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Key Points The glucose-lowering, insulin-sensitizing agent metformin works mainly by reducing gluconeogenesis and opposing glucagon-mediated signalling in the liver and, to a lesser extent, by increasing glucose uptake in skeletal muscle The primary site of metformin action is the mitochondrion The antihyperglycaemic effect of metformin is probably owing to defective protein kinase A signalling Metformin affects lipid metabolism primarily via 5′-AMP-activated protein kinase (AMPK) activation Antitumourigenic effects of metformin, which require further study, might be partially due to systemic metabolic alterations, including the reduced availability of insulin In cancer cells, metformin acts as an inducer of energetic stress; AMPK-driven inhibition of mTOR seems to be required for much of its antimitotic activity This Review discusses the molecular mechanisms through which metformin acts on metabolism, mainly focussing on liver gluconeogenesis, and on tumourigenesis. In addition, the authors review the potential implications of new discoveries about the molecular targets of metformin for the development of antidiabetic and anticancer therapies. Metformin has been the mainstay of therapy for diabetes mellitus for many years; however, the mechanistic aspects of metformin action remained ill-defined. Recent advances revealed that this drug, in addition to its glucose-lowering action, might be promising for specifically targeting metabolic differences between normal and abnormal metabolic signalling. The knowledge gained from dissecting the principal mechanisms by which metformin works can help us to develop novel treatments. The centre of metformin's mechanism of action is the alteration of the energy metabolism of the cell. Metformin exerts its prevailing, glucose-lowering effect by inhibiting hepatic gluconeogenesis and opposing the action of glucagon. The inhibition of mitochondrial complex I results in defective cAMP and protein kinase A signalling in response to glucagon. Stimulation of 5′-AMP-activated protein kinase, although dispensable for the glucose-lowering effect of metformin, confers insulin sensitivity, mainly by modulating lipid metabolism. Metformin might influence tumourigenesis, both indirectly, through the systemic reduction of insulin levels, and directly, via the induction of energetic stress; however, these effects require further investigation. Here, we discuss the updated understanding of the antigluconeogenic action of metformin in the liver and the implications of the discoveries of metformin targets for the treatment of diabetes mellitus and cancer.

Pituitary adenomas are the third most common central nervous system tumors and arise from the anterior pituitary within the pituitary fossa. Literature review and discussion. The signs and symptoms of patients with pituitary adenomas vary from 'mass effects' caused by a large adenoma to features secondary to excess pituitary hormones produced by the functioning pituitary adenoma. Detailed histopathologic assessment, based on novel classifications and the latest World Health Organization guidelines, helps to categorize pituitary adenomas into different subtypes and identify features that, in some cases, help to predict their behavior. Most of the pituitary tumors occur sporadically without known genetic predisposition, but in a significant minority of cases, somatic mutations can be identified in the GNAS and USP8 genes. A small proportion of the cases have germline genetic defects or embryonic mutations leading to mosaicism. Genes with germ-line mutations predisposing to pituitary adenomas include AIP, GPR101, MEN1, CDKN1B, PRKAR1A, PRKAR2A, DICER1, NF1, and SDHx, whereas more recently, CABLES1 has also been implicated. Understanding the pathogenesis of pituitary adenomas will allow clinicians to correlate the pathologic and genetic features with clinical data, helping decisions on the best management of these tumors. ACTH = adrenocorticotropic hormone; AIP = aryl hydrocarbon receptor-interacting protein; αSU = alpha-subunit; EGFR = epithelial growth factor receptor; ER = estrogen receptor; FSH = follicle-stimulating hormone; GH = growth hormone; GHRH = growth hormone-releasing hormone; IGF-1 = insulin-like growth factor 1; LH = luteinizing hormone; MEN1 = multiple endocrine neoplasia 1; MRI = magnetic resonance imaging; NFPA = nonfunctioning pituitary adenoma; PRL = prolactin; TSH = thyroid-stimulating hormone; USP8 = ubiquitin-specific peptidase 8; WHO = World Health Organization.

