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Human Pathology Aug 2021Follicular cells (FCs) are thought to be agranular, non-hormone-producing stellate cells distributed throughout the adenohypophysis, occasionally arranged around...
Follicular cells (FCs) are thought to be agranular, non-hormone-producing stellate cells distributed throughout the adenohypophysis, occasionally arranged around colloid-filled follicles, and thought to be more prominent in the vicinity of necrosis and apoptotic cells. A distinct but similar cell type, the folliculostellate cell (FSC), is a sustentacular cell that is negative for keratins and stains for S100, GFAP, and SOX10. While several studies have examined FSCs in pituitary neuroendocrine tumors (PitNETs), the distribution and derivation of FCs in these lesions is unclear. We examined the presence and distribution of FCs in 104 PitNETs obtained by trans-sphenoidal surgery, using immunohistochemistry for keratins as well as the full complement of immunohistochemical stains for tumor characterization. The tumors included 9 somatotroph, 5 mammosomatotroph, 7 lactotroph, 7 immature PIT1-lineage, 2 acidophil stem cell, 17 corticotroph, 53 gonadotroph, 2 null cell, and 2 unusual plurihormonal tumors. CK-positive FCs were only identified in gonadotroph PitNETs and were found in 12 (23%) of those tumors; all other tumor types were negative for FCs. FCs express keratins identified by CAM5.2, AE1/AE3, CK18, and CK19 antibodies. FCs were identified scattered singly among hormone-producing neuroendocrine cells, in small clusters of 3-5 cells and surrounding colloid-filled follicles, as well as linearly along intratumoral blood vessels. Sequential stains showed that FCs express nuclear SF1 and GATA3, transcription factors of gonadotrophs, and multiplex immunohistochemistry confirmed colocalization of SF1 in the nucleus of keratin-positive FCs. In this series, FCs were exclusively found in gonadotroph PitNETs and occurred in 23% of those tumors. Co-expression of gonadotroph transcription factors in FCs supports the concept of cellular plasticity and transformation of neoplastic hormone-producing neuroendocrine cells to FCs. Further studies are required to determine if and why gonadotrophs alone undergo this transformation, the function of these cells and whether they have prognostic value.
Topics: Biomarkers, Tumor; Cell Plasticity; Humans; Immunohistochemistry; Neuroendocrine Tumors; Phenotype; Pituitary Neoplasms; Prognosis; Retrospective Studies
PubMed: 33991528
DOI: 10.1016/j.humpath.2021.05.002 -
The Journal of Clinical Endocrinology... Jun 2013GH secretion is controlled by hypothalamic as well as intrapituitary and peripheral signals, all of which converge upon the somatotroph, resulting in integrated GH... (Review)
Review
GH secretion is controlled by hypothalamic as well as intrapituitary and peripheral signals, all of which converge upon the somatotroph, resulting in integrated GH synthesis and secretion. Enabling an accurate diagnosis of idiopathic adult GH deficiency (IAGHD) is challenged by the pulsatility of GH secretion, provocative test result variability, and suboptimal GH assay standardization. The spectrum between attenuated GH secretion associated with the normal aging process and with obesity and truly well-defined IAGHD is not distinct and may mislead the diagnosis. Adult-onset GHD is mainly caused by an acquired pituitary deficiency, commonly including prior head/neck irradiation, or an expanding pituitary mass causing functional somatotroph compression. To what extent rare cryptic causes account for those patients seemingly classified as IAGHD is unclear. About 15% of patients with adult GHD and receiving GH replacement in open-label surveillance studies are reported as being due to an idiopathic cause. These patients may also reflect a pool of subjects with an as yet to be determined occult defect, or those with unclear or incomplete medical histories (including forgotten past sports head injury or motor vehicle accident). Therefore, submaximal diagnostic evaluation likely leads to an inadvertent diagnosis of IAGHD. In these latter cases, adherence to rigorous biochemical diagnostic criteria and etiology exclusion may result in reclassification of a subset of these patients to a distinct known acquired etiology, or as GH-replete. Accordingly, rigorously verified IAGHD likely comprises less than 10% of adult GHD patients, an already rare disorder. Regardless of etiology, patients with adult GHD, including those with IAGHD, exhibit a well-defined clinical phenotype including increased fat mass, loss of lean muscle mass, decreased bone mass, and enhanced cardiac morbidity. Definition of unique efficacy and dosing parameters for GH replacement and resultant therapeutic efficacy markers in true IAGHD requires prospective study.
