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1.
Neuroendocrinology ; 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31940630

RESUMO

INTRODUCTION: Pituitary neuroendocrine tumors (PitNETs), the most abundant of all intracranial tumors, entail severe comorbidities. First-line therapy is transsphenoidal surgery, but subsequent pharmacological therapy is often required. Unfortunately, many patients are/become unresponsive to available drugs [somatostatin analogues (SSAs)/dopamine agonists], underscoring the need for new therapies. Statins are well-known drugs commonly prescribed to treat hyperlipidemia/cardiovascular diseases, but can convey additional beneficial effects, including antitumor actions. The direct effects of statins on normal human pituitary or PitNETs are poorly known. Thus, we aimed to explore the direct effects of statins, especially simvastatin, on key functional parameters in normal and tumoral pituitary cells, and to evaluate the combined effects of simvastatin with metformin or SSAs. METHODS: Effects of statins in cell proliferation/viability, hormone secretion, and signaling pathways were evaluated in normal pituitary cells from a primate model (Papio anubis), tumor cells from corticotropinomas, somatotropinomas, non-functioning pituitary-tumors (NFPTs), and PitNET cell-lines (AtT20/GH3-cells). RESULTS: All statins decreased AtT20-cell proliferation, simvastatin showing stronger effects. Indeed, simvastatin reduced cell viability and/or hormone secretion in all PitNETs subtypes and cell-lines, and ACTH/GH/PRL/FSH/LH secretion (but not expression), in primate cell cultures, by modulating MAPK/PI3K/mTOR pathways and expression of key receptors (GHRH-R/ghrelin-R/Kiss1-R) regulating pituitary function. Addition of MF or SSAs did not enhance simvastatin antitumor effects. CONCLUSION: Our data reveal direct antitumor effects of simvastatin on PitNET-cells, paving the way to explore these compounds as a possible tool to treat PitNETs.

2.
EBioMedicine ; 51: 102547, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31902674

RESUMO

BACKGROUND: Dysregulation of splicing variants (SVs) expression has recently emerged as a novel cancer hallmark. Although the generation of aberrant SVs (e.g. AR-v7/sst5TMD4/etc.) is associated to prostate-cancer (PCa) aggressiveness and/or castration-resistant PCa (CRPC) development, whether the molecular reason behind such phenomena might be linked to a dysregulation of the cellular machinery responsible for the splicing process [spliceosome-components (SCs) and splicing-factors (SFs)] has not been yet explored. METHODS: Expression levels of 43 key SCs and SFs were measured in two cohorts of PCa-samples: 1) Clinically-localized formalin-fixed paraffin-embedded PCa-samples (n = 84), and 2) highly-aggressive freshly-obtained PCa-samples (n = 42). FINDINGS: A profound dysregulation in the expression of multiple components of the splicing machinery (i.e. 7 SCs/19 SFs) were found in PCa compared to their non-tumor adjacent-regions. Notably, overexpression of SNRNP200, SRSF3 and SRRM1 (mRNA and/or protein) were associated with relevant clinical (e.g. Gleason score, T-Stage, metastasis, biochemical recurrence, etc.) and molecular (e.g. AR-v7 expression) parameters of aggressiveness in PCa-samples. Functional (cell-proliferation/migration) and mechanistic [gene-expression (qPCR) and protein-levels (western-blot)] assays were performed in normal prostate cells (PNT2) and PCa-cells (LNCaP/22Rv1/PC-3/DU145 cell-lines) in response to SNRNP200, SRSF3 and/or SRRM1 silencing (using specific siRNAs) revealed an overall decrease in proliferation/migration-rate in PCa-cells through the modulation of key oncogenic SVs expression levels (e.g. AR-v7/PKM2/XBP1s) and alteration of oncogenic signaling pathways (e.g. p-AKT/p-JNK). INTERPRETATION: These results demonstrate that the spliceosome is drastically altered in PCa wherein SNRNP200, SRSF3 and SRRM1 could represent attractive novel diagnostic/prognostic and therapeutic targets for PCa and CRPC.