Abstract Context Silent pituitary adenomas are anterior pituitary tumors with hormone synthesis but without signs or symptoms of hormone hypersecretion. They have been increasingly recognized and represent challenging diagnostic issues. Evidence Acquisition A comprehensive literature search was performed using MEDLINE and EMBASE databases from January 2000 to March 2018 with the following key words: (i) pituitary adenoma/tumor and nonfunctioning; or (ii) pituitary adenoma/tumor and silent. All titles and abstracts of the retrieved articles were reviewed, and recent advances in the field of silent pituitary adenomas were summarized. Evidence Synthesis The clinical and biochemical picture of pituitary adenomas reflects a continuum between functional and silent adenomas. Although some adenomas are truly silent, others will show some evidence of biochemical hypersecretion or could have subtle clinical signs and, therefore, can be referred to as clinically silent or “whispering” adenomas. Silent tumors seem to be more aggressive than their secreting counterparts, with a greater recurrence rate. Transcription factors for pituitary cell lineages have been introduced into the 2017 World Health Organization guidelines: steroidogenic factor 1 staining for gonadotroph lineage; PIT1 (pituitary-specific positive transcription factor 1) for growth hormone, prolactin, and TSH lineage, and TPIT for the corticotroph lineage. Prospective studies applying these criteria will establish the value of the new classification. Conclusions A concise review of the clinical and pathological aspects of silent pituitary adenomas was conducted in view of the new World Health Organization classification of pituitary adenomas. New classifications, novel prognostics markers, and emerging imaging and therapeutic approaches need to be evaluated to better serve this unique group of patients. We present a concise review of the clinical and pathological aspects of silent pituitary adenomas in view of the new World Health Organization classification of pituitary adenomas.

Aryl hydrocarbon receptor-interacting protein (AIP) is a co-chaperone to heat shock proteins and nuclear receptors. Loss-of-function heterozygote germline mutations lead to predisposition to growth hormone- or prolactin-secreting pituitary typically presenting in childhood. Based on these data AIP behaves as a tumour suppressor. However, previously in diffuse large B cell lymphoma and now in this new manuscript in the British Journal of Cancer on colorectal cancer, it seems that high expression of AIP is associated with tumour development and more aggressive disease. AIP, therefore, joins a distinguished group of proteins that can behave both as a tumour suppressor and as an oncogene.

Abstract Substantial advances have been made recently in the pathobiology of pituitary tumors. Similar to many other endocrine tumors, over the last few years we have recognized the role of germline and somatic mutations in a number of syndromic or nonsyndromic conditions with pituitary tumor predisposition. These include the identification of novel germline variants in patients with familial or simplex pituitary tumors and establishment of novel somatic variants identified through next generation sequencing. Advanced techniques have allowed the exploration of epigenetic mechanisms mediated through DNA methylation, histone modifications and noncoding RNAs, such as microRNA, long noncoding RNAs and circular RNAs. These mechanisms can influence tumor formation, growth, and invasion. While genetic and epigenetic mechanisms often disrupt similar pathways, such as cell cycle regulation, in pituitary tumors there is little overlap between genes altered by germline, somatic, and epigenetic mechanisms. The interplay between these complex mechanisms driving tumorigenesis are best studied in the emerging multiomics studies. Here, we summarize insights from the recent developments in the regulation of pituitary tumorigenesis. Graphical Abstract Graphical Abstract

Pituitary adenomas are usually benign monoclonal tumours presenting either due to hypersecretion of pituitary hormones, and/or due to local space occupying effects and hyposecretion of some or all of the pituitary hormones. Some pituitary adenomas cause prominent symptoms, while others may result in slowly developing, insidious, non-specific complains delaying accurate diagnosis, with a third group remaining symptomless and recognised only incidentally. Therefore, it is a challenge to accurately determine the prevalence and incidence of pituitary adenomas in the general population. The vast majority of pituitary adenomas occur sporadically, but familial cases are now increasingly recognised. Hereditary predisposition, somatic mutations and endocrine factors were shown to have a pathophysiologic role in the initiation and progression of pituitary adenomas, which interestingly almost always remain benign. Here, we summarize the available epidemiological data and the known pathogenesis of the pituitary adenomas.

The molecular mechanisms leading to aryl hydrocarbon receptor interacting protein ( AIP ) mutation-induced aggressive, young-onset growth hormone-secreting pituitary tumors are not fully understood. In this study, we have identified that AIP -mutation-positive tumors are infiltrated by a large number of macrophages compared to sporadic tumors. Tissue from pituitary-specific Aip -knockout ( Aip Flox/Flox ;Hesx1 Cre/+ ) mice recapitulated this phenotype. Our human pituitary tumor transcriptome data revealed the “epithelial-to-mesenchymal transition (EMT) pathway” as one of the most significantly altered pathways in AIP pos tumors. Our in vitro data suggest that bone marrow-derived macrophage-conditioned media induces more prominent EMT-like phenotype and enhanced migratory and invasive properties in Aip -knockdown somatomammotroph cells compared to non-targeting controls. We identified that tumor-derived cytokine CCL5 is upregulated in AIP -mutation-positive human adenomas. Aip -knockdown GH3 cell-conditioned media increases macrophage migration, which is inhibited by the CCL5/CCR5 antagonist maraviroc. Our results suggest that a crosstalk between the tumor and its microenvironment plays a key role in the invasive nature of AIP -mutation-positive tumors and the CCL5/CCR5 pathway is a novel potential therapeutic target.