Topics: Adult; Hormone Replacement Therapy; Human Growth Hormone; Humans
PubMed: 23539718
DOI: 10.1210/jc.2012-4012 -
Cancers Sep 2023About a third of Pituitary Neuroendocrine Tumors (PitNETs) may show aggressive behavior. Many efforts have been performed for identifying possible predictive factors to...
BACKGROUND AND AIM
About a third of Pituitary Neuroendocrine Tumors (PitNETs) may show aggressive behavior. Many efforts have been performed for identifying possible predictive factors to early determine the future behavior of PitNETs. Programmed cell death ligand 1 (PD-L1) expression was associated with a more aggressive biology in different solid tumors, but its role in PitNET is not well-established yet. Our study aims to analyze PD-L1 expression in a surgical cohort of PitNETs to determine its association with radiological invasion and pathology findings, as well as with long-term recurrence rates.
METHODS
We performed a retrospective analysis in a series of 86 PitNETs. Clinical presentation and radiological features of the preoperative period were collected, as well as pathological data and follow-up data. The rate of PD-L1 expression was immunohistochemically evaluated and expressed as a tumor proportion score (TPS). We assessed its relationship with cavernous sinus invasion and Trouillas' classification as primary outcomes. Secondary outcomes included the TPS' relationship with histopathological markers of proliferation, hormonal expression, tumor size and long-term recurrence rates. We calculated the optimal cut-point for the primary outcomes while maximizing the product of the sensitivity and specificity and then we evaluated the significance of secondary outcomes with logistic regression analysis.
RESULTS
Eighty-six patients were included in the analysis; 50 cases were non-functional PitNETs. The TPS for PD-L1 showed a highly right-skewed distribution in our sample, as 30.2% of patients scored 0. Using Trouillas' classification, we found that "proliferative" cases have a significantly higher probability to express PD-L1 in more than 30% of tumor cells (OR: 5.78; CI 95%: 1.80-18.4). This same cut-point was also associated with p53 expression. A positive association was found between PD-L1 expression and GH expression ( = 0.001; OR: 5.44; CI 95%: 1.98-14.98), while an inverse relationship was found with FSH/LH expression ( = 0.014; OR = 0.27, CI 95%: 0.10-0.76). No association was found with CS invasion, tumor size, bone erosion or dura invasion. We could not find any association between PD-L1 expression and recurrence.
CONCLUSIONS
PD-L1 expression was associated with proliferative grades of Trouillas' classification and p53 expression. We also confirmed a higher expression of PD-L1 in somatotroph tumors. Larger studies are necessary to investigate the relationship between PD-L1 expression and aggressive behaviors.
PubMed: 37760441
DOI: 10.3390/cancers15184471 -
International Journal of Molecular... Sep 2023Prolactin (PRL) and growth hormone (GH) are peptide hormones that bind to the class 1 cytokine receptor superfamily, a highly conserved cell surface class of receptors.... (Review)
Review
Prolactin (PRL) and growth hormone (GH) are peptide hormones that bind to the class 1 cytokine receptor superfamily, a highly conserved cell surface class of receptors. Both hormones control their own secretion via a negative autocrine loop in their own mammosomatotroph, lactotroph or somatotroph. In this regard, GH and PRL are regulated by similar signaling pathways involving cell growth and hormone secretion. Thus, GH and PRL dysregulation and pituitary neuroendocrine tumor (PitNET) development may have common pathogenic pathways. Based on cell linage, lactotroph and somatotroph PitNETs come from pituitary-specific POU-class homeodomain transcription factor (Pit-1). Mammosomatotroph and plurihormonal PitNETs are a unique subtype of PitNETs that arise from a single-cell population of Pit-1 lineage. In contrast, mixed somatotroph-lactotroph PitNETs are composed of two distinct cell populations: somatotrophs and lactotrophs. Morphologic features that distinguish indolent PitNETs from locally aggressive ones are still unidentified, and no single prognostic parameter can predict tumor aggressiveness or treatment response. In this review, we aim to explore the latest research on lactotroph and somatotroph PitNETs, the molecular mechanisms involved in PRL and GH axis regulation and the signaling pathways involved in their aggressiveness, particularly focused on mammosomatotroph and mixed subtypes. Finally, we summarize epidemiological, clinical, and radiological features of these exceptional tumors. We aim to shed light, from basic to clinical settings, on new perspectives and scientific gaps in this field.