3.
Neuroendocrinology ; 110(1-2): 70-82, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31272096

RESUMO

BACKGROUND: Pituitary neuroendocrine tumors (PitNETs) represent approximately 15% of all intracranial tumors and usually are associated with severe comorbidities. Unfortunately, a relevant number of patients do not respond to currently available pharmacological treatments, that is, somatostatin analogs (SSAs) or dopamine-agonists (DA). Thus, novel, chimeric somatostatin/dopamine compounds (dopastatins) that could improve medical treatment of PitNETs have been designed. OBJECTIVE: This study aims to determine the direct therapeutic effects of a new-generation dopastatin, BIM-065, on primary cell cultures from different PitNETs subtypes. METHODS: Thirty-one PitNET-derived cell cultures (9 corticotropinomas, 9 somatotropinomas, 11 nonfunctioning pituitary adenomas [NFPAs], and 2 prolactinomas), were treated with BIM-065, and key functional endpoints were assessed (cell viability, apoptosis, hormone secretion, expression levels of key genes, free cytosolic [Ca2+]i dynamics, etc.). AtT-20 cell line was used to evaluate signaling pathways in response to BIM-065. RESULTS: This chimeric compound decreased cell viability in all corticotropinomas and somatotropinomas tested, but not in NFPAs. BIM-065 reduced ACTH, GH, chromogranin-A and PRL secretion, and increased apoptosis in corticotropinomas, somatotropinomas, and NFPAs. These effects were possibly mediated through modulation of pivotal signaling cascades like [Ca2+]i kinetic and Akt- or ERK1/2-phosphorylation. CONCLUSIONS: Our results unveil a robust antitumoral effect in vitro of the novel chimeric compound BIM-065 on the main PitNET subtypes, inform on the mechanisms involved, and suggest that BIM-065 could be an efficacious therapeutic option to be considered in the treatment of PitNETs.

4.
Endocrinol. diabetes nutr. (Ed. impr.) ; 66(10): 654-662, dic. 2019.
Artigo em Espanhol | IBECS | ID: ibc-184793

RESUMO

Las enfermedades endocrinas están experimentando un importante incremento de su prevalencia, debido a causas de diversa índole, entre ellas la epidemia de obesidad y de desnutrición, el envejecimiento de la población, pero también el efecto de los disruptores endocrinos, entre otros. Por otra parte, las nuevas tecnologías, tanto a nivel de analítica molecular y genética, de imagen y de nuevos dispositivos terapéuticos, obligan a que la comunidad profesional endocrina en España tenga que estar en constante formación. La conexión con los pacientes a través de sus asociaciones, cada vez más activas, y con la sociedad civil en general, el compromiso profesional y la demanda de diversos colectivos sociales de una atención moderna y equitativa, y a llevar a cabo investigación que facilite la consecución de avances para los pacientes, obligan al especialista en Endocrinología y Nutrición, y a la Sociedad Española de Endocrinología y Nutrición (SEEN), a posicionarse y dar respuesta a todos estos retos. En el presente documento, la SEEN expone sus propuestas y su estrategia hasta el 2022


Endocrine diseases are experiencing an important increase in their prevalence, due to causes of various kinds, including the epidemic of obesity and malnutrition, the aging of the population, but also the effect of endocrine disruptors, among others. On the other hand, new technologies, both in terms of molecular and genetic analysis, image and new therapeutic devices, require that the endocrine professional community in Spain must be in constant training. The connection with patients through their associations, increasingly active, and with the civil society in general, the professional commitment and demand of various social groups for a modern and equitable care, and to carry out research that facilitates the achievement of advances for patients, forces the specialist in endocrinology and nutrition and the Spanish Society of Endocrinology and Nutrition (SEEN) to position themselves and respond to all these challenges. In this document, the SEEN presents its proposals and its strategy until 2022


Assuntos
Endocrinologia/organização & administração , Sociedades Médicas/organização & administração , Sociedades Médicas/tendências , Estratégias , Endocrinologia/tendências , Sistemas Nacionais de Saúde , Medicina/organização & administração , Promoção da Saúde , Espanha
5.
J Clin Med ; 8(12)2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31766715

