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Botelho L, Dezonne RS, Wildemberg LE, Miranda RL, Gadelha MR, Andreiuolo F. Somatostatin receptors in pituitary somatotroph adenomas as predictors of response to somatostatin receptor ligands: A pathologist's perspective. Brain Pathol 2025; 35:e13313. [PMID: 39473262 DOI: 10.1111/bpa.13313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Accepted: 10/04/2024] [Indexed: 12/28/2024] Open
Abstract
There are five subtypes of somatostatin receptors (SST1-5), which are expressed in several types of solid neoplasms, neuroendocrine tumors, and pituitary adenomas. Most commonly, SST2 and SST5, are of interest regarding diagnostic, treatment, and prognostic purposes. In this article the basic biological characteristics of SST are briefly reviewed, and focus given to the immunohistochemical evaluation of SST2 and SST5 in growth hormone (GH)-secreting pituitary tumors, and their quantification as predictors of response to treatment with somatostatin receptor ligands (SRL), the mainstay of the pharmacological therapy available for these tumors. Although many different scoring systems for SST2 immunohistochemistry showing correlation with SRL response have been reported, among which the immunoreactivity score (IRS) has been the most consistently used, a universally validated immunohistochemical technique and scoring scheme is lacking. Efforts should be made on collaborative multicenter studies aiming at validating homogeneous immunostaining protocols and a scoring system for SST2 and SST5 expression, to help clinicians to define the optimal therapeutic strategy for the patients with somatotroph tumors.
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Affiliation(s)
- Laura Botelho
- Neuropathology and Molecular Genetics Laboratory, Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil
- Department of Pathology, Rede D'Or, Rio de Janeiro, Brazil
| | - Rômulo Sperduto Dezonne
- Neuropathology and Molecular Genetics Laboratory, Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil
| | - Luiz Eduardo Wildemberg
- Neuroendocrinology Research Center, Endocrinology Division, Medical School and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Neuroendocrinology Division, Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil
| | - Renan Lyra Miranda
- Neuropathology and Molecular Genetics Laboratory, Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil
| | - Mônica R Gadelha
- Neuropathology and Molecular Genetics Laboratory, Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil
- Neuroendocrinology Research Center, Endocrinology Division, Medical School and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Neuroendocrinology Division, Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil
| | - Felipe Andreiuolo
- Neuropathology and Molecular Genetics Laboratory, Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil
- Department of Pathology, Rede D'Or, Rio de Janeiro, Brazil
- D'Or Institute for Research and Education, Rio de Janeiro, Brazil
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Sampedro-Nuñez M, Herrera-Martínez AD, Ibáñez-Costa A, Rivero-Cortés E, Venegas E, Robledo M, Martínez-Hernández R, García-Martínez A, Gil J, Jordà M, López-Fernández J, Gavilán I, Maraver S, Marqués-Pamies M, Cámara R, Fajardo-Montañana C, Valassi E, Dios E, Aulinas A, Biagetti B, Álvarez Escola C, Araujo-Castro M, Blanco C, Paz DM, Villar-Taibo R, Álvarez CV, Gaztambide S, Webb SM, Castaño L, Bernabéu I, Picó A, Gálvez MÁ, Soto-Moreno A, Puig-Domingo M, Castaño JP, Marazuela M, Luque RM. Integrative clinical, hormonal, and molecular data associate with invasiveness in acromegaly: REMAH study. Eur J Endocrinol 2024; 190:421-433. [PMID: 38701338 DOI: 10.1093/ejendo/lvae045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 02/18/2024] [Accepted: 03/04/2024] [Indexed: 05/05/2024]
Abstract