PubMed: 37762304
DOI: 10.3390/ijms241814002 -
Pituitary Apr 2023Pit-1 tumours are derived from neoplastic cells of either somatotroph, lactotroph or thyrotroph cell lineages, but there are also distinct mixed tumours and... (Review)
Review
Pit-1 tumours are derived from neoplastic cells of either somatotroph, lactotroph or thyrotroph cell lineages, but there are also distinct mixed tumours and plurihormonal tumours within this category as described within the 2022 edition of the WHO classification of pituitary tumours. Plurihormonal tumours and thyrotroph adenomas are transcriptionally similar and grouped together to discuss in this review, although it is clear an immature type of plurihormonal tumour exists which are more commonly associated with refractory disease. Management of residual or recurrent disease should follow that of other aggressive pituitary tumours, although a trial of somatostatin analogue therapy is certainly warranted before considering temozolomide therapy.
Topics: Humans; Pituitary Neoplasms; Thyrotrophs; Transcription Factors; Somatotrophs; Adenoma
PubMed: 37117845
DOI: 10.1007/s11102-023-01312-9 -
Postgraduate Medical Journal Jan 2006Growth hormone (GH) is synthesised and secreted by the somatotroph cells of the anterior lobe of the pituitary gland. Its actions involve multiple organs and systems,... (Review)
Review
Growth hormone (GH) is synthesised and secreted by the somatotroph cells of the anterior lobe of the pituitary gland. Its actions involve multiple organs and systems, affecting postnatal longitudinal growth as well as protein, lipid, and carbohydrate metabolism. GH hypersecretion results in gigantism or acromegaly, a condition associated with significant morbidity and mortality, while GH deficiency results in growth retardation in children and the GH deficiency syndrome in adults. This article, aimed at non-paediatric physicians, examines the clinical features, diagnosis, and current concepts in the management of these conditions.
Topics: Acromegaly; Dopamine Agonists; Growth Disorders; Growth Hormone; Humans; Receptors, Somatotropin; Referral and Consultation; Somatostatin
PubMed: 16397076
DOI: 10.1136/pgmj.2005.036087 -
Cell Reports Dec 2022Nonalcoholic fatty liver disease (NAFLD) can be ameliorated by calorie restriction, which leads to the suppressed somatotroph axis. Paradoxically, the suppressed...
Nonalcoholic fatty liver disease (NAFLD) can be ameliorated by calorie restriction, which leads to the suppressed somatotroph axis. Paradoxically, the suppressed somatotroph axis is associated with patients with NAFLD and is correlated with the severity of fibrosis. How the somatotroph axis becomes dysregulated and whether the repressed somatotroph axis impacts liver damage during the progression of NAFLD are unclear. Here, we identify a regulatory branch of the hepatic integrated stress response (ISR), which represses the somatotroph axis in hepatocytes through ATF3, resulting in enhanced cell survival and reduced cell proliferation. In mouse models of NAFLD, the ISR represses the somatotroph axis, leading to reduced apoptosis and inflammation but decreased hepatocyte proliferation and exacerbated fibrosis in the liver. NAD repletion reduces the ISR, rescues the dysregulated somatotroph axis, and alleviates NAFLD. These results establish that the hepatic ISR suppresses the somatotroph axis to control cell fate decisions and liver damage in NAFLD.
Topics: Mice; Animals; Non-alcoholic Fatty Liver Disease; Somatotrophs; Liver; Hepatocytes; Liver Cirrhosis
PubMed: 36516757
DOI: 10.1016/j.celrep.2022.111803 -
Frontiers in Endocrinology 2021Growth hormone (GH) and the insulin-like growth factor (IGF) system are involved in many biological processes and have growth-promoting actions regulating cell... (Review)
Review
Growth hormone (GH) and the insulin-like growth factor (IGF) system are involved in many biological processes and have growth-promoting actions regulating cell proliferation, differentiation, apoptosis and angiogenesis. A recent chapter in epigenetics is represented by microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) which regulate gene expression. Dysregulated miRNAs and lncRNAs have been associated with several diseases including cancer. Herein we report the most recent findings concerning miRNAs and lncRNAs regulating GH and the IGF system in the context of pituitary adenomas, osteosarcoma and colorectal cancer, shedding light on new possible therapeutic targets. Pituitary adenomas are increasingly common intracranial tumors and somatotroph adenomas determine supra-physiological GH secretion and cause acromegaly. Osteosarcoma is the most frequent bone tumor in children and adolescents and was reported in adults who were treated with GH in childhood. Colorectal cancer is the third cancer in the world and has a higher prevalence in acromegalic patients.