RESUMO

Recent data suggested that plasma Ghrelin O-Acyl Transferase enzyme (GOAT) levels could represent a new diagnostic biomarker for prostate cancer (PCa). In this study, we aimed to explore the diagnostic and prognostic/aggressiveness capacity of GOAT in urine, as well as to interrogate its putative pathophysiological role in PCa. We analysed urine/plasma levels of GOAT in a cohort of 993 patients. In vitro (i.e., cell-proliferation) and in vivo (tumor-growth in a xenograft-model) approaches were performed in response to the modulation of GOAT expression/activity in PCa cells. Our results demonstrate that plasma and urine GOAT levels were significantly elevated in PCa patients compared to controls. Remarkably, GOAT significantly outperformed PSA in the diagnosis of PCa and significant PCa in patients with PSA levels ranging from 3 to 10 ng/mL (the so-called PSA grey-zone). Additionally, urine GOAT levels were associated to clinical (e.g., Gleason-score, PSA levels) and molecular (e.g., CDK2/CDK6/CDKN2A expression) aggressiveness parameters. Indeed, GOAT overexpression increased, while its silencing/blockade decreased cell-proliferation in PCa cells. Moreover, xenograft tumors derived from GOAT-overexpressing PCa (DU145) cells were significantly higher than those derived from the mock-overexpressing cells. Altogether, our results demonstrate that GOAT could be used as a diagnostic and aggressiveness marker in urine and a therapeutic target in PCa.

6.
Clin Cancer Res ; 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31624102

RESUMO

PURPOSE: Somatostatin analogues (SSA) are efficacious and safe treatments for a variety of neuroendocrine tumors, especially pituitary neuroendocrine tumors (PitNET). Their therapeutic effects are mainly mediated by somatostatin receptors SST2 and SST5. Most SSAs, such as octreotide/lanreotide/pasireotide, are either nonselective or activate mainly SST2. However, nonfunctioning pituitary tumors (NFPTs), the most common PitNET type, mainly express SST3 and finding peptides that activate this particular somatostatin receptor has been very challenging. Therefore, the main objective of this study was to identify SST3-agonists and characterize their effects on experimental NFPT models. EXPERIMENTAL DESIGN: Binding to SSTs and cAMP level determinations were used to screen a peptide library and identify SST3-agonists. Key functional parameters (cell viability/caspase activity/chromogranin-A secretion/mRNA expression/intracellular signaling pathways) were assessed on NFPT primary cell cultures in response to SST3-agonists. Tumor growth was assessed in a preclinical PitNET mouse model treated with a SST3-agonist. RESULTS: We successfully identified the first SST3-agonist peptides. SST3-agonists lowered cell viability and chromogranin-A secretion, increased apoptosis in vitro, and reduced tumor growth in a preclinical PitNET model. As expected, inhibition of cell viability in response to SST3-agonists defined two NFPT populations: responsive and unresponsive, wherein responsive NFPTs expressed more SST3 than unresponsive NFPTs and exhibited a profound reduction of MAPK, PI3K-AKT/mTOR, and JAK/STAT signaling pathways upon SST3-agonist treatments. Concurrently, SSTR3 silencing increased cell viability in a subset of NFPTs. CONCLUSIONS: This study demonstrates that SST3-agonists activate signaling mechanisms that reduce NFPT cell viability and inhibit pituitary tumor growth in experimental models that expresses SST3, suggesting that targeting this receptor could be an efficacious treatment for NFPTs.

7.
Cancers (Basel) ; 11(10)2019 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-31561558

RESUMO

Pituitary neuroendocrine tumors (PitNETs) constitute approximately 15% of all brain tumors, and most have a sporadic origin. Recent studies suggest that altered alternative splicing and, consequently, appearance of aberrant splicing variants, is a common feature of most tumor pathologies. Moreover, spliceosome is considered an attractive therapeutic target in tumor pathologies, and the inhibition of SF3B1 (e.g., using pladienolide-B) has been shown to exert antitumor effects. Therefore, we aimed to analyze the expression levels of selected splicing-machinery components in 261 PitNETs (somatotropinomas/non-functioning PitNETS/corticotropinomas/prolactinomas) and evaluated the direct effects of pladienolide-B in cell proliferation/viability/hormone secretion in human PitNETs cell cultures and pituitary cell lines (AtT-20/GH3). Results revealed a severe dysregulation of splicing-machinery components in all the PitNET subtypes compared to normal pituitaries and a unique fingerprint of splicing-machinery components that accurately discriminate between normal and tumor tissue in each PitNET subtype. Moreover, expression of specific components was associated with key clinical parameters. Interestingly, certain components were commonly dysregulated throughout all PitNET subtypes. Finally, pladienolide-B reduced cell proliferation/viability/hormone secretion in PitNET cell cultures and cell lines. Altogether, our data demonstrate a drastic dysregulation of the splicing-machinery in PitNETs that might be associated to their tumorigenesis, paving the way to explore the use of specific splicing-machinery components as novel diagnostic/prognostic and therapeutic targets in PitNETs.

