormalities and developmental context.643

More recent work has extended the concept of growth programs beyond classic receptor signaling. Noncoding RNAs at the IGF2-H19 locus, mitochondrial and glycolytic reprogramming, DNA repair programs, and telomere-maintenance states may all modulate malignant fitness in ACC subsets.44454647 These findings are promising for biologic subclassification, but most remain insufficiently validated for routine clinical use.

Role in Management and Research

Because these pathways differ in prevalence and functional importance across tumors, their current value is mainly interpretive and investigational. Molecular growth programs may help distinguish ACC from adenoma at the cohort level and may improve prognostic models, but they do not replace standard diagnostic workflows based on imaging, endocrine assessment, pathology, and stage.2513

Therapeutically, the high frequency of IGF-axis dysregulation made it an early focus for targeted strategies, but the broader literature suggests that many ACCs depend on interacting pathways rather than on a single dominant signaling node.4515 Relative to surgery, which remains the principal potentially curative treatment, growth-program targeting remains investigational and is primarily relevant to advanced disease, biomarker development, and combination-strategy research.

Limitations and Interpretive Pitfalls

Interpretation of this literature requires caution. Many studies are retrospective, underpowered, or based on transcript abundance rather than direct pathway activity, and functional claims often derive from a small number of cell systems that may not capture the full diversity of human ACC.121314 Historical signaling studies remain useful for showing disrupted trophic control, but they provide indirect context rather than definitive modern evidence for specific driver mechanisms.1617

A dependable practical conclusion is that recurrent molecular findings in ACC are best interpreted as components of cooperating biologic states rather than isolated biomarkers. For research, this supports integrated models that combine IGF-axis status with genomic subclassification, epigenetic profiling, steroid phenotype, and markers of chromosomal instability or telomere maintenance when generating hypotheses about prognosis or treatment sensitivity.481447

Included Articles

  • PMID 13086: In a rat adrenocortical carcinoma model, tumor membranes showed ectopic beta-adrenergic receptor binding sites that were largely absent in normal adrenal tissue. These receptors had pharmacologic properties consistent with beta-adrenergic signaling and were proposed to explain aberrant catecholamine-responsive adenylate cyclase activity in the tumor.49
  • PMID 20888: An isolated adrenocortical carcinoma cell model showed ACTH-induced increases in cyclic GMP without corresponding rises in protein kinase activity or corticosterone synthesis, while cyclic AMP responses were blunted. The authors interpret this as evidence of abnormal cyclic nucleotide signaling, including defective downstream kinase regulation in ACC cells.50
  • PMID 169292: This study of hormone-producing adrenocortical tumors found heterogeneous ACTH signaling defects, including cases with preserved ACTH binding but reduced affinity differences between ACTH fragments, suggesting alteration or loss of the receptor region recognizing the biologically active N-terminal ACTH sequence.51
  • PMID 2799809: In functioning adrenocortical tumors, microsomal steroidogenic enzyme activity differed by tumor type: aldosteronomas often showed increased 21-hydroxylase activity, whereas the two adrenocortical carcinomas had reduced 21-hydroxylase and low 17alpha-hydroxylase activity relative to normal adrenal cortex.52
  • PMID 2984236: This study found functional ectopic beta-adrenergic receptors linked to adenylate cyclase in a subset of human adrenocortical carcinomas, unlike normal adrenal cortex. ACC showed biologic heterogeneity, with variable preservation or loss of ACTH-responsive adenylate cyclase alongside acquisition of beta-adrenergic signaling.16
  • PMID 3034558: An in vitro study of two ACTH-unresponsive adrenocortical carcinomas found absent adenylate cyclase stimulation by ACTH, with preserved forskolin responsiveness, suggesting intact catalytic activity but impaired receptor-level or guanine nucleotide-binding protein-mediated signaling in different tumor phenotypes.17
  • PMID 3261901: This case-series measured mitochondrial 11 beta-hydroxylase activity across adrenocortical tumors and found reduced activity in ACC with adrenogenital syndrome, aligning with androgen excess and relatively suppressed mineralocorticoid or glucocorticoid production. The report also describes bizarre mitochondrial ultrastructure in ACC, suggesting steroidogenic enzyme dysfunction linked to tumor biology.53