Topics: Gene Expression Regulation; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; MicroRNAs; Neoplasms; RNA, Long Noncoding
PubMed: 34484116
DOI: 10.3389/fendo.2021.701246 -
The Journal of Clinical Endocrinology... Jan 2022The identification and biological actions of pituitary-derived exosomes remain elusive.
CONTEXT
The identification and biological actions of pituitary-derived exosomes remain elusive.
OBJECTIVE
This work aimed to validate production of exosomes derived from human and rat pituitary and elucidate their actions.
METHODS
Isolated extracellular vesicles (EVs) were analyzed by Nanoparticle Tracking Analysis (NTA) and expressed exosomal markers detected by Western blot, using nonpituitary fibroblast FR and myoblast H9C2 cells as controls. Exosome inhibitor GW4869 was employed to detect attenuated EV release. Exosomal RNA contents were characterized by RNA sequencing. In vitro and in vivo hepatocyte signaling alterations responding to GH1-derived exosomes (GH1-exo) were delineated by mRNA sequencing. GH1-exo actions on protein synthesis, cAMP (3',5'-cyclic adenosine 5'-monophosphate) response, cell motility, and metastases were assessed.
RESULTS
NTA, exosomal marker detection, and GW4869 attenuated EV release, confirming the exosomal identity of pituitary EVs. Hydrocortisone increased exosome secretion in GH1 and GH3 cells, suggesting a stress-associated response. Exosomal RNA contents showed profiles distinct for pituitary cells, and rat primary hepatocytes exposed to GH1-exo exhibited transcriptomic alterations distinct from those elicited by growth hormone or prolactin. Intravenous GH1-exo injection into rats attenuated hepatic Eif2ak2 and Atf4 mRNA expression, both involved in cAMP responses and amino acid biosynthesis. GH1-exo suppressed protein synthesis and forskolin-induced cAMP levels in hepatocytes. GH1-exo-treated HCT116 cells showed dysregulated p53 and mitogen-activated protein kinase (MAPK) pathways and attenuated motility of malignant HCT116 cells, and decreased tumor metastases in nude mice harboring splenic HCT116 implants.
CONCLUSION
Our findings elucidate biological actions of somatotroph-derived exosomes and implicate exosomes as nonhormonal pituitary-derived messengers.
Topics: Adenoma; Adult; Aniline Compounds; Animals; Benzylidene Compounds; Cell Communication; Coculture Techniques; Exosomes; Female; Growth Hormone-Secreting Pituitary Adenoma; Hepatocytes; Humans; Male; Pituitary Gland; Primary Cell Culture; Rats; Rats, Wistar; Tumor Cells, Cultured
PubMed: 34467411
DOI: 10.1210/clinem/dgab651 -
Endocrine-related Cancer Oct 2011The role of ErbB family in discreet pituitary functions is reviewed. Several ErbB receptor ligands, EGF, TGFα, and heregulin are differentially expressed in normal... (Review)
Review
The role of ErbB family in discreet pituitary functions is reviewed. Several ErbB receptor ligands, EGF, TGFα, and heregulin are differentially expressed in normal gonadotroph and lacto-somatotroph lineages, and other elements of the anterior pituitary. ErbB receptors, i.e. EGFR and ErbB2, are also localized to the anterior pituitary with preferential EGFR lactosomatotroph expression. EGF regulates CRH and ACTH secretion and corticotroph proliferation as well as exhibiting autocrine and paracrine effects on gonadotrophs and on lactosomatotroph proliferation, gene and protein expression, and hormonal secretion. EGF and EGFR are expressed in both functioning and non-functioning pituitary adenomas, with higher expression in more aggressive tumor subtypes. ErbB2 receptor is detected in all tumor subtypes, particularly in invasive tumors. ErbB tyrosine kinase inhibitors regulate hormonal secretion, cell morphology, and proliferation in lacto-somatotroph tumors, reflecting the emerging application of targeted pituitary therapeutics.
Topics: Animals; Epidermal Growth Factor; Humans; Neuregulin-1; Oncogene Proteins v-erbB; Pituitary Gland; Pituitary Neoplasms; Receptor, ErbB-2; Transforming Growth Factor alpha
PubMed: 21917845
DOI: 10.1530/ERC-11-0066