Abstract
Simple SummaryCorticotroph pituitary adenomas present a spectrum of functionality regarding hormonal production, ranging from functioning to silent tumors. Moreover, they show different invasiveness and recurrent behavior profiles, the silent being considered an aggressive type of adenomas. Through analyses of global transcriptome and proteome, we show that both groups expressed genes and protein related to protein synthesis and vesicular transport, and present a distinct pattern of collagen/ extracellular matrix proteins. Endoplasmic reticulum protein processing is a key factor for hormone production in functioning corticotroph adenomas. Furthermore, a distinct cell adhesion profile in silent corticotroph adenomas may explain the aggressive behavior. Together, our findings shed light on the different repertoires of activated signaling pathways in corticotroph pituitary adenomas and may reveal new potential medical targets.Functioning (FCA) and silent corticotroph (SCA) pituitary adenomas act differently from a clinical perspective, despite both subtypes showing positive TBX19 (TPIT) and/or adrenocorticotropic hormone (ACTH) staining by immunohistochemistry. They are challenging to treat, the former due to functional ACTH production and consequently hypercortisolemia, and the latter due to invasive and recurrent behavior. Moreover, the molecular mechanisms behind their distinct behavior are not clear. We investigated global transcriptome and proteome changes in order to identify signaling pathways that can explain FCA and SCA differences (e.g., hormone production vs. aggressive growth). In the transcriptomic study, cluster analyses of differentially expressed genes revealed two distinct groups in accordance with clinical and histological classification. However, in the proteomic study, a greater degree of heterogeneity within the SCA group was found. Genes and proteins related to protein synthesis and vesicular transport were expressed by both adenoma groups, although different types and a distinct pattern of collagen/extracellular matrix proteins were presented by each group. Moreover, several genes related to endoplasmic reticulum protein processing were overexpressed in the FCA group. Together, our findings shed light on the different repertoires of activated signaling pathways in corticotroph adenomas, namely, the increased protein processing capacity of FCA and a specific pattern of adhesion molecules that may play a role in the aggressiveness of SCA.
Highlights
Non-functioning pituitary adenomas (NFPAs) comprise up to a half of all pituitary neuroendocrine tumors (PitNETs) [1,2], and they are characterized as silent, patients present increased morbidity and decreased quality of life due to clinical manifestations caused by the tumor pressure [3,4]
Cortisol levels were higher in the functioning corticotroph pituitary adenoma (FCA) group (p = 0.007), as expected
Data visualization showed up-regulation of several genes involved in the protein processing in the endoplasmic reticulum (ER)-pathway in the FCA group. suggesting that an increased protein processing activity may lead to functioning corticotroph adenomas and raising the possibility for identification of a medical treatable target
Summary
Non-functioning pituitary adenomas (NFPAs) comprise up to a half of all pituitary neuroendocrine tumors (PitNETs) [1,2], and they are characterized as silent, patients present increased morbidity and decreased quality of life due to clinical manifestations caused by the tumor pressure [3,4].The latest World Health Organization (WHO) classification using immunohistochemistry (IHC) for transcription factors and anterior pituitary hormones illustrates that the most common NFPA subtype is the silent gonadotroph followed by the silent corticotroph adenoma (SCA) [5]. Non-functioning pituitary adenomas (NFPAs) comprise up to a half of all pituitary neuroendocrine tumors (PitNETs) [1,2], and they are characterized as silent, patients present increased morbidity and decreased quality of life due to clinical manifestations caused by the tumor pressure [3,4]. SCA comprise 5–19% of the NFPAs, depending on the cohort, and approximately 3% of all adenomas, whereas their functional counterpart, functioning corticotroph pituitary adenoma (FCA), represent only 2–6% [1,2,6,7]. SCA is categorized as a potentially more aggressive neuroendocrine tumor posing a high risk of increased invasiveness and parasellar growth, a tendency for multiple and earlier recurrences, and higher rates of hemorrhage and apoplexy [8,9,10,11,12]. Due to the presence of clinical symptoms, FCA is discovered at an earlier stage in tumor development, most often as a microadenoma located in the sellar area (in 80% of cases) [13], whereas SCA present as a macroadenoma with extrasellar expansion at the time of diagnosis [14]
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