  • PMID 3471309: This case report describes a primary nonfunctional adrenocortical carcinoma with a complex clonal karyotype, including recurrent structural abnormalities involving chromosomes 3, 4, 5, 12, 14, 15, 18, and 20. The authors highlight 3p14 involvement as potentially relevant to malignant biology and suggest recurring cytogenetic aberrations may help distinguish adrenal tumors from other primary cancers.54
  • PMID 3476190: This case report describes a functional adrenocortical carcinoma with a clonal 46,XX,t(4;11)(q35;p13) translocation present in nearly all analyzed metaphases, plus a minor additional deletion in a small subclone. The authors interpret this as a tumor-specific cytogenetic abnormality and note that more ACC cases are needed to determine whether such changes are recurrent or biologically meaningful.55
  • PMID 4325311: In a corticosterone-producing rat adrenocortical carcinoma, adenyl cyclase remained ACTH-responsive but was also aberrantly stimulated by epinephrine, norepinephrine, and TSH, unlike normal adrenal tissue. The authors interpreted this as possible receptor specificity loss or the presence of multiple cyclase regulatory receptors in tumor cells.56
  • PMID 4362943: Using rat adrenocortical carcinoma cells, the study found that ACTH and dibutyryl cAMP inhibited conversion of 20-hydroxycholesterol into deoxycorticosterone and corticosterone, opposite to normal adrenal cells. The findings support aberrant ACTH/cAMP-sensitive steroidogenic control within ACC tumor cells.57
  • PMID 6244937: An experimental ACC cell study found ectopic alpha-adrenergic receptor signaling not present in normal adrenal cells, with epinephrine inducing cGMP but not cAMP accumulation. ACTH- and epinephrine-driven cGMP responses were additive, supporting distinct receptor pathways and altered malignant cell signaling biology.58
  • PMID 6244938: This experimental study identified ectopic alpha-adrenergic receptors on adrenocortical carcinoma cells, with rapid, reversible, high-affinity and saturable binding of dihydroergocryptine, while normal adrenal cells showed no detectable binding. Competitive binding patterns supported receptor specificity and linked this aberrant receptor expression to catecholamine-responsive guanylate cyclase signaling.59
  • PMID 6245081: A 1980 biochemical study of adrenocortical carcinoma tissue identified a novel autophosphorylating cAMP-binding protein kinase, AUT-PK 134, characterized as a 134-kDa dimer with specific cAMP binding and no phosphorylation of standard exogenous substrates. The authors suggest this kinase class may be characteristic of certain adrenal neoplasms and linked to abnormal cAMP-dependent steroidogenic signaling in tumor tissue.60
  • PMID 6376081: This review notes that adrenocortical tumor cells can show insulin-stimulated growth at physiological concentrations in serum-free media, with potency suggesting signaling through high-affinity insulin receptors rather than IGF receptors. It supports insulin-pathway growth signaling as a biologically relevant feature in adrenocortical tumor cells.61
  • PMID 7725728: In a 1994 cohort of 56 primary adrenocortical tumors, activating N-ras codon 61 mutations were detected in 12.5% of both carcinomas and adenomas, while no K-ras, H-ras, or Gs alpha mutations were found and no ras or Gs alpha mutations were identified in adrenocortical hyperplasia.62
  • PMID 7910530: X-chromosome inactivation analysis in female patients found adrenocortical carcinomas to be monoclonal, supporting a somatic mutation-driven origin. In contrast, secreting adenomas showed mixed monoclonal and polyclonal patterns, suggesting biological heterogeneity and possibly distinct or multistep pathways of adrenal tumorigenesis.19
  • PMID 7911125: In sporadic adult adrenocortical tumors, 11p15 abnormalities and marked IGF-II overexpression were enriched in carcinomas, with frequent uniparental disomy and correlation between high IGF-II mRNA and IGF-II locus demethylation. The authors propose these alterations as late events in multistep tumorigenesis.7
  • PMID 8288710: This study examined steroidogenic enzyme activity in adrenocortical tumors and found that ACC-associated androgen excess was linked to reduced 3β-hydroxysteroid dehydrogenase activity and lower 3β-HSD mRNA despite similar P45017α expression. In contrast, low-androgen adenomas showed reduced 17,20-lyase activity with lower cytochrome b5 and reductase levels.63
  • PMID 8501773: In a small series including eight adrenocortical carcinomas, PCR-based screening found no activating point mutations in codons 12, 13, or 61 of N-ras, H-ras, or K-ras. The study suggests canonical ras hotspot mutations are rare or absent in adrenocortical neoplasms.64