INTRODUCTION Growth hormone (GH)-secreting pituitary tumors (GHomas) are the most common acromegaly cause. At diagnosis, most of them are macroadenomas, and up to 56% display cavernous sinus invasion. Biomarker assessment associated with tumor growth and invasion is important to optimize their management. OBJECTIVES The study aims to identify clinical/hormonal/molecular biomarkers associated with tumor size and invasiveness in GHomas and to analyze the influence of pre-treatment with somatostatin analogs (SSAs) or dopamine agonists (DAs) in key molecular biomarker expression. METHODS Clinical/analytical/radiological variables were evaluated in 192 patients from the REMAH study (ambispective multicenter post-surgery study of the Spanish Society of Endocrinology and Nutrition). The expression of somatostatin/ghrelin/dopamine system components and key pituitary/proliferation markers was evaluated in GHomas after the first surgery. Univariate/multivariate regression studies were performed to identify association between variables. RESULTS Eighty percent of patients harbor macroadenomas (63.8% with extrasellar growth). Associations between larger and more invasive GHomas with younger age, visual abnormalities, higher IGF1 levels, extrasellar/suprasellar growth, and/or cavernous sinus invasion were found. Higher GH1 and lower PRL/POMC/CGA/AVPR1B/DRD2T/DRD2L expression levels (P < .05) were associated with tumor invasiveness. Least Absolute Shrinkage and Selection Operator's penalized regression identified combinations of clinical and molecular features with areas under the curve between 0.67 and 0.82. Pre-operative therapy with DA or SSAs did not alter the expression of any of the markers analyzed except for DRD1/AVPR1B (up-regulated with DA) and FSHB/CRHR1 (down-regulated with SSAs). CONCLUSIONS A specific combination of clinical/analytical/molecular variables was found to be associated with tumor invasiveness and growth capacity in GHomas. Pre-treatment with first-line drugs for acromegaly did not significantly modify the expression of the most relevant biomarkers in our association model. These findings provide valuable insights for risk stratification and personalized management of GHomas.
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Affiliation(s)
- Miguel Sampedro-Nuñez
- Department of Endocrinology and Nutrition Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa, Universidad Autónoma de Madrid, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER GCV14/ER/12), Madrid, Spain
| | - Aura Dulcinea Herrera-Martínez
- Endocrinology and Nutrition Service, Reina Sofia University Hospital, Córboba, Spain
- Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córboba, Spain
| | - Alejandro Ibáñez-Costa
- Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córboba, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain
- Reina Sofia University Hospital, Córdoba, Spain
| | - Esther Rivero-Cortés
- Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córboba, Spain
- Reina Sofia University Hospital, Córdoba, Spain
| | - Eva Venegas
- Unidad de Gestión de Endocrinología y Nutrición, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío, Sevilla, Spain
| | - Mercedes Robledo
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Rebeca Martínez-Hernández
- Department of Endocrinology and Nutrition Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa, Universidad Autónoma de Madrid, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER GCV14/ER/12), Madrid, Spain
| | - Araceli García-Martínez
- Alicante General University Hospital-Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
| | - Joan Gil
- Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Department of Endocrinology and Nutrition, Barcelona, Spain
| | - Mireia Jordà
- Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Department of Endocrinology and Nutrition, Barcelona, Spain
| | - Judith López-Fernández
- Servicio de Endocrinología y Nutrición, Hospital Universitario de Canarias, La Laguna, Santa Cruz de Tenerife, Spain
| | - Inmaculada Gavilán
- Hospital Universitario Puerta del Mar de Cádiz, Department of Endocrinology, Cádiz, Spain
| | - Silvia Maraver
- Servicio de Endocrinología y Nutrición, Hospital Universitario Virgen de la Victoria, Málaga, Spain
| | | | - Rosa Cámara
- Hospital Universitari i Politecnic La Fe, Department of Endocrinology, Valencia, Spain
| | | | - Elena Valassi
- Hospital Universitari Germans Trias i Pujol, Department of Endocrinology and Nutrition, Barcelona, Spain
| | - Elena Dios
- Virgen del Rocio University Hospital, Department of Endocrinology, Sevilla, Spain
| | - Anna Aulinas
- Hospital de la Santa Creu i Sant Pau, Department of Endocrinology, IIB-Sant Pau, CIBER de Enfermedades Raras (CIBER-ER), University of Vic-Central University of Catalonia, Barcelona, Spain
| | - Betina Biagetti
