Recent advances in understanding corticotroph pituitary tumor initiation and progression

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.

Cushing’s Disease

“…Most pituitary corticotroph tumors causing CD develop sporadically, and only a few cases involving various hereditary endocrine syndromes [17,18,19,20]. These include familial isolated pituitary tumor (FIPA; AIP ), multiple endocrine neoplasia type 1 ( MEN1 ) and type 4 ( CDKN1B ), Carney complex ( PRKAR1A ), and DICER 1 syndrome ( DICER1 ).…”

“…The pathogenic mechanisms of corticotroph tumors remain largely unknown [23]. One of the recent important advancements is the detection of ubiquitin-specific peptidase 8 ( USP8 ) gene mutations in approximately 23–60% of functioning corticotroph tumors [17,18,20,24,25,26,27,28,29,30] (Table 1). The somatic mutations are specific for corticotroph tumors and lead to the increased EGFR expression and activation of proopiomelanocortin ( POMC ) gene transcription.…”

“…BRAF V600E variants were extremely rare in corticotroph tumors while TP53 pathogenic variants were more frequent than previously assumed, especially in the larger tumors. In contrast, overexpression of HSP90 is involved in CD and causes partial glucocorticoid resistance [20,24,39,40].…”

“…Recent meta-analysis, in which pituitary carcinomas were compared with aggressive tumors, demonstrated that 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 upregulated, whereas several factors, including growth inhibitors and apoptosis inducers (p16Ink4A, p27Kip1, MT3, BCL-2, Bax, Bcl-X, and MGMT) were downregulated [312,313]. It is speculated that an accumulation of these changes is associated with increased pituitary tumor aggressiveness rather than a carcinoma-specific mutation or epigenetic change that leads to the development of pituitary carcinomas [20]. Trouillas et al [314] proposed a new clinicopathological classification, graded by invasion and proliferation, and demonstrated its usefulness in a retrospective multicentric, case-control study.…”

Differential Expression of MicroRNAs in Silent and Functioning Corticotroph Tumors

“…On the other hand, there are other ACTH-secreting pituitary tumors named silent CTs, which are not associated with any of the most important clinical and biochemical features of Cushing disease (i.e., hypercortisolemia) [ 2 ]. Together, CTs represent up to 17% of all PitNETs [ 3 , 4 ] of which approximately 45% are silent CTs [ 5 , 6 ]. However, the silencing mechanisms and pathogenesis of CTs remain unclear.…”