  • PMID 8509216: In sporadic adrenocortical tumors, p53 missense mutations were identified in 3 of 15 primary carcinomas but not meaningfully in adenomas, while no H-, K-, or N-ras mutations were detected. The findings suggest p53 alteration contributes to a subset of ACCs and may represent a relatively late event in malignant transformation.65
  • PMID 9100555: This study found that adult adrenocortical tissue contains intact IGF-I and IGF-II receptors, and that IGF-I receptor abundance was markedly increased in most hormonally active adrenocortical carcinomas compared with normal adrenal tissue, hyperplasias, and adenomas, while receptor binding affinity remained similar.29
  • PMID 9232190: Using the NCI-H295 adrenocortical carcinoma cell line, this study shows that steroidogenic factor 1 directly enhances DAX1 promoter activity through a defined SF1 response element, supporting an SF1-DAX1 regulatory axis relevant to adrenal cortical developmental biology.66
  • PMID 9284742: This study found loss of heterozygosity at the ACTH receptor gene locus in 2 of 4 informative adrenocortical carcinomas, with reduced ACTH-R mRNA expression and association with advanced stage and rapid clinical course. The authors suggest ACTH-R deletion may contribute to adrenal tumor dedifferentiation and tumorigenesis.67
  • PMID 9367863: In 12 primary sporadic adrenocortical carcinomas, investigators identified a novel IGF2 exon 9 splicing event detectable by PCR in all tumors, with preferential allelic expression imbalance in some cases. The study supports abnormal IGF2 transcript processing as a recurring molecular feature of ACC.28
  • PMID 9851669: This study links hormonally active adrenocortical carcinomas to very high IGF-II mRNA expression together with relatively low IGFBP-2, -4, -5, and -6 mRNA levels, suggesting altered IGF pathway regulation in a biologically distinct ACC subset.68
  • PMID 9918804: In the human ACC cell line NCI-H295R, TGF-beta1 suppressed StAR mRNA and protein expression, and Smad3 overexpression reproduced this effect while dominant-negative Smad3 partially reversed it. The findings identify Smad3 as a mediator of TGF-beta-dependent regulation of adrenocortical steroidogenesis.69
  • PMID 10022445: In a genotyping study of sporadic adrenocortical tumors, loss of heterozygosity was far more common in carcinomas than adenomas, with strong associations for deletions at 2p16 and 11q13. The 2p16 minimal deleted region was distinct from the Carney complex locus, and frequent 11q13 loss occurred without MEN1 mutation, supporting additional tumor suppressor loci in ACC.70
  • PMID 11196469: This study of adrenocortical adenomas and carcinomas found reduced TGFβ1 mRNA and increased Smad4 mRNA in carcinomas, without detectable somatic mutations in TGFβ receptor genes. The findings suggest quantitative dysregulation of the TGFβ signaling pathway may contribute to adrenal tumorigenesis and malignant progression.39
  • PMID 11281372: This review summarizes early molecular features of adrenocortical tumorigenesis, noting that ACC is typically monoclonal and is associated with p53 alterations, 11p15.5 rearrangements with IGF II overexpression, and recurrent chromosomal losses and gains distinct from other endocrine tumors. It also reports that constitutive ACTH receptor pathway activation does not appear to drive adrenal tumor formation.71
  • PMID 11281373: This review summarizes evidence that the IGF axis contributes to adrenocortical tumorigenesis, with IGF-II overexpression reported in ACC and strong IGF-I receptor overexpression seen in most examined carcinomas but not adenomas or hyperplasias. Experimental models suggest receptor overexpression enhances mitogenic signaling, while IGF-II excess alone may drive adrenal hyperplasia and steroidogenesis without being sufficient for malignant transformation.1
  • PMID 11774288: Sequencing of the StAR gene in 40 functional and nonfunctional adrenocortical tumors, including carcinomas, found no tumor-specific mutations. The recurrent Asp203Ala exon 5 change was also present homozygously in patient germline DNA and all controls, supporting that StAR alteration is unlikely to drive adrenal tumorigenesis.72
  • PMID 12107267: Comparative genomic hybridization in adult adrenocortical tumors found far more copy-number alterations in carcinomas than adenomas, with recurrent ACC gains on chromosomes 5, 12, 19, and 4 and losses at 1p, 17p, 22, 2q, and 11q. The authors propose chromosome 4 gain as an early event and progression to carcinoma through additional oncogenic gains and tumor suppressor losses.20