- Hospital Vall d'Hebron, Department of Endocrinology, Barcelona, Spain
| | | | | | - Concepción Blanco
- Hospital Universitario Principe de Asturias, Department of Endocrinology, Alcalá de Henares, Madrid, Spain
| | - de Miguel Paz
- Hospital Clinico San Carlos, Department of Endocrinology, Madrid, Spain
| | - Rocío Villar-Taibo
- Complejo Hospitalario Universitario de Santiago de Compostela, Department of Endocrinology, La Coruña, Spain
| | - Clara V Álvarez
- Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), University of Santiago de Compostela (USC), Santiago de Compostela, Spain
| | - Sonia Gaztambide
- Biobizkaia Health Research Institute, Hospital Universitario Cruces, University of the Basque Country (UPV/EHU), CIBERDEM, CIBERER, EndoERN, Barakaldo, Bizkaia, Spain
| | - Susan M Webb
- Hospital de la Santa Creu i Sant Pau, Department of Endocrinology, IIB-Sant Pau, Research Center for Pituitary Diseases, CIBERER, Univ Autonoma Barcelona, Barcelona, Spain
| | - Luis Castaño
- Biobizkaia Health Research Institute, Hospital Universitario Cruces, University of the Basque Country (UPV/EHU), CIBERDEM, CIBERER, EndoERN, Barakaldo, Bizkaia, Spain
| | - Ignacio Bernabéu
- Complejo Hospitalario Universitario de Santiago de Compostela, Department of Endocrinology, Santiago de Compostela, A Coruña, Spain
| | - Antonio Picó
- Department of Endocrinology and Nutrition, Alicante General University Hospital, Alicante, Spain
- Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- University Miguel Hernandez, CIBERER, Alicante, Spain
| | - María-Ángeles Gálvez
- Endocrinology and Nutrition Service, Reina Sofia University Hospital, Córboba, Spain
- Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córboba, Spain
| | - Alfonso Soto-Moreno
- Unidad de Gestión de Endocrinología y Nutrición, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío, Sevilla, Spain
| | - Manel Puig-Domingo
- Department of Endocrinology and Nutrition, Department of Medicine, Germans Trias i Pujol Research Institute and Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Justo P Castaño
- Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córboba, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain
- Reina Sofia University Hospital, Córdoba, Spain
| | - Mónica Marazuela
- Department of Endocrinology and Nutrition Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa, Universidad Autónoma de Madrid, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER GCV14/ER/12), Madrid, Spain
| | - Raúl M Luque
- Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córboba, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain
- Reina Sofia University Hospital, Córdoba, Spain
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Araujo-Castro M, Marazuela M, Puig-Domingo M, Biagetti B. Prolactin and Growth Hormone Signaling and Interlink Focused on the Mammosomatotroph Paradigm: A Comprehensive Review of the Literature. Int J Mol Sci 2023; 24:14002. [PMID: 37762304 PMCID: PMC10531307 DOI: 10.3390/ijms241814002] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 09/01/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
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.
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Affiliation(s)
- Marta Araujo-Castro
- Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Colmenar Viejo Street km 9, 28034 Madrid, Spain
- Instituto de Investigación Biomédica Ramón y Cajal (IRYCIS), Colmenar Viejo Street km 9, 28034 Madrid, Spain
| | - Mónica Marazuela
- Department of Endocrinology and Nutrition, Hospital Universitario La Princesa, 28006 Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER GCV14/ER/12), Monforte de Lemos Avenue, 28029 Madrid, Spain
| | - Manel Puig-Domingo
- Department of Endocrinology and Nutrition, Department of Medicine, Germans Trias i Pujol Research Institute and Hospital, Universitat Autònoma de Barcelona, 08916 Badalona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras CIBERER G747, Monforte de Lemos Avenue, 28029 Madrid, Spain
| | - Betina Biagetti
- Department of Endocrinology and Nutrition, Vall d’Hebron University Hospital, Reference Networks (ERN) and Vall d’Hebron Research Institute (VHIR), Vall d’Hebron Avenue, 119, 08035 Barcelona, Spain
- Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute and CIBERDEM (ISCIII), Universidad Autónoma de Barcelona, Avenida Can Domènech s/n, 08193 Bellaterra, Spain
