Inhibins and activins: Their roles in the adrenal gland and the development of adrenocortical tumors

Hofland, Johannes; Jong, Frank H. de

doi:10.1016/j.mce.2011.06.005

Cited by 18 publications

(15 citation statements)

References 92 publications

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“…In the normal human adrenal cortex, expression of inhibin a-subunit is mainly observed in zona reticularis while b-subunit is principally expressed in the outer zones (211,212). In agreement with this observation, expression of inhibin a-subunit is predominantly stimulated by ACTH whereas that of inhibin b-subunit is activated by ANG II (45). The activin receptors and the inhibin co-receptor b-glycan mRNAs are also detected in the adrenal cortex raising the possibility that activins and inhibins may control corticosteroidogenesis through autocrine and paracrine mechanisms.…”

Section: Factorssupporting

confidence: 75%

“…Finally, adrenocortical cells themselves can synthesize and secrete cytokines (30,31,32), insulin-like growth factors (IGFs) (44), and inhibin/activin (45) and express the diverse components of the reninangiotensin system (RAS) (46) resulting in autocrine regulations of the adrenocortical function. Autocrine/paracrine regulatory factors in adrenocortical hyperplasias and tumors Several paracrine regulatory loops have been shown to play a role in the physiopathology of steroid hypersecretion associated with adrenocortical hyperplasias and tumors responsible for aldosterone or cortisol excess.…”

Section: Methodsmentioning

confidence: 99%

“…The activin receptors and the inhibin co-receptor b-glycan mRNAs are also detected in the adrenal cortex raising the possibility that activins and inhibins may control corticosteroidogenesis through autocrine and paracrine mechanisms. Adrenomedullary chromaffin cells, which express inhibin b-subunits A and B (45), may also influence the adrenocortical function in a paracrine manner via the release of activins in the vicinity of adrenocortical cells. The physiological roles of activins and inhibins in the adrenal cortex are not completely understood.…”

Section: Factorsmentioning

confidence: 99%

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MECHANISMS IN ENDOCRINOLOGY: Autocrine/paracrine regulatory mechanisms in adrenocortical neoplasms responsible for primary adrenal hypercorticism

Lefebvre

Prévost

Louiset

2013

European Journal of Endocrinology

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A wide variety of autocrine/paracrine bioactive signals are able to modulate corticosteroid secretion in the human adrenal gland. These regulatory factors, released in the vicinity of adrenocortical cells by diverse cell types comprising chromaffin cells, nerve terminals, cells of the immune system, endothelial cells, and adipocytes, include neuropeptides, biogenic amines, and cytokines. A growing body of evidence now suggests that paracrine mechanisms may also play an important role in the physiopathology of adrenocortical hyperplasias and tumors responsible for primary adrenal steroid excess. These intra-adrenal regulatory systems, although globally involving the same actors as those observed in the normal gland, display alterations at different levels, which reinforce the capacity of paracrine factors to stimulate the activity of adrenocortical cells. The main modifications in the adrenal local control systems reported by now include hyperplasia of cells producing the paracrine factors and abnormal expression of the latter and their receptors. Because steroid-secreting adrenal neoplasms are independent of the classical endocrine regulatory factors angiotensin II and ACTH, which are respectively suppressed by hyperaldosteronism and hypercortisolism, these lesions have long been considered as autonomous tissues. However, the presence of stimulatory substances within the neoplastic tissues suggests that steroid hypersecretion is driven by autocrine/paracrine loops that should be regarded as promising targets for pharmacological treatments of primary adrenal disorders. This new potential therapeutic approach may constitute an alternative to surgical removal of the lesions that is classically recommended in order to cure steroid excess.European Journal of Endocrinology 169 R115-R138

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Section: Factorssupporting

confidence: 75%

Section: Methodsmentioning

confidence: 99%

Section: Factorsmentioning

confidence: 99%

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MECHANISMS IN ENDOCRINOLOGY: Autocrine/paracrine regulatory mechanisms in adrenocortical neoplasms responsible for primary adrenal hypercorticism

Lefebvre

Prévost

Louiset

2013

European Journal of Endocrinology

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“…The role of its antagonist inhibin in adrenocortical physiology is even more obscure, since it has failed to show consistent effects on steroidogenesis (33,36,39). On the other hand, the inhibin ␣-subunit has been implicated in adrenocortical tumor formation in murine models (14,24) and can function as a tumor marker in patients (16).…”

mentioning

confidence: 99%

Protein kinase C-induced activin A switches adrenocortical steroidogenesis to aldosterone by suppressing CYP17A1 expression

Hofland¹,

Steenbergen²,

Hofland³

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Functional zonation of the adrenal cortex is a consequence of the zone-specific expression of P450c17 (CYP17A1) and its cofactors. Activin and inhibin peptides are differentially produced within the zones of the adrenal cortex and have been implicated in steroidogenic control. In this study, we investigated whether activin and inhibin can function as intermediates in functional zonation of the human adrenal cortex. Activin A suppressed CYP17A1 expression and P450c17 function in adrenocortical cell lines as well as in primary adrenal cell cultures. Inhibin βA-subunit mRNA and activin A protein levels were found to be increased up to 1,900-fold and 49-fold, respectively, after protein kinase C (PKC) stimulation through PMA or angiotensin II in H295R adrenocortical carcinoma cells. This was confirmed in HAC15 cells and for PMA in primary adrenal cell cultures. Both PMA and Ang II decreased CYP17A1 expression in the adrenocortical cell lines, whereas PMA concurrently suppressed CYP17A1 levels in the primary cultures. Inhibition of activin signaling during PKC stimulation through silencing of the inhibin βA-subunit or blocking of the activin type I receptor opposed the PMA-induced downregulation of CYP17A1 expression and P450c17 function. In contrast, PKA stimulation through adrenocorticotrophin or forskolin increased expression of the inhibin α-subunit and betaglycan, both of which are antagonists of activin action. These data indicate that activin A acts as a PKC-induced paracrine factor involved in the suppression of CYP17A1 in the zona glomerulosa and can thereby contribute to functional adrenocortical zonation.

