Molecular adrenocortical tumourigenesis

Reincke, Martín; Beuschlein, Felix; Slawik, Marc; Borm, Katrin

doi:10.1046/j.1365-2362.2000.0300s3063.x

Cited by 32 publications

(19 citation statements)

References 48 publications

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“…On the other hand, hyperinsulinemia mediated pathogenesis has been considered by other authors who observed a proliferative effect of insulin on adrenal cancer cells without effect on cortisol synthesis (8).…”

Section: Introductionmentioning

confidence: 99%

Circulating E-selectin levels and insulin resistance are associated with early stages of atherosclerosis in nonfunctional adrenal incidentaloma

Delibaşı

Karbek²,

Bozkurt

et al. 2015

Arch. Endocrinol. Metab.

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Objective: To evaluate circulating E-selectin levels in patients with nonfunctional adrenal incidentaloma (NFA) in relation to insulin resistance and early atherosclerosis. Subjects and methods: A total of 40 patients with NFA (mean [SD] age: 55.6 [10.7] years; 70% were females) and 35 controls (mean [SD] age: 51.5 [8.1] years; 71.4% were females) selected from age-, gender-and body mass index (BMI)-matched healthy subjects were enrolled. Serum hsCRP, lipid profile, insulin levels and the homeostasis model assessment of insulin resistance (HOMA-IR) were evaluated. High-resolution Bmode ultrasonography was performed. Serum levels of E-selectin were evaluated by enzyme-linked immunosorbent assay. Results: Patients with NFA had significantly higher values for E-selectin (14.9 (4.8) vs. 12.2 (4.1) ng/mL, p < 0.01) and CIMT (0.6 (0.1) vs. 0.5 (0.1) mm, p < 0.05) than controls. Serum E-selectin levels showed a statistically significant association with hsCRP (r = 0.751, p < 0.001), HOMA-IR (r = 0.575, p < 0.001) and CIMT (r = 0.762, p < 0.001). CIMT (Carotid intima media thickness) was increased in patients with NFA patients with NFA were more insulin resistant than controls and statistically significant relationship was found between size of tumor and HOMA-IR (r = 0.361, p < 0.001). Conclusion: In conclusion, based on significantly higher values for E-selectin, CIMT and HOMA-IR in patients with NFA than controls along with significant correlation of E-selectin levels to CIMT, HOMA-IR and hs-CRP, our findings seems to indicate an increased risk of early atherosclerosis and impaired endothelial function in NFA patients, particularly in case of insulin resistance. Arch Endocrinol Metab. 2015;59(4):310-7

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Section: Introductionmentioning

confidence: 99%

Circulating E-selectin levels and insulin resistance are associated with early stages of atherosclerosis in nonfunctional adrenal incidentaloma

Delibaşı

Karbek²,

Bozkurt

et al. 2015

Arch. Endocrinol. Metab.

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“…However, benign, clinically occult adrenal adenomas, adrenal "incidentalomas," are encountered frequently by abdominal imaging performed for unrelated indications. The unsuspected adrenal mass is detected in 2-4% of the general population and in Յ6% of abdominal computed tomography scans in patients aged 60 -70 years (1,2). The size of the adrenal mass is considered to be the most reliable predictor of malignancy.…”

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confidence: 99%

Adrenocortical Adenoma and Carcinoma: Histopathological and Molecular Comparative Analysis

