Architects of Pituitary Tumour Growth

Abstract

The pituitary is a master gland responsible for the modulation of critical endocrine functions. Pituitary neuroendocrine tumours (PitNETs) display a considerable prevalence of 1/1106, frequently observed as benign solid tumours. PitNETs still represent a cause of important morbidity, due to hormonal systemic deregulation, with surgical, radiological or chronic treatment required for illness management. The apparent scarceness, uncommon behaviour and molecular features of PitNETs have resulted in a relatively slow progress in depicting their pathogenesis. An appropriate interpretation of different phenotypes or cellular outcomes during tumour growth is desirable, since histopathological characterization still remains the main option for prognosis elucidation. Improved knowledge obtained in recent decades about pituitary tumorigenesis has revealed that this process involves several cellular routes in addition to proliferation and death, with its modulation depending on many signalling pathways rather than being the result of abnormalities of a unique proliferation pathway, as sometimes presented. PitNETs can display intrinsic heterogeneity and cell subpopulations with diverse biological, genetic and epigenetic particularities, including tumorigenic potential. Hence, to obtain a better understanding of PitNET growth new approaches are required and the systematization of the available data, with the role of cell death programs, autophagy, stem cells, cellular senescence, mitochondrial function, metabolic reprogramming still being emerging fields in pituitary research. We envisage that through the combination of molecular, genetic and epigenetic data, together with the improved morphological, biochemical, physiological and metabolically knowledge on pituitary neoplastic potential accumulated in recent decades, tumour classification schemes will become more accurate regarding tumour origin, behaviour and plausible clinical results.

Ultrastructural and Molecular Evidence of Macroautophagy in Functioning PitNETs and Experimental Pituitary Tumors

“…The complex pathophysiology of PitNETs varies both between and among subtypes, with no single unifying explanation for how and why PitNETs arise having been elucidated [35]. A new pituitary tumorigenic model postulates that PitNETs can display intrinsic heterogeneity and cell subpopulations with diverse biological, genetic, and epigenetic particularities [35].…”

“…The complex pathophysiology of PitNETs varies both between and among subtypes, with no single unifying explanation for how and why PitNETs arise having been elucidated [35]. A new pituitary tumorigenic model postulates that PitNETs can display intrinsic heterogeneity and cell subpopulations with diverse biological, genetic, and epigenetic particularities [35]. Autophagy is an evolutionary conserved process for the self-degradation and recycling of cellular components in the cytoplasm [6], and it is now clear that autophagy can be either nonselective or selective [12].…”

“…These antecedents and our results allow us to hypothesize that pituitary macroautophagy might constitute a beneficial cellular mechanism, possibly interacting with the senescence program to regulate pituitary cell growth. Although our observations do not allow us to make any general conclusions about the actual role of macroautophagy/mitophagy in all PitNET types, we consider that the role of autophagy in tumor cell biology might be context dependent [35].…”

Pathogenesis, clinical features, and treatment of plurihormonal pituitary adenoma

“…It also suggests that these pituitary tumors may be polyclonal. In addition, a growing number of studies have found that pituitary tumors can display intrinsic heterogeneity and cellular subpopulations with different biological, genetic and epigenetic properties ( Sabatino et al, 2022 ). Tissue structure and microenvironment play a crucial role in tumors.…”

“…In 2022, the WHO proposed that the adenohypophyseal is composed of at least six cell types: somatotrophs, lactotrophs, mammosomatotrophs, and thyrotrophs of the PIT1 lineage; corticotrophs of the T-box family member TBX19 (T-PIT) lineage; and gonadotrophs of the steroidogenic factor-1 (SF1) lineage ( Mariniello et al, 2019 ; Alatzoglou et al, 2020 ; Asa et al, 2021 ; Kobalka et al, 2021 ; Asa et al, 2022 ; Villa et al, 2023 ). Studies have shown that the pathogenesis of pituitary adenoma may be related to gene mutations, chromosome number variations, DNA methylation, microRNA regulation, and transcription factor regulation ( Asa and Ezzat, 2009 ; Salomon et al, 2018 ; Vandeva et al, 2019 ; Chang et al, 2020 ; Sabatino et al, 2022 ). However, the pathogenesis of PPA is still unclear.…”