Abstract
Cushing’s disease is the most frequent form of hypercortisolism and is caused by hypophyseal corticotroph adenomas secreting excessive amounts of adrenocorticotropic hormone. Most of the tumors develop sporadically and only a limited number of corticotroph adenomas have been found to be associated with different neuroendocrine syndromes or with familial isolated pituitary adenomas. The pathogenic mechanisms of corticotroph adenomas are largely unknown, but the discovered aberrant chaperoning activity of heat shock protein 90 on the one hand and the presence of ubiquitin-specific protease 8 mutations on the other hand partially explained the causes of their development. Corticotroph tumors arise initially as benign microadenomas but with time form invasively growing aggressive macroadenomas which can switch to corticotroph carcinomas in extremely rare cases. The mechanisms through which corticotroph tumors escape from glucocorticoid negative feedback are still poorly understood, as are the processes that trigger the progression of benign corticotroph adenomas toward aggressive and malignant phenotypes. This review summarizes recent findings regarding initiation and progression of corticotroph pituitary tumors.
Highlights
Corticotroph adenomas (CAs) derive from normal corticotroph cells of the anterior pituitary and account for about 4% to 8% of all clinically hormone-active anterior pituitary tumor types[1]
Corticotroph carcinomas According to the 2017 World Health Organization (WHO) classification, pituitary carcinomas, which represent less than 0.1% of all pituitary tumors, are characterized by their ability to form metastases and both hereditary and sporadic pituitary tumors can transform into carcinomas[2]
In a recent meta-analysis, in which pituitary carcinomas were compared with aggressive adenomas, a number of factors related to the stimulation of cell growth, angiogenesis, and invasiveness were found to be up-regulated, whereas several factors, including growth inhibitors and apoptosis inducers (p16Ink4A, p27Kip[1], MT3, BCL-2, Bax, Bcl-X, and O6-methylguanine DNA methyltransferase [MGMT]), were down-regulated[95,96]
Summary
Corticotroph adenomas (CAs) derive from normal corticotroph cells of the anterior pituitary and account for about 4% to 8% of all clinically hormone-active anterior pituitary tumor types[1]. As the previously mentioned USP8 protein interferes with HIF-1α deubiquitination processes[25,79], it would be interesting to study whether HIF-1 levels are different in corticotropinomas with and without mutated USP8 and whether corticotropinoma vascularization might be affected as in the case of the product of the RWWD3 gene, RWD-domain-containing sumoylation enhancer (RSUME)[80] The latter is upregulated under hypoxia and overexpressed in pituitary tumors, including corticotropinomas[81]. In a recent meta-analysis, in which pituitary carcinomas were compared with aggressive adenomas, a number of factors related to the stimulation of cell growth, angiogenesis, and invasiveness (cyclin D1, VEGF, MMP9, miR-122, and miR-493) were found to be up-regulated, whereas several factors, including growth inhibitors and apoptosis inducers (p16Ink4A, p27Kip[1], MT3, BCL-2, Bax, Bcl-X, and O6-methylguanine DNA methyltransferase [MGMT]), were down-regulated[95,96] These factors are differently expressed in invasive versus noninvasive adenomas, in micro- versus macro-adenomas, or in poorly versus densely vascularised pituitary tumors[76,84,87]. This suggests that advanced aggressive corticotropinoma types may already be treated with temozolomide to prevent transformation into corticotroph carcinomas[101]
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