et al. 2003

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We compared histomorphological features and molecular expression profiles of adrenocortical adenomas (ACAd) and carcinomas (ACCa). A critical histopathological review (mean, 11 slides per patient) was conducted of 37 ACAd and 67 ACCa. Paraffinembedded tissue cores of ACAd (n ‫؍‬ 33) and ACCa (n ‫؍‬ 38) were arrayed in triplicate on tissue microarrays. Expression profiles of p53, mdm-2, p21, Bcl-2, cyclin D1, p27, and Ki-67 were investigated by immunohistochemistry and correlated with histopathology and patient outcome using standard statistical methodology. Median follow-up period was 5 years. Tumor necrosis, atypical mitoses, and >1 mitosis per 50 high-power fields were factors that were highly specific for ACCa (P < .001). Number (0 to 4) of unfavorable markers [Ki-67 (؉), p21 (؉), p27 (؉), mdm-2(؊)] expressed was significantly associated with mitotic activity and morphologic index (i.e., number of adverse morphologic features) and highly predictive of malignancy (P < .001). Ki-67 overexpression occurred in 0 ACAd and 36% ACCa (P < .001) and was significantly associated with mitotic rate and unfavorable morphologic index (P < .001). Tumor necrosis, atypical mitoses, >5 mitoses per 50 high-power fields, sinusoidal invasion, histologic index of >5, and presence of more than two unfavorable molecular markers were associated significantly with metastasis in ACCa. Wellestablished histopathologic criteria and Ki-67 can specifically distinguish ACCAd from ACCa. Tumor cell proliferation (Ki-67) correlates with mitotic activity and morphologic index. Tumor morphology is a better predictor of metastatic risk in ACCa than current immunohistochemistry-detected cell cycle regulatory and proliferation-associated proteins.KEY WORDS: Adenoma, Adrenal, Carcinoma, IHC, Tissue microarray. Mod Pathol 2003;16(8):742-751Adrenocortical carcinoma is a highly aggressive, rare endocrine malignancy. However, benign, clinically occult adrenal adenomas, adrenal "incidentalomas," are encountered frequently by abdominal imaging performed for unrelated indications. The unsuspected adrenal mass is detected in 2-4% of the general population and in Յ6% of abdominal computed tomography scans in patients aged 60 -70 years (1, 2). The size of the adrenal mass is considered to be the most reliable predictor of malignancy. As 8 -13.5% of resected adrenocortical carcinomas are Ͻ5 cm, size alone is an imperfect criterion for malignancy (3). In a study of metastasizing and nonmetastasizing adrenocortical tumors among 43 patients followed for a median of 11 years, Weiss (4) demonstrated the utility of nine histomorphologic criteria in predicting the biology of adrenocortical neoplasms. The histologic findings most predictive of malignancy were Ͼ5 mitoses per 50 high-power fields, atypical mitoses, and venous invasion. No single criterion could distinguish benign from malignant tumor biology; all but one of the benign adrenocortical tumors had two or fewer criteria. In a later study, Weiss et al. (5) modified the diagnostic criteria for benign and malig...

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“…Adrenal incidentalomas are the most common neoplasia of the adrenal cortex with a prevalence of up to 6% in the otherwise healthy population (25). Although the vast majority of cases represent endocrine-inactive adrenal adenomas and although there is only a minimal chance for the presence of an adrenal carcinoma in patients with small adrenal lesions, in individual patients it can prove difficult to distinguish between these benign adenomas and adrenal carcinomas even with histopathological and immunohistochemical methods.…”

Section: Discussionmentioning

confidence: 99%

Clinical and molecular evidence for DAX-1 inhibition of steroidogenic factor-1-dependent ACTH receptor gene expression

et al. 2005

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Background: The ACTH receptor (ACTH-R) is a member of the seven transmembrane domain receptor super-family. In non-functional adrenal adenomas and adrenocortical carcinomas, ACTH-R expression is low. However, no inhibitory factor for ACTH-R expression has been defined to date. DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome, gene-1) is a general repressor of steroid production, inhibiting steroidogenic factor-1 (SF-1)-dependent expression of multiple steroidogenic enzymes. The aim of this study was to investigate whether ACTH-R gene transcription is affected by DAX-1 and whether this mechanism is involved in down-regulation of ACTH-R expression in adrenocortical tumors. Methods: We screened 22 adrenocortical tumors for ACTH-R and DAX-1 mRNA expression by Northern blot. For in vitro analyses we co-transfected mouse Y1 adrenocortical carcinoma cells with the luciferase reporter gene vector pGL3 containing full-length constructs of human (h) or mouse (m) ACTH-R promoter together with a DAX-1 expression plasmid. These experiments were also performed using ACTH-R promoter 5 0 -deletion constructs and constructs mutated at the SF-1-binding sites. Results: We found a negative correlation between DAX-1 and ACTH-R mRNA expression (R ¼ 20.47, P , 0.02). Accordingly, in vitro expression of DAX-1 significantly reduced hACTH-R and mACTH-R promoter activity by 89 and 55% respectively. DAX-1 inhibition was also present in the shortest construct of a series of 5 0 -deletion constructs of the human promoter extending from 2 64 to þ40 bp relative to the transcription start site. Mutation of the SF-1-binding sites within the hACTH-R promoter resulted in reduced or abolished DAX-1 inhibition, arguing for a mechanism that involves SF-1 for DAX-1 inhibition. Conclusions: These data support the concept that DAX-1 is a major repressor of ACTH-R gene expression in vitro and in vivo.

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Molecular adrenocortical tumourigenesis

Cited by 32 publications

References 48 publications

Circulating E-selectin levels and insulin resistance are associated with early stages of atherosclerosis in nonfunctional adrenal incidentaloma

Circulating E-selectin levels and insulin resistance are associated with early stages of atherosclerosis in nonfunctional adrenal incidentaloma

Adrenocortical Adenoma and Carcinoma: Histopathological and Molecular Comparative Analysis

Clinical and molecular evidence for DAX-1 inhibition of steroidogenic factor-1-dependent ACTH receptor gene expression

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