Growth hormone (GH)-secreting pituitary tumours represent the most genetically determined pituitary tumour type. This is true both for germline and somatic mutations. Germline mutations occur in several known genes (AIP, PRKAR1A, GPR101, GNAS, MEN1, CDKN1B, SDHx, MAX) as well as familial cases with currently unknown genes, while somatic mutations in GNAS are present in up to 40% of tumours. If the disease starts before the fusion of the epiphysis, then accelerated growth and increased final height, or gigantism, can develop, where a genetic background can be identified in half of the cases. Hereditary GH-secreting pituitary adenoma (PA) can manifest as isolated tumours, familial isolated pituitary adenoma (FIPA) including cases with AIP mutations or GPR101 duplications (X-linked acrogigantism, XLAG) or can be a part of systemic diseases like multiple endocrine neoplasia type 1 or type 4, McCune–Albright syndrome, Carney complex or phaeochromocytoma/paraganglioma-pituitary adenoma association. Family history and a search for associated syndromic manifestations can help to draw attention to genetic causes; many of these are now tested as part of gene panels. Identifying genetic mutations allows appropriate screening of associated comorbidities as well as finding affected family members before the clinical manifestation of the disease. This review focuses on germline and somatic mutations predisposing to acromegaly and gigantism.

Non-tumoural cells within the tumour microenvironment (TME) influence tumour proliferation, invasiveness and angiogenesis. Little is known about TME in pituitary neuroendocrine tumours (PitNETs). We aimed to characterise the role of TME in the aggressive behaviour of PitNETs, focusing on immune cells and cytokines. The cytokine secretome of 16 clinically non-functioning PitNETs (NF-PitNETs) and 8 somatotropinomas was assessed in primary culture using an immunoassay panel with 42 cytokines. This was correlated with macrophage (CD68, HLA-DR, CD163), T-lymphocyte (CD8, CD4, FOXP3), B-lymphocyte (CD20), neutrophil (neutrophil elastase) and endothelial cells (CD31) content, compared to normal pituitaries (NPs, n  = 5). In vitro tumour–macrophage interactions were assessed by conditioned medium (CM) of GH3 (pituitary tumour) and RAW264.7 (macrophage) cell lines on morphology, migration/invasion, epithelial-to-mesenchymal transition and cytokine secretion. IL-8, CCL2, CCL3, CCL4, CXCL10, CCL22 and CXCL1 are the main PitNET-derived cytokines. PitNETs with increased macrophage and neutrophil content had higher IL-8, CCL2, CCL3, CCL4 and CXCL1 levels. CD8+ T-lymphocytes were associated to higher CCL2, CCL4 and VEGF-A levels. PitNETs had more macrophages than NPs ( p  < 0.001), with a 3-fold increased CD163:HLA-DR macrophage ratio. PitNETs contained more CD4+ T-lymphocytes ( p  = 0.005), but fewer neutrophils ( p  = 0.047) with a 2-fold decreased CD8:CD4 ratio. NF-PitNETs secreted more cytokines and had 9 times more neutrophils than somatotropinomas ( p  = 0.002). PitNETs with higher Ki-67 had more FOXP3+ T cells, as well as lower CD68:FOXP3, CD8:CD4 and CD8:FOXP3 ratios. PitNETs with “deleterious immune phenotype” (CD68 hi CD4 hi FOXP3 hi CD20 hi ) had a Ki-67 ≥ 3%. CD163:HLA-DR macrophage ratio was positively correlated with microvessel density ( p  = 0.015) and area ( p  < 0.001). GH3 cell-CM increased macrophage chemotaxis, while macrophage-CM changed morphology, invasion, epithelial-to-mesenchymal transition and secreted cytokines of GH3 cells. PitNETs are characterised by increased CD163:HLA-DR macrophage and reduced CD8:CD4 and CD8:FOXP3 T cell ratios. PitNET-derived chemokines facilitate macrophage, neutrophil and T cell recruitment into the tumours which can determine aggressive behaviour.