  • PMID 12119279: This review summarizes early ACC signaling biology, highlighting frequent IGF-II upregulation and reported TP53 and RAS alterations, while discussing proliferative pathways involving Akt/PKB and MAPKs. It also notes that ACTH-cAMP/PKA signaling may restrain adrenal tumor growth, with possible tumor-promoting effects from loss of ACTH receptor signaling.18
  • PMID 12547710: DNA microarray profiling showed that ACC has a distinct transcriptional signature compared with adenoma, hyperplasia, and normal adrenal cortex, with 91 genes differentially expressed. IGF2 overexpression was a dominant and frequent finding, and other dysregulated transcripts such as SPP1 and STK15 were proposed as potential diagnostic and pathogenetic markers.25
  • PMID 12951842: This review notes that adult adrenocortical tumors show increasing genomic imbalance with clinical progression on comparative genomic hybridization, suggesting greater cytogenetic complexity in more advanced malignant disease. It also emphasizes that adrenal tumors had only limited cytogenetic study because of rarity and technical constraints.12
  • PMID 12967339: Using the NCI-H295R adrenocortical carcinoma cell line, the study shows that activin signaling components are present in adrenal cortex and that activin A suppresses steroidogenic gene expression and secretion while increasing apoptosis. These findings suggest a regulatory role for the activin-inhibin pathway in ACC cell biology.40
  • PMID 13790248: An experimental rat adrenocortical carcinoma showed altered steroidogenic metabolism, with accumulation of deoxycorticosterone and reduced corticosterone and aldosterone production, consistent with impaired 11-hydroxylation. A related tumor subline displayed a different metabolite distribution, suggesting biologic heterogeneity in steroid metabolism.73
  • PMID 14580759: This review frames adrenocortical tumorigenesis as a multistep genetic process in which polyclonal hyperplasia and monoclonal adenoma may precede carcinoma, with increasing chromosomal aberrations as tumors enlarge. It highlights recurrent involvement of TP53, IGF2, PRKAR1A and related cAMP-PKA pathway defects, while emphasizing biologic heterogeneity and incomplete molecular characterization.21
  • PMID 15241730: This review summarizes evidence that the inhibin/activin system and luteinizing hormone may influence adrenocortical tumorigenesis. Activin appears growth-inhibitory and pro-apoptotic in adrenal cortex, whereas LH may promote adrenocortical growth in experimental models, highlighting candidate molecular pathways for future therapeutic development.74
  • PMID 15241731: This review identifies dysregulation of the IGF system, especially marked IGF-II overexpression linked to 11p15 alterations, as a central feature of ACC biology. It also notes increased IGF-I receptor and IGFBP-2 expression in advanced tumors, with evidence suggesting these factors may drive progression rather than initiation.4
  • PMID 15292355: This study found lower Nurr1 and NGFI-B expression in adrenocortical carcinoma than in aldosteronoma, with Nurr1 mRNA strongly associated with CYP11B2 expression. The findings support a role for these orphan nuclear receptors in adrenocortical steroidogenic regulation across normal cortex and neoplasms.75
  • PMID 16360395: Gene-expression profiling of sporadic adrenocortical tumors showed that adenomas had relatively homogeneous transcriptional patterns, whereas carcinomas were more heterogeneous and could be clearly separated from adenomas by hierarchical clustering. ACC was associated with upregulation of IGF-related genes including IGF2, IGF2R, IGFBP3, and IGFBP6, alongside other differentially expressed genes.26
  • PMID 16556722: cDNA microarray profiling of adrenocortical tumors found ACC to have a markedly distinct gene-expression pattern from adenoma and normal adrenal cortex, with many more differentially expressed genes in ACC. IGF2 was significantly upregulated in ACC and validated by real-time PCR, supporting a role for altered molecular programs in adrenocortical tumorigenesis.27
  • PMID 16721033: This laboratory study reports CRH receptor expression in normal human adrenal cortex, adrenocortical adenomas, and ACC-related model systems, with functional evidence that CRH can increase DHEA secretion in adrenocortical cells. The authors suggest enhanced CRH1R expression may contribute to adrenocortical tumorigenesis.76
  • PMID 17121532: Quantitative RT-PCR of adult adrenocortical tissues found that ACC showed reduced expression of inhibin betaA, follistatin, betaglycan, ActRIIA, ActRIIB, and CYP17 compared with non-tumorous adrenal tissue. The authors interpret these coordinated changes as evidence that activin-inhibin signaling is altered in adrenocortical tumorigenesis.77