8.
J Clin Med ; 8(9)2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31500112

RESUMO

Engrailed variant-2 (EN2) has been suggested as a potential diagnostic biomarker; however, its presence and functional role in prostate cancer (PCa) cells is still controversial or unknown. Here, we analyzed 1) the expression/secretion profile of EN2 in five independent samples cohorts from PCa patients and controls (prostate tissues and/or urine) to determine its utility as a PCa biomarker; and 2) the functional role of EN2 in normal (RWPE1) and tumor (LNCaP/22Rv1/PC3) prostate cells to explore its potential value as therapeutic target. EN2 was overexpressed in our two cohorts of PCa tissues compared to control and in tumor cell lines compared with normal-like prostate cells. This profile was corroborated in silico in three independent data sets [The Cancer Genome Atlas(TCGA)/Memorial Sloan Kettering Cancer Center (MSKCC)/Grasso]. Consistently, urine EN2 levels were elevated and enabled discrimination between PCa and control patients. EN2 treatment increased cell proliferation in LNCaP/22Rv1/PC3 cells, migration in RWPE1/PC3 cells, and PSA secretion in LNCaP cells. These effects were associated, at least in the androgen-sensitive LNCaP cells, with increased AKT and androgen-receptor phosphorylation levels and with modulation of key cancer-associated genes. Consistently, EN2 treatment also regulated androgen-receptor activity (full-length and splicing variants) in androgen-sensitive 22Rv1 cells. Altogether, this study demonstrates the potential utility of EN2 as a non-invasive diagnostic biomarker for PCa and provides novel and valuable information to further investigate its putative utility to develop new therapeutic tools in PCa.

9.
Endocrinol Diabetes Nutr ; 66(10): 654-662, 2019 Dec.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31272927

RESUMO

Endocrine diseases are experiencing an important increase in their prevalence, due to causes of various kinds, including the epidemic of obesity and malnutrition, the aging of the population, but also the effect of endocrine disruptors, among others. On the other hand, new technologies, both in terms of molecular and genetic analysis, image and new therapeutic devices, require that the endocrine professional community in Spain must be in constant training. The connection with patients through their associations, increasingly active, and with the civil society in general, the professional commitment and demand of various social groups for a modern and equitable care, and to carry out research that facilitates the achievement of advances for patients, forces the specialist in endocrinology and nutrition and the Spanish Society of Endocrinology and Nutrition (SEEN) to position themselves and respond to all these challenges. In this document, the SEEN presents its proposals and its strategy until 2022.

10.
Neuroendocrinology ; 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31319410

RESUMO


Serotonin, a biologically active amine, is related to carcinoid syndrome in functioning neuroendocrine tumors (NETs). Telotristat ethyl is a novel inhibitor of the tryptophan hydroxylase (TPH), a key enzyme in the production of serotonin. While its use in patients with carcinoid syndrome and uncontrolled diarrhea under somatostatin analogs (SSAs) has been recently approved, in vitro data evaluating it effectiveness are lacking. For this reason, we aimed to evaluate the effect of telotristat as monotherapy, and in combination with SSAs, on proliferation and secretion in a NET cell line model. The human pancreatic NET cell lines BON-1/QGP-1 were used as 2D and 3D cultured models; somatostatin receptor and TPH mRNA expression, as well as the potential autocrine effect of serotonin on tumor cell proliferation using a 3D culture system were evaluated. Telotristat decreased serotonin production in a dose-dependent manner at a clinically feasible concentration, without affecting cell proliferation. Its combination with pasireotide, but not with octreotide, had an additive inhibitory effect on serotonin secretion. The effect of telotristat was slightly less potent, when BON-1 cells were co-treated with octreotide. Octreotide and pasireotide had no effect on the expression of TPH. Telotristat did not have an effect on mRNA expression of somatostatin receptor subtypes. Finally, we showed that serotonin did not have an autocrine effect on NET cell proliferation on the 3D cell model. These results suggest that telotristat is an effective drug for serotonin inhibition, but the effectiveness of its combination with SST2-preferring SSA should be evaluated in more detail.
.