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“…Jednakże większość ACT wykazuje ekspresję INHA, co można wykorzystać jako marker odróżniający je od guzów niepochodzących z kory nadnercza. Wśród nowotworów wieku dziecięce-go dominują ACT charakteryzujące się sporadycznymi stratami chromosomowymi w genie INHA [89].…”

Section: Prace Poglądoweunclassified

Szlaki molekularne w raku kory nadnercza — od wiedzy o sygnalizacji komórkowej do metod diagnostyki i leczenia

Szyszka

Grossman

Díaz‐Cano

et al. 2015

Endokrynologia Polska

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Adrenocortical carcinoma is associated with a low cure rate and a high recurrence rate. The prognosis is poor, and at diagnosis 30-40% of cases are already metastatic. The current therapeutic options (surgical resection, followed by adjuvant mitotane treatment +/-chemotherapy) are limited, and the results remain unsatisfactory. Key molecular events that contribute to formation of adrenocortical cancer are IGF2 overexpression, TP53-inactivating mutations, and constitutive activation of the Wnt/b-catenin signalling pathway via activating mutations of the b-catenin gene. The underlying genetic causes of inherited tumour syndromes have provided insights into molecular pathogenesis. The increased occurrence of adrenocortical tumours in Li-Fraumeni and Beckwith-Wiedemann syndromes, and Carney complex, has highlighted the roles of specific susceptibility genes: TP53, IGF2, and PRKAR1A, respectively. Further studies have confirmed that these genes are also involved in sporadic tumour cases. Crucially, transcriptome-wide studies have determined the differences between malignant and benign adrenocortical tumours, providing potential diagnostic tools. In conclusion, enhancing our understanding of the molecular events of adrenocortical tumourigenesis, especially with regard to the signalling pathways that may be disrupted, will greatly contribute to improving a range of available diagnostic, prognostic, and treatment approaches. StreszczenieRak kory nadnercza charakteryzuje się niską wyleczalnością i wysokim ryzykiem nawrotu. Rokowanie jest złe, a 30-40% przypadków okazuje się być przerzutami już przy diagnozie. Obecnie dostępne opcje terapeutyczne (chirurgiczna resekcja z następującym adjuwantowym leczeniem mitotanem, czasem połączonym z chemoterapią) są ograniczone, a ich wyniki są mało satysfakcjonujące. Kluczowe zmiany molekularne przyczyniające się to rozwoju raka kory nadnercza to nadekspresja IGF2, mutacje inaktywujące TP53 oraz konstytutywna aktywacja szklaku sygnałowego Wnt/b-katenina poprzez mutacje aktywujące gen b-kateniny. Genetyczne przyczyny leżące u podstaw dziedzicznych zespołów nowotworowych dostarczyły wgląd w ich patogenezę molekularną. Zespoły: Li-Fraumeni, Beckwitha-Wiedemanna oraz Carneya, charakteryzujące się zwiększoną predyspozycją do nowotworów kory nadnercza, uwidoczniły określone geny podatności, odpowiednio: TP53, IGF2 oraz PRKAR1A. Dalsze badania potwierdziły udział tych genów także w nowotworach sporadycznych. Co istotne, badania transkryptomu wykazały istotne różnice między nowotworami złośli-wymi i łagodnymi, dostarczając potencjalnych opcji diagnostycznych. Podsumowując, wzbogacenie wiedzy na temat molekularnych podstaw, a szczególnie szlaków sygnałowych, które mogą być zaburzone w procesie nowotworzenia w obrębie kory nadnercza znacznie przyczyni się poprawieniu możliwości diagnostycznych, rokowniczych oraz leczniczych. (Endokrynol Pol 2016; 67 (4): 427-440) Słowa kluczowe: rak kory nadnerczy; nowotwory kory nadnercza; patologia molekularna; szlaki transdukcji sygnałów; zespoły n...

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Inhibins and activins: Their roles in the adrenal gland and the development of adrenocortical tumors

Cited by 18 publications

References 92 publications

MECHANISMS IN ENDOCRINOLOGY: Autocrine/paracrine regulatory mechanisms in adrenocortical neoplasms responsible for primary adrenal hypercorticism

MECHANISMS IN ENDOCRINOLOGY: Autocrine/paracrine regulatory mechanisms in adrenocortical neoplasms responsible for primary adrenal hypercorticism

Protein kinase C-induced activin A switches adrenocortical steroidogenesis to aldosterone by suppressing CYP17A1 expression

Szlaki molekularne w raku kory nadnercza — od wiedzy o sygnalizacji komórkowej do metod diagnostyki i leczenia

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