  • PMID 17566092: In childhood adrenocortical tumors, NOV/CCN3 is downregulated at both mRNA and protein levels relative to normal adrenal cortex, without a clear adenoma-versus-carcinoma difference. The study links SF-1 overexpression to transcriptional repression of NOV and shows NOV has selective proapoptotic activity in human adrenocortical cells, supporting a role in pediatric tumorigenesis.78
  • PMID 17904549: In cortisol-secreting adrenocortical tumors, this study found loss of PKA R2B expression in adenomas but preserved expression of all PKA regulatory subunits in carcinomas, with wild-type PRKAR1A and PRKAR2B sequences. Functional experiments suggested that a higher R1/R2 balance promotes adrenocortical cell proliferation and hormone-producing differentiation rather than malignant transformation.79
  • PMID 17934868: This review summarizes core molecular drivers of ACC pathogenesis, emphasizing TP53 abnormalities and 11p15 dysregulation with marked IGF-II overexpression. It also notes gene-expression signatures that distinguish carcinoma from adenoma and may correlate with metastatic recurrence risk.2
  • PMID 18515740: This review summarizes molecular mechanisms implicated in adrenocortical tumorigenesis, emphasizing hereditary syndrome genes and sporadic alterations involving TP53, 11p15 imprinting abnormalities, and IGF2 overexpression. It also highlights roles for the ACTH-cAMP-protein kinase A and Wnt pathways and genomic profiling approaches in understanding ACC biology.80
  • PMID 19584291: This study identifies reduced BMP2 and BMP5 expression in adrenocortical carcinoma and ACC cell lines versus normal adrenal tissue, with lower pSMAD1/5/8 signaling in tumors. In vitro, BMP2 and BMP5 suppress proliferation, reduce AKT phosphorylation, and alter steroidogenic gene expression, implicating BMP pathway loss in ACC biology.41
  • PMID 19688782: This experimental study reports that human cytomegalovirus can productively infect primary adrenocortical cells and ACC cell lines, causing cytopathic changes and an early increase in cortisol and estrogen production with upregulation of steroidogenic regulators and enzymes. The findings suggest a virus-related mechanism that may influence adrenocortical tumor biology, particularly in cortisol-secreting tumors.81
  • PMID 19738044: In adrenocortical cells, PRKAR1A inactivation increased PKA signaling, reduced SMAD3 expression, and blunted TGF-beta pathway activity. In H295R cells this was associated with reduced TGF-beta-stimulated apoptosis, supporting a mechanistic link between dysregulated cAMP/PKA signaling and adrenocortical tumorigenesis.42
  • PMID 19878765: This review summarizes molecular mechanisms implicated in ACC tumorigenesis, highlighting hereditary-syndrome genes and recurrent pathway alterations involving IGF2/IGF1R, Wnt/beta-catenin, and TGF-beta family signaling. It emphasizes that these abnormalities may support future markers of malignancy, prognosis, and therapeutic targeting.5
  • PMID 20484036: In childhood adrenocortical tumors, miR-99a and miR-100 are downregulated and directly regulate IGF-1R, mTOR, and raptor, linking altered microRNA expression to activation of the IGF-mTOR pathway. The study also associates specific miRNA expression subclusters with relapse risk and shows preclinical growth suppression with everolimus.82
  • PMID 22019901: This review emphasizes that adrenocortical tumorigenesis differs between pediatric and adult disease, with distinct roles for TP53 alterations, the IGF pathway, and SF1. In adults, somatic TP53 mutation, IGF2 overexpression, and SF1 overexpression are linked to poorer behavior, whereas pediatric tumors more often involve germline TP53 p.R337H and IGF1R overexpression.6
  • PMID 22266195: This review links adrenocortical stem and progenitor cell biology to ACC tumorigenesis, emphasizing adrenal capsular and subcapsular niches and the roles of Sonic Hedgehog and Wnt/beta-catenin signaling in lineage maintenance. It suggests aberrant Wnt activation may be an early oncogenic event, with p53 loss and IGF2 abnormalities potentially cooperating in malignant progression.23
  • PMID 22419722: This study found that MRAP and MRAP2 mRNA expression is markedly suppressed in adrenocortical carcinoma compared with other adrenal tissues, while MC2R expression is not significantly altered. ACTH and angiotensin II induced MRAP and MC2R in most adrenal tissues, but this regulatory response was absent in ACC.22
  • PMID 22427350: This study identifies JAG1 as the predominant upregulated Notch ligand in ACC, with higher mRNA and protein expression than in adenoma or normal adrenal tissue. Functional experiments indicate JAG1-driven canonical Notch signaling promotes ACC cell proliferation, and JAG1 expression correlates with tumor grade and stage.36