11.
Transl Res ; 212: 89-103, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31344348

RESUMO

Prostate cancer (PCa) is one of the most common cancers types among men. Development and progression of PCa is associated with aberrant expression of oncogenic splicing-variants (eg, AR-v7), suggesting that dysregulation of the splicing process might represent a potential actionable target for PCa. Expression levels (mRNA and protein) of SF3B1, one of the main components of the splicing machinery, were analyzed in different cohorts of PCa patients (clinically localized [n = 84], highly aggressive PCa [n = 42], and TCGA dataset [n = 497]). Functional and mechanistic assays were performed in response to pladienolide-B in nontumor and tumor-derived prostate cells. Our results revealed that SF3B1 was overexpressed in PCa tissues and its levels were associated with clinically relevant PCa-aggressive features (eg, metastasis/AR-v7 expression). Moreover, inhibition of SF3B1 activity by pladienolide-B reduced functional parameters of aggressiveness (proliferation/migration/tumorspheres-formation/apoptosis) in PCa cell lines, irrespective of AR-v7 expression, and reduced viability of primary PCa cells. Antitumor actions of pladienolide-B involved: (1) inhibition of PI3K/AKT and JNK signaling pathways, (2) modulation of tumor markers and splicing variants (AR-v7/In1-ghrelin), and (3) regulation of key components of mRNA homeostasis-associated machineries (spliceosome/SURF/EJC). Altogether, our results demonstrated that SF3B1 is overexpressed and associated with malignant features in PCa, and its inhibition reduces PCa aggressiveness, suggesting that SF3B1 could represent a novel prognostic biomarker and a therapeutic target in PCa.

12.
Horm Cancer ; 10(2-3): 107-119, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31102172

RESUMO

Prolonged remission of hypercortisolism with steroidogenesis inhibitors has been described in patients with ectopic adrenocorticotropic hormone (ACTH) syndrome. The anti-proliferative and pro-apoptotic effect of ketoconazole in human cancer cells was previously suggested. The aim of this study was to explore the effects of ketoconazole on ACTH-producing and non-ACTH-producing neuroendocrine tumor (NET) cell lines. The effects of ketoconazole alone, and in combination with somatostatin analogs, were evaluated in two human cell lines: DMS-79 (ectopic ACTH-producing small cell lung carcinoma) and BON-1 (human pancreatic NET). Total DNA measurement, apoptosis, cell cycle, chromogranin A (CgA)/proopiomelanocortin (POMC) expression by qRT-PCR, serotonin, CgA, and ACTH secretion assays were performed. In both cell lines, ketoconazole significantly suppressed cell growth and colony formation in a dose and time-dependent manner. The effect in DMS-79 was primarily cytotoxic, while it was more apoptotic in BON-1 cells. Ketoconazole also induced increase in G0/G1 phase in both cell lines and arrest in phase G2/M of BON-1 cells. Ketoconazole did not affect the secretion of serotonin, CgA, ACTH, or the mRNA expression of CgA and POMC. Decreased serotonin secretion was observed after the combination treatment with pasireotide. These results suggest a direct effect of ketoconazole on cell proliferation, apoptosis, and cell cycle in both ACTH- and non-ACTH-producing NET cells.