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Gatto F, Feelders RA, van Koetsveld PM, Dogan F, Neggers SJCCMM, van der Lelij AJ, Amarù J, Ferone D, Hofland LJ. Dissecting the in vitro efficacy of octreotide and cabergoline in GH- and GH/PRL-secreting pituitary tumors. J Clin Endocrinol Metab 2022; 108:e98-e109. [PMID: 36413489 DOI: 10.1210/clinem/dgac675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 11/17/2022] [Accepted: 11/17/2022] [Indexed: 11/23/2022]
Abstract
CONTEXT Cabergoline (CAB) is an off-label medical therapy for acromegaly, overshadowed by first-generation somatostatin receptor ligands, e.g. octreotide (OCT). OBJECTIVE Head-to-head comparison between OCT and CAB in inhibiting growth hormone (GH) secretion in primary cultures of GH- and GH/PRL-secreting tumors. To investigate the role of somatostatin (SST) and dopamine type 2 (D2R) receptor expression. DESIGN To evaluate the antisecretory effect of OCT and CAB, together with receptor mRNA expression, in 23 tumor cultures. SETTING AND PATIENTS Acromegaly patients referred to the Erasmus Medical Center (Rotterdam, The Netherlands). INTERVENTIONS 72-hour OCT and CAB treatment (10 nM). MAIN OUTCOME MEASURES GH concentrations in cell culture media. RESULTS OCT showed a slightly higher efficacy compared with CAB (GH decrease -39.5% vs. -32.5%, p = 0.079). The effect of the two drugs was superimposable in GH/PRL co-secreting tumors (-42.1% vs. -44.8%), where SST1 and D2R had a higher expression compared to the pure GH-secreting ones (p = 0.020 and p = 0.026). OCT was more effective than CAB in 8/23 cultures, while CAB was more effective than OCT in 3/23 (CAB + group). In CAB + tumors, SST1 expression was higher compared to the other groups (p = 0.034). At ROC curve analysis, SST1 and D2R discriminated between GH and GH/PRL co-secretion (AUC 0.856, p = 0.013; AUC 0.822, p = 0.024). SST1 was the best predictor of CAB response (≥50% GH reduction, AUC 0.913, p = 0.006; 80% sensitivity, 94% specificity). CONCLUSIONS OCT is 5-10% more effective than CAB in vitro. SST1 mRNA expression can represent a reliable marker of GH/PRL co-secreting tumors showing a preferential response to CAB treatment.
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Affiliation(s)
- Federico Gatto
- Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
- Department of Internal Medicine, Division of Endocrinology
- Pituitary Center Rotterdam, Erasmus MC, Rotterdam, The Netherlands
| | - Richard A Feelders
- Department of Internal Medicine, Division of Endocrinology
- Pituitary Center Rotterdam, Erasmus MC, Rotterdam, The Netherlands
| | | | - Fadime Dogan
- Department of Internal Medicine, Division of Endocrinology
| | - Sebastian J C C M M Neggers
- Department of Internal Medicine, Division of Endocrinology
- Pituitary Center Rotterdam, Erasmus MC, Rotterdam, The Netherlands
| | - Aart-Jan van der Lelij
- Department of Internal Medicine, Division of Endocrinology
- Pituitary Center Rotterdam, Erasmus MC, Rotterdam, The Netherlands
| | - Jessica Amarù
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties, University of Genova, Italy
| | - Diego Ferone
- Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties, University of Genova, Italy
| | - Leo J Hofland
- Department of Internal Medicine, Division of Endocrinology
- Pituitary Center Rotterdam, Erasmus MC, Rotterdam, The Netherlands
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Moreno-Moreno P, Ibáñez-Costa A, Venegas-Moreno E, Fuentes-Fayos AC, Alhambra-Expósito MR, Fajardo-Montañana C, García-Martínez A, Dios E, Vázquez-Borrego MC, Remón-Ruiz P, Cámara R, Lamas C, Carlos Padillo-Cuenca J, Solivera J, Cano DA, Gahete MD, Herrera-Martínez AD, Picó A, Soto-Moreno A, Gálvez-Moreno MÁ, Castaño JP, Luque RM. Integrative Clinical, Radiological, and Molecular Analysis for Predicting Remission and Recurrence of Cushing Disease. J Clin Endocrinol Metab 2022; 107:e2938-e2951. [PMID: 35312002 DOI: 10.1210/clinem/dgac172] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT Adrenocorticotropin (ACTH)-secreting pituitary tumors (ACTHomas) are associated with severe comorbidities and increased mortality. Current treatments mainly focus on remission and prevention of persistent disease and recurrence. However, there are still no useful biomarkers to accurately predict the clinical outcome after surgery, long-term