  • PMID 22559973: This review summarizes molecular alterations in adrenocortical tumors, highlighting recurrent dysregulation of IGF2, TP53, CTNNB1, cell-cycle genes, steroidogenic programs, retinoic acid signaling, and microRNAs in ACC. It also notes transcriptomic heterogeneity and shows that gene-expression profiling can separate ACA from ACC and define prognostic subgroups.13
  • PMID 22800756: This study supports a multistep model of adrenocortical tumorigenesis in which Wnt/beta-catenin activation promotes adrenal hyperplasia and adenoma formation, while concurrent IGF2 overexpression accelerates progression and can permit carcinoma development. In human ACC, abnormal beta-catenin accumulation and CTNNB1 mutation were associated with worse survival.9
  • PMID 23293338: This editorial reviews emerging epigenetic data in ACC, highlighting promoter CpG island hypermethylation patterns and a proposed CpG island methylator phenotype associated with worse prognosis. It also notes links between methylation, gene expression, and known ACC pathways such as IGF2, beta-catenin, and p53, while emphasizing important methodological limitations.48
  • PMID 23295462: This review summarizes ACC molecular data showing frequent IGF2 overexpression from 11p15 dysregulation, while arguing that IGF2 is unlikely to be a primary driver of adrenocortical tumorigenesis. Mouse models found that IGF2 alone did not induce tumors and only mildly accelerated progression when combined with beta-catenin activation.10
  • PMID 23313103: This experimental study identifies POD-1/TCF21 as a negative regulator of SF-1 in adrenocortical tumor cells, showing direct binding to E-box elements in the SF-1 promoter and reduced downstream StAR expression. POD-1 was downregulated in ACC relative to adenoma and normal adrenal tissue and inversely correlated with cell-cycle-associated genes in ACC samples.34
  • PMID 24066089: High-resolution SNP array profiling showed markedly greater copy-number alteration and copy-neutral loss of heterozygosity burden in ACC than in adenomas, with recurrent chromosome 5 amplification strongly associated with malignancy. Shared alterations, early IGF2-locus gain, and later allele losses with increased IGF2 expression support a multistep adenoma-to-carcinoma progression model.24
  • PMID 24909752: In a small ACC series, near-homozygous genome status consistent with near-haploidization and endoreduplication was found in 6 of 11 tumors and was strongly associated with oncocytic morphology. Mitochondrial DNA mutations were frequent but did not correlate with the oncocytic phenotype or with near-haploidization.83
  • PMID 25047265: This study identifies ZNF367 as overexpressed in adrenocortical carcinoma relative to adenoma and normal adrenal tissue, while functional experiments suggest it suppresses proliferation, invasion, migration, and adhesion. The data also support a miR-195-ZNF367-ITGA3 regulatory axis linked to ACC progression biology.84
  • PMID 25089899: This study examines IGF2 biology in ACC, showing that IGF2 knockdown in H295R cells reduces proliferation, causes G1 arrest, and increases apoptosis, while ACC tumors with high versus low IGF2 expression have similar clinical and transcriptomic features. Low-IGF2 tumors may rely on compensatory growth pathways such as FGF9 and PDGFA, with additional 11p15 epigenetic changes influencing IGF2 expression.30
  • PMID 25743702: Comprehensive genomic profiling of pediatric adrenocortical tumors identified early copy-neutral loss of heterozygosity at 11p and 17, universal IGF2 overexpression, frequent TP53 alterations, and recurrent ATRX or CTNNB1 mutations. Concomitant TP53 and ATRX abnormalities were linked to chromosomal instability, alternative telomere lengthening, advanced stage, and poorer event-free survival.43
  • PMID 26038203: This review summarizes the recurrent genetic alterations in adrenocortical carcinoma, highlighting TP53 disruption and Wnt pathway abnormalities involving CTNNB1 or ZNRF3, with IGF2 overexpression also identified through familial-syndrome and genomic studies as key molecular drivers of ACC.11
  • PMID 26400872: Integrated analysis of adrenal tumors found IGF2 overexpression in most ACCs and linked it to chromosome 11p15.5 copy number changes with loss of the maternal allele, producing a uniparental disomy-like state and H19 imprinting control region hypermethylation. The findings suggest H19 hypermethylation is a consequence of allele loss rather than an independent driver.8
  • PMID 26454676: In a clinically characterized ACC cohort, SLC12A7 copy-number amplification at 5p15.33 was frequent and associated with increased mRNA expression relative to normal adrenal tissue. Amplification correlated with nonfunctional tumors, supporting SLC12A7 as a recurrent molecular alteration that may contribute to ACC biology.85