13.
J Clin Endocrinol Metab ; 104(8): 3501-3513, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30860580

RESUMO

CONTEXT: Pituitary neuroendocrine tumors (PitNETs) are a commonly underestimated pathology in terms of incidence and associated morbimortality. Currently, an appreciable subset of patients are resistant or poorly responsive to the main current medical treatments [i.e., synthetic somatostatin analogs (SSAs) and dopamine agonists]. Thus, development and optimization of novel and available medical therapies is necessary. Biguanides (metformin, buformin, and phenformin) are antidiabetic drugs that exert antitumoral actions in several tumor types, but their pharmacological effects on PitNETs are poorly known. OBJECTIVE: We aimed to explore the direct effects of biguanides on key functions (cell viability, hormone release, apoptosis, and signaling pathways) in primary cell cultures from human PitNETs and cell lines. Additionally, we evaluated the effect of combined metformin with SSAs on cell viability and hormone secretion. DESIGN: A total of 13 corticotropinomas, 13 somatotropinomas, 13 nonfunctioning PitNETs, 3 prolactinomas, and 2 tumoral pituitary cell lines (AtT-20 and GH3) were used to evaluate the direct effects of biguanides on cell viability, hormone release, apoptosis, and signaling pathways. RESULTS: Biguanides reduced cell viability in all PitNETs and cell lines (with phenformin being the most effective biguanide) and increased apoptosis in somatotropinomas. Moreover, buformin and phenformin, but not metformin, reduced hormone secretion in a cell type-specific manner. Combination metformin/SSA therapy did not increase SSA monotherapy effectiveness. Effects of biguanides on PitNETs could involve the modulation of AMP-activated protein kinase-dependent ([Ca2+]i, PI3K/Akt) and independent (MAPK) mechanisms. CONCLUSION: Altogether, our data unveil clear antitumoral effects of biguanides on PitNET cells, opening avenues to explore their potential as drugs to treat these pathologies.

14.
J Clin Endocrinol Metab ; 104(8): 3389-3402, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30901032

RESUMO

CONTEXT: Nonalcoholic fatty liver disease (NAFLD) is a common obesity-associated pathology characterized by hepatic fat accumulation, which can progress to fibrosis, cirrhosis, and hepatocellular carcinoma. Obesity is associated with profound changes in gene-expression patterns of the liver, which could contribute to the onset of comorbidities. OBJECTIVE: As these alterations might be linked to a dysregulation of the splicing process, we aimed to determine whether the dysregulation in the expression of splicing machinery components could be associated with NAFLD. PARTICIPANTS: We collected 41 liver biopsies from nonalcoholic individuals with obesity, with or without hepatic steatosis, who underwent bariatric surgery. INTERVENTIONS: The expression pattern of splicing machinery components was determined using a microfluidic quantitative PCR-based array. An in vitro approximation to determine lipid accumulation using HepG2 cells was also implemented. RESULTS: The liver of patients with obesity and steatosis exhibited a severe dysregulation of certain splicing machinery components compared with patients with obesity without steatosis. Nonsupervised clustering analysis allowed the identification of three molecular phenotypes of NAFLD with a unique fingerprint of alterations in splicing machinery components, which also presented distinctive hepatic and clinical-metabolic alterations and a differential response to bariatric surgery after 1 year. In addition, in vitro silencing of certain splicing machinery components (i.e., PTBP1, RBM45, SND1) reduced fat accumulation and modulated the expression of key de novo lipogenesis enzymes, whereas conversely, fat accumulation did not alter spliceosome components expression. CONCLUSION: There is a close relationship between splicing machinery dysregulation and NAFLD development, which should be further investigated to identify alternative therapeutic targets.

15.
J Cell Mol Med ; 23(5): 3088-3096, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30843342

RESUMO

Acromegaly is a rare disease resulting from hypersecretion of growth hormone (GH) and insulin-like growth factor 1 (IGF1) typically caused by pituitary adenomas, which is associated with increased mortality and morbidity. Somatostatin analogues (SSAs) represent the primary medical therapy for acromegaly and are currently used as first-line treatment or as second-line therapy after unsuccessful pituitary surgery. However, a considerable proportion of patients do not adequately respond to SSAs treatment, and therefore, there is an urgent need to identify biomarkers predictors of response to SSAs. The aim of this study was to examine E-cadherin expression by immunohistochemistry in fifty-five GH-producing pituitary tumours and determine the potential association with response to SSAs as well as other clinical and histopathological features. Acromegaly patients with tumours expressing low E-cadherin levels exhibit a worse response to SSAs. E-cadherin levels are associated with GH-producing tumour histological subtypes. Our results indicate that the immunohistochemical detection of E-cadherin might be useful in categorizing acromegaly patients based on the response to SSAs.