remission, or disease relapse. OBJECTIVES This work aimed to identify clinical, biochemical, and molecular markers for predicting long-term clinical outcome and remission in ACTHomas. METHODS A retrospective multicenter study was performed with 60 ACTHomas patients diagnosed between 2004 and 2018 with at least 2 years' follow-up. Clinical/biochemical variables were evaluated yearly. Molecular expression profile of the somatostatin/ghrelin/dopamine regulatory systems components and of key pituitary factors and proliferation markers were evaluated in tumor samples after the first surgery. RESULTS Clinical variables including tumor size, time until diagnosis/first surgery, serum prolactin, and postsurgery cortisol levels were associated with tumor remission and relapsed disease. The molecular markers analyzed were distinctly expressed in ACTHomas, with some components (ie, SSTR1, CRHR1, and MKI67) showing instructive associations with recurrence and/or remission. Notably, an integrative model including selected clinical variables (tumor size/postsurgery serum cortisol), and molecular markers (SSTR1/CRHR1) can accurately predict the clinical evolution and remission of patients with ACTHomas, generating a receiver operating characteristic curve with an area under the curve of 1 (P < .001). CONCLUSION This study demonstrates that the combination of a set of clinical and molecular biomarkers in ACTHomas is able to accurately predict the clinical evolution and remission of patients. Consequently, the postsurgery molecular profile represents a valuable tool for clinical evaluation and follow-up of patients with ACTHomas.
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Affiliation(s)
- Paloma Moreno-Moreno
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain
- Service of Endocrinology and Nutrition, IMIBIC, HURS, 14004 Cordoba, Spain
| | - Alejandro Ibáñez-Costa
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain
- Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain
- CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 Cordoba, Spain
| | - Eva Venegas-Moreno
- Unidad de Gestión de Endocrinología y Nutrición. Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Sevilla, Spain
| | - Antonio C Fuentes-Fayos
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain
- Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain
- CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 Cordoba, Spain
| | - María R Alhambra-Expósito
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain
- Service of Endocrinology and Nutrition, IMIBIC, HURS, 14004 Cordoba, Spain
| | - Carmen Fajardo-Montañana
- Department of Endocrinology, Hospital Universitario de La Ribera, Alzira, 46600, Valencia, Spain
| | - Araceli García-Martínez
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain
- Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain
| | - Elena Dios
- Unidad de Gestión de Endocrinología y Nutrición. Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Sevilla, Spain
| | - Mari C Vázquez-Borrego
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain
- Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain
- CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 Cordoba, Spain
| | - Pablo Remón-Ruiz
- Unidad de Gestión de Endocrinología y Nutrición. Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Sevilla, Spain
| | - Rosa Cámara
- Department of Endocrinology and Nutrition, Polytechnic University Hospital La Fe, 46026, Valencia, Spain
| | - Cristina Lamas
- Department of Endocrinology and Nutrition, Albacete University Hospital, 02006, Albacete, Spain
| | - José Carlos Padillo-Cuenca
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain
- Service of Endocrinology and Nutrition, IMIBIC, HURS, 14004 Cordoba, Spain
| | | | - David A Cano
- Unidad de Gestión de Endocrinología y Nutrición. Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Sevilla, Spain
| | - Manuel D Gahete
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain
- Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain
- CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 Cordoba, Spain
| | - Aura D Herrera-Martínez
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain
- Service of Endocrinology and Nutrition, IMIBIC, HURS, 14004 Cordoba, Spain
| | - Antonio Picó
- Department of Endocrinology and Nutrition, Alicante General University Hospital. Institute for Health and Biomedical Research (ISABIAL). University Miguel Hernandez, CIBER Rare Diseases, 03010, Alicante, Spain
| | - Alfonso Soto-Moreno
- Unidad de Gestión de Endocrinología y Nutrición. Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Sevilla, Spain
| | - María Ángeles Gálvez-Moreno
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain
- Service of Endocrinology and Nutrition, IMIBIC, HURS, 14004 Cordoba, Spain
| | - Justo P Castaño
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain
- Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain
- CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 Cordoba, Spain
| | - Raúl M Luque
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain
- Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain
- CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 Cordoba, Spain
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6
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Octreotide and Pasireotide Combination Treatment in Somatotroph Tumor Cells: Predominant Role of SST 2 in Mediating Ligand Effects. Cancers (Basel) 2021; 13:cancers13081816. [PMID: 33920241 PMCID: PMC8069349 DOI: 10.3390/cancers13081816] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 04/08/2021] [Indexed: 12/16/2022] Open
Abstract
Simple Summary First-generation somatostatin receptor ligands, such as octreotide, are the first-line medical therapy in acromegaly. Octreotide shows preferential binding for somatostatin receptor subtype 2 (SST2), while the second-generation ligand, pasireotide, has high affinity for multiple SSTs. We aimed to elucidate whether pasireotide acts via other receptors than SST2 in somatotroph tumors, and to investigate the potential role of the combination therapy octreotide plus pasireotide. We found that octreotide and pasireotide are superimposable in reducing GH secretion in cultured somatotroph tumor cells, as well as in inhibiting cell proliferation and intracellular pathway activity in rat GH4C1 cells (a model of somatotroph tumors). We did not find any additive/synergistic effect for the combination treatment. Furthermore, we observed that co-incubation with a SST2-selective antagonist reversed the inhibitory effect of both compounds. Therefore, the two drugs act mainly via SST2 in somatotroph tumor cells, and their combination is not superior to single agent treatment. Abstract First-generation somatostatin receptor ligands (fg-SRLs), such as octreotide (OCT), represent the first-line medical therapy in acromegaly. Fg-SRLs show a preferential binding affinity for somatostatin receptor subtype-2 (SST2), while the second-generation ligand, pasireotide (PAS), has high affinity for multiple SSTs (SST5 > SST2 > SST3 > SST1). Whether PAS acts via SST2 in somatotroph tumors, or through other SSTs (e.g., SST5), is a matter of debate. In this light, the combined treatment OCT+PAS could result in additive/synergistic effects. We evaluated the efficacy of OCT and PAS (alone and in combination) on growth hormone (GH) secretion in primary cultures from human somatotroph tumors, as well as on cell proliferation, intracellular signaling and receptor trafficking in the rat GH4C1 cell line. The results confirmed the superimposable efficacy of OCT and PAS in reducing GH secretion (primary cultures), cell proliferation, cAMP accumulation and intracellular [Ca2+] increase (GH4C1 cells), without any additive effect observed for OCT+PAS. In GH4C1 cells, co-incubation with a SST2-selective antagonist reversed the inhibitory effect of OCT and PAS on cell proliferation and cAMP accumulation, while both compounds resulted in a robust internalization of SST2 (but not SST5). In conclusion, OCT and PAS seem to act mainly through SST2 in somatotroph tumor cells in vitro, without inducing any additive/synergistic effect when tested in combination.
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Fuentes-Fayos AC, García-Martínez A, Herrera-Martínez AD, Jiménez-Vacas JM, Vázquez-Borrego MC, Castaño JP, Picó A, Gahete MD, Luque RM. Molecular determinants of the response to medical treatment of growth hormone secreting pituitary neuroendocrine tumors. MINERVA ENDOCRINOL 2019; 44:109-128. [PMID: 30650942 DOI: 10.23736/s0391-1977.19.02970-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
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.
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Affiliation(s)
- Antonio C Fuentes-Fayos
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Cordoba, Spain.,Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain.,Reina Sofia University Hospital (HURS), Cordoba, Spain.,CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Cordoba, Spain
| | - Araceli García-Martínez
- Research Laboratory, Hospital General Universitario de Alicante-Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
| | - Aura D Herrera-Martínez
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Cordoba, Spain.,Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain.,Reina Sofia University Hospital (HURS), Cordoba, Spain.,CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Cordoba, Spain
| | - Juan M Jiménez-Vacas
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Cordoba, Spain.,Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain.,Reina Sofia University Hospital (HURS), Cordoba, Spain.,CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Cordoba, Spain
| | - Mari C Vázquez-Borrego
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Cordoba, Spain.,Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain.,Reina Sofia University Hospital (HURS), Cordoba, Spain.,CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Cordoba, Spain
| | - Justo P Castaño
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Cordoba, Spain.,Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain.,Reina Sofia University Hospital (HURS), Cordoba, Spain.,CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Cordoba, Spain
| | - Antonio Picó
- Department of Endocrinology and Nutrition, Hospital General Universitario de Alicante-ISABIAL, Miguel Hernández University, CIBERER, Alicante, Spain
| | - Manuel D Gahete
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Cordoba, Spain.,Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain.,Reina Sofia University Hospital (HURS), Cordoba, Spain.,CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Cordoba, Spain
| | - Raúl M Luque
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Cordoba, Spain - .,Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain.,Reina Sofia University Hospital (HURS), Cordoba, Spain.,CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Cordoba, Spain
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8
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Marazuela M, Ramos-Leví AM, Borges de Souza P, Zatelli MC. Is receptor profiling useful for predicting pituitary therapy? Eur J Endocrinol 2018; 179:D15-D25. [PMID: 30139823 DOI: 10.1530/eje-18-0549] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 08/13/2018] [Accepted: 08/22/2018] [Indexed: 12/31/2022]
Abstract
Medical treatment of pituitary tumours may present important challenges in the presence of resistance to first line therapy. In this setting, the availability of specific markers of responsiveness/resistance could be helpful to provide tailored patients' treatment. Pituitary receptor profiling has emerged as a potentially useful tool for predicting the response to specific pituitary-directed medical therapy, mainly somatostatin analogues and dopamine agonists. However, its utility is not always straightforward. In fact, agonist-receptor coupling to the consequent biological response is complex and sometimes jeopardizes the understanding of the molecular basis of pharmacological resistance. Defective expression of pituitary receptors, genetic alterations, truncated variants, impaired signal transduction or involvement of other proteins, such as cytoskeleton proteins or the Aryl hydrocarbon receptor interacting protein amongst others, have been linked to differential tumour phenotype or treatment responsiveness with conflicting results, keeping the debate on the utility of pituitary receptor profiling open. Why does this occur? How can we overcome the difficulties? Is there a true role for pituitary receptor profiling in the near future? All authors of this debate article agree on the need of prospective studies using standardized methods in order to assess the efficacy of receptor profiling as a reliable clinical predictive factor.
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Affiliation(s)
- Monica Marazuela
- Department of Endocrinology, Hospital Universitario La Princesa, Instituto de Investigación Princesa, Universidad Autónoma de Madrid, Madrid, Spain
| | - Ana M Ramos-Leví
- Department of Endocrinology, Hospital Universitario La Princesa, Instituto de Investigación Princesa, Universidad Autónoma de Madrid, Madrid, Spain
| | - Patricia Borges de Souza
- Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Maria Chiara Zatelli
- Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
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Ibáñez-Costa A, Korbonits M. AIP and the somatostatin system in pituitary tumours. J Endocrinol 2017; 235:R101-R116. [PMID: 28835453 DOI: 10.1530/joe-17-0254] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Accepted: 08/22/2017] [Indexed: 12/22/2022]
Abstract
Classic somatostatin analogues aimed at somatostatin receptor type 2, such as octreotide and lanreotide, represent the mainstay of medical treatment for acromegaly. These agents have the potential to decrease hormone secretion and reduce tumour size. Patients with a germline mutation in the aryl hydrocarbon receptor-interacting protein gene, AIP, develop young-onset acromegaly, poorly responsive to pharmacological therapy. In this review, we summarise the most recent studies on AIP-related pituitary adenomas, paying special attention to the causes of somatostatin resistance; the somatostatin receptor profile including type 2, type 5 and truncated variants; the role of G proteins in this pathology; the use of first and second generation somatostatin analogues; and the role of ZAC1, a zinc-finger protein with expression linked to AIP in somatotrophinoma models and acting as a key mediator of octreotide response.
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Affiliation(s)
- Alejandro Ibáñez-Costa
- Centre for EndocrinologyWilliam Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK
| | - Márta Korbonits
- Centre for EndocrinologyWilliam Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK
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Paragliola RM, Corsello SM, Salvatori R. Somatostatin receptor ligands in acromegaly: clinical response