  • PMID 26548814: This review identifies JAG1 as a Notch-pathway ligand implicated in ACC biology, noting that JAG1 upregulation may enhance ACC cell proliferation and tumor aggressiveness through activation of NOTCH signaling in adjacent cells. It frames JAG1 as part of a broader developmental signaling pathway linked to cancer behavior.37
  • PMID 27865598: This translational study identifies marked CYP4B1 suppression across adrenocortical tumors, with a graded decrease from adenoma to near-absent expression in carcinoma, suggesting an early event in adrenal tumorigenesis and dedifferentiation. Forced CYP4B1 expression was cytotoxic in ACC cell lines and increased sensitivity to mitotane and cisplatin.86
  • PMID 31378849: This study supports IGF2 as a major biologic driver in ACC, showing markedly higher tumor expression than in adenoma or normal adrenal tissue and linking exogenous IGF2 to increased H295R proliferation, viability, and glycolytic reprogramming through MAPK/ERK and mTOR signaling.32
  • PMID 28658440: Cell-line experiments support a regulatory axis in adrenocortical tumors in which POD1/TCF21 represses SF-1 expression. POD1/TCF21 was reported as downregulated in ACC cells, and its loss increased SF-1 expression while overexpression reduced SF-1 protein, consistent with a tumor-suppressive role.35
  • PMID 29233839: This review summarizes key molecular alterations in adrenocortical carcinoma, highlighting IGF2 overexpression, TP53 pathway abnormalities, CTNNB1 activation, and ZNRF3 inactivation. It also notes that genome-wide transcriptomic, SNP, methylome, and miRome studies identify ACC subgroups with differing prognosis and support development of prognostic markers.3
  • PMID 29383116: Analysis of TCGA ACC data and cell models found that HSD17B4 is overexpressed in a substantial subset of tumors, is associated with a normo-hormonal phenotype rather than hormone excess, and shows tumor-suppressive effects in ACC cells with links to altered p53-pathway signaling.87
  • PMID 29516499: This study identifies miR-483-5p and miR-139-5p as drivers of ACC aggressiveness through direct repression of NDRG2 and NDRG4, respectively. These microRNA-target axes were linked to invasion, anchorage-independent growth, epithelial-to-mesenchymal transition, and poorer prognosis in aggressive tumor cohorts.88
  • PMID 29735160: This review notes that integrated genomic studies in adrenocortical carcinoma identified distinct molecular classes with markedly different outcomes. It highlights ZNRF3 alterations and broader Wnt/beta-catenin dysregulation, alongside subgroup features such as IGF2 overexpression, cell-cycle alterations, and promoter hypermethylation.14
  • PMID 29884238: In ACC cell-line models, SLC12A7 overexpression increased migration, invasion, and adhesion-detachment turnover without materially changing growth or viability, while SLC12A7 silencing reduced these aggressive behaviors. The study links recurrent SLC12A7 amplification and overexpression to invasive phenotype and implicates osmotic stress, BMP, and Hippo-related signaling.89
  • PMID 30069455: This review summarizes IGF and EGF pathway dysregulation in ACC, highlighting frequent IGF-2 overexpression, IGF-1R and EGFR overexpression, and downstream MAPK and PI3K/AKT/mTOR signaling. It also notes that despite IGF-2 prevalence, expression level does not clearly distinguish biologic behavior or prognosis.15
  • PMID 30591455: A preliminary gene-expression study in adrenocortical tumors found that Twist1 mRNA in ACC correlates positively with the mesenchymal markers fibronectin and vimentin, while showing no significant association with E-cadherin. The findings support a possible role for epithelial-mesenchymal transition programs in ACC progression biology.90
  • PMID 30989475: This experimental study reports reduced SIRT6 expression in ACC tissues and shows that SIRT6 knockdown in H295R cells increases proliferation, invasion, and migration while suppressing apoptosis. The observed effects were associated with upregulation of TLR4, increased NF-κB pathway phosphorylation, higher TRPV1 and CGRP expression, and increased reactive oxygen species.91
  • PMID 31034883: This study reports that IGF1 gene amplification and overexpression occur in a subset of ACC and are associated with SLC12A7 overexpression, particularly in non-functional early-stage tumors, while IGF2 overexpression is linked to larger tumors. The findings suggest distinct IGF pathway dysregulation patterns within ACC biology.31