16.
Minerva Endocrinol ; 44(2): 109-128, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30650942

RESUMO

Acromegaly is a chronic systemic disease mainly caused by a growth hormone (GH)-secreting pituitary neuroendocrine tumor (PitNETs), which is associated with many health complications and increased mortality when not adequately treated. Transsphenoidal surgery is considered the treatment of choice in GH-secreting PitNETs, but patients in whom surgery cannot be considered or with persistent disease after surgery require medical therapy. Treatment with available synthetic somatostatin analogues (SSAs) is considered the mainstay in the medical management of acromegaly which exert their beneficial effects through the binding to a family of G-protein coupled receptors encoded by 5 genes (SSTR1-5). However, although it has been demonstrated that the SST1-5 receptors are physically present in tumor cells, SSAs are in many cases ineffective (i.e. approximately 10-30% of patients with GH-secreting PitNET are unresponsive to SSAs), suggesting that other cellular/molecular determinants could be essential for the response to the pharmacological treatment in patients with GH-secreting PitNETs. Therefore, the scrutiny of these determinants might be used for the identification of subgroups of patients in whom an appropriate pharmacological treatment can be successfully employed (responders vs. non-responders). In this review, we will describe some of the existing, classical and novel, genetic and molecular determinants involved in the response of patients with GH-secreting PitNETs to the available therapeutic treatments, as well as new molecular/therapeutic approaches that could be potentially useful for the treatment of GH-secreting PitNETs.


Assuntos
Acromegalia/tratamento farmacológico , Acromegalia/genética , Adenoma/tratamento farmacológico , Adenoma/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Humanos , Neoplasias Hipofisárias/complicações
17.
Endocr Relat Cancer ; 26(3): R157-R179, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30615596

RESUMO

Some biomarkers for functioning and non-functioning neuroendocrine neoplasms (NENs) are currently available. Despite their application in clinical practice, results should be interpreted cautiously. Considering the variable sensitivity and specificity of these parameters, there is an unmet need for novel biomarkers to improve diagnosis and predict patient outcome. Nowadays, several new biomarkers are being evaluated and may become future tools for the management of NENs. These biomarkers include (1) peptides and growth factors; (2) DNA and RNA markers based on genomics analysis, for example, the so-called NET test, which has been developed for analyzing gene transcripts in circulating blood; (3) circulating tumor/endothelial/progenitor cells or cell-free tumor DNA, which represent minimally invasive methods that would provide additional information for monitoring treatment response and (4) improved imaging techniques with novel radiolabeled somatostatin analogs or peptides. Below we summarize some future directions in the development of novel diagnostic and predictive/prognostic biomarkers in NENs. This review is focused on circulating and selected tissue markers.

18.
J Clin Endocrinol Metab ; 104(1): 57-73, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30265346

RESUMO

Context: Biguanides and statins exert beneficial effects on various cancer types. Their precise effects and underlying molecular mechanisms are poorly understood. Materials and Methods: We analyzed the relationship between metabolic syndrome and histological, epidemiological, and prognosis variables in two cohorts of patients with neuroendocrine tumors (NETs): those with lung carcinoids (LCs; n = 81) and those with gastroenteropancreatic NET (GEP-NET; n = 100). Biguanide and statin antitumor effects were investigated by evaluating proliferation, migration, secretion, gene expression, and involved molecular pathways in BON1/QGP1 cell cultures. Results: Pleura invasion was higher (LCs group; P < 0.05) and tumor diameter tended to be increased (GEP-NET group) in patients with type 2 diabetes (T2DM) than in those without. Somatostatin and ghrelin systems mRNA levels differed in tumor tissue of patients with T2DM taking metformin or not. Biguanides decreased proliferation rate in BON1/QGP1 cells; the effects of statins on proliferation rate depended on the statin and cell types, and time. Specifically, only simvastatin and atorvastatin decreased proliferation in BON1 cells, whereas all statins decreased proliferation rate in QGP1 cells. Metformin and simvastatin decreased migration capacity in BON1 cells; biguanides decreased serotonin secretion in BON1 cells. Phenformin increased apoptosis in BON1/QGP1 cells; simvastatin increased apoptosis in QGP1 cells. These antitumor effects likely involved altered expression of key genes related to cancer aggressiveness. Conclusion: A clear inhibitory effect of biguanides and statins was seen on NET-cell aggressiveness. Our results invite additional exploration of the potential therapeutic role of these drugs in treatment of patients with NETs.


Assuntos
Biguanidas/uso terapêutico , Diabetes Mellitus Tipo 2/etiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Tumores Neuroendócrinos/complicações , Adulto , Idoso , Apoptose/efeitos dos fármacos , Tumor Carcinoide/tratamento farmacológico , Tumor Carcinoide/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Neoplasias Intestinais/tratamento farmacológico , Neoplasias Intestinais/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Masculino , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pleurais/patologia , Neoplasias Pleurais/secundário , Prognóstico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo
19.
Drugs ; 79(1): 21-42, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30560479

RESUMO

Neuroendocrine tumors (NETs) originate from the neuroendocrine cell system in the bronchial and gastrointestinal tract and can produce hormones leading to distinct clinical syndromes. Systemic treatment of patients with unresectable NETs aims to control symptoms related to hormonal overproduction and tumor growth. In the last decades prognosis has improved as a result of increased detection of early stage disease and the introduction of somatostatin analogs (SSAs) as well as several new therapeutic options. SSAs are the first-line medical treatment of NETs and can control hormonal production and tumor growth. The development of next-generation multireceptor targeted and radiolabelled somatostatin analogs, as well as target-directed therapies (as second-line treatment options) further improve progression-free survival in NET patients. To date, however, a significant prolongation of overall survival with systemic treatment in NET has not been convincingly demonstrated. Several new medical options and treatment combinations will become available in the upcoming years, and although preliminary results of preclinical and clinical trials are encouraging, large, preferrably randomized clinical studies are required to provide definitive evidence of their effect on survival and symptom control.


Assuntos
Antineoplásicos , Tumores Neuroendócrinos/tratamento farmacológico , Somatostatina , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Terapia Combinada , Humanos , Terapia de Alvo Molecular/tendências , Tumores Neuroendócrinos/radioterapia , Intervalo Livre de Progressão , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico
20.
EBioMedicine ; 37: 356-365, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30446432

RESUMO

BACKGROUND: Type-2 diabetes mellitus (T2DM) is a major health problem with increasing incidence, which severely impacts cardiovascular disease. Because T2DM is associated with altered gene expression and aberrant splicing, we hypothesized that dysregulations in splicing machinery could precede, contribute to, and predict T2DM development. METHODS: A cohort of patients with cardiovascular disease (CORDIOPREV study) and without T2DM at baseline (at the inclusion of the study) was used (n = 215). We determined the expression of selected splicing machinery components in fasting and 4 h-postprandial peripheral blood mononuclear cells (PBMCs, obtained at baseline) from all the patients who developed T2DM during 5-years of follow-up (n = 107 incident-T2DM cases) and 108 randomly selected non-T2DM patients (controls). Serum from incident-T2DM and control patients was used to analyze in vitro the modulation of splicing machinery expression in control PBMCs from an independent cohort of healthy subjects. FINDINGS: Expression of key splicing machinery components (e.g. RNU2, RNU4 or RNU12) from fasting and 4 h-postprandial PBMCs of incident-T2DM patients was markedly altered compared to non-T2DM controls. Moreover, in vitro treatment of healthy individuals PBMCs with serum from incident-T2DM patients (compared to non-T2DM controls) reduced the expression of splicing machinery elements found down-regulated in incident-T2DM patients PBMCs. Finally, fasting/postprandial levels of several splicing machinery components in the PBMCs of CORDIOPREV patients were associated to higher risk of T2DM (Odds Ratio > 4) and could accurately predict (AUC > 0.85) T2DM development. INTERPRETATION: Our results reveal the existence of splicing machinery alterations that precede and predict T2DM development in patients with cardiovascular disease. FUND: ISCIII, MINECO, CIBERObn.


Assuntos
Doenças Cardiovasculares/sangue , Diabetes Mellitus Tipo 2/sangue , Leucócitos Mononucleares/metabolismo , Processamento de RNA , Biomarcadores/sangue , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/patologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Leucócitos Mononucleares/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes
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