  • PMID 32784588: A TCGA pan-cancer analysis identified adrenocortical carcinoma as a tumor type with high alternative lengthening of telomeres activity and low or absent telomerase activity, with significant enrichment of the homologous recombination ALT pathway in telomere-lengthened ACC samples. In ACC, telomere maintenance mechanism scores also showed a strong positive correlation with pathologic tumor stage.45
  • PMID 33090184: This mechanistic study suggests adrenocortical carcinoma cells can bypass normal adrenal Sonic Hedgehog signaling constraints. In NCI-H295R cells, SHH secreted on lipoproteins was signaling-inactive, while ectopic activation of SHH target genes appeared to occur through TGF-β-responsive, cilia-independent pathway crosstalk.38
  • PMID 33195693: This in vitro and tissue-based study identifies circ-CCAC1 as an overexpressed circular RNA in ACC that is associated with worse postoperative overall survival and promotes proliferation, migration, invasion, and reduced apoptosis through a miR-514a-5p/C22orf46 regulatory axis.92
  • PMID 33219221: This study identifies the lncRNA ASB16-AS1 as downregulated in ACC and functioning as a tumor suppressor. ASB16-AS1 promotes BTRC-mediated ubiquitination and degradation of HuR, thereby reducing HuR-dependent IGF1R and CDK6 expression and suppressing ACC cell proliferation and xenograft growth.93
  • PMID 33544460: The article notes that ARMC5 is implicated in hereditary adrenocortical tumorigenesis and that ARMC5 missense variants in the H295R adrenocortical cancer cell line impair pro-apoptotic activity, supporting a tumor-suppressor role for ARMC5 in adrenal cortical tumor biology.94
  • PMID 34943980: This review notes that adrenocortical carcinoma has been reported to exhibit oncogene-induced senescence, described as a compensatory response following carcinogenesis and tumor progression. It frames senescence pathways as part of ACC biology rather than providing diagnostic or treatment guidance.95
  • PMID 36169175: This study links ACC to dysregulation of the IGF2-H19 locus, with IGF2 and miR-483-3p/5p overexpression alongside reduced H19 and miR-675 compared with adenoma and normal adrenal tissue. It also associates miR-483-5p with altered mitochondrial respiratory proteins, including reduced complex I and IV expression and lower NDUFC1.44
  • PMID 36725890: This study identifies a BMAL1-CLOCK axis that promotes homologous recombination-mediated double-strand break repair through ATM-dependent BMAL1 phosphorylation, recruitment to damage sites, and histone H4 acetylation. In ACC models, BMAL1 depletion increased sensitivity to DNA damage-based therapy, linking circadian machinery to chemoresistance biology.46
  • PMID 36860927: This review identifies adrenocortical carcinoma as one of the tumor types that can use alternative lengthening of telomeres rather than telomerase for telomere maintenance. It summarizes ALT-associated features, candidate detection methods, and proposed mechanisms involving recombination, replication stress, chromatin state, and TERRA.47
  • PMID 39518893: This review places adrenocortical carcinoma within a broader molecular discussion of primary adrenocortical hyperfunction, emphasizing next-generation sequencing and in silico analyses to identify genetic and pathway alterations underlying transition from normal adrenal physiology to hyperfunctional and malignant states.96
  • PMID 40695292: This mechanistic study uses ACC as a steroidogenic model and reports that β-catenin functions as a molecular adapter linking cBAF chromatin remodelers to SF-1, ARID1A, and other partners, sustaining enhancer occupancy and steroidogenic gene expression. In TCGA ACC, high SMARCA4 expression correlated with β-catenin targets, SF-1 targets, and high-steroid phenotypes.33
  • PMID 41121295: This translational study identifies SorCS3 as a downregulated tumor suppressor candidate in ACC, with low expression associated with shorter overall and disease-specific survival. Functional data suggest SorCS3 stabilizes IGF2R, enhances endocytic trafficking, and attenuates PI3K/Akt and MAPK/Erk signaling, implicating a new trafficking-based regulatory axis in ACC progression.97
  • PMID 41226387: This review describes how cytoskeleton-associated pathways contribute to ACC biology, linking proteins such as FLNA, FSCN1, RASSF1A, and VAV2 to oncogenic signalling, proliferation, motility, invasion, and poor prognosis. It frames cytoskeletal dysregulation as a component of malignant behavior and a source of emerging therapeutic hypotheses.98
  • PMID 41294009: This mechanistic study identifies SYTL5 as a RAB27A-dependent regulator of mitophagy and mitochondrial metabolism, with loss of SYTL5 shifting cells toward glycolysis under stress. In ACC, SYTL5 expression is reported as reduced in adrenal tumors and positively associated with patient survival.99

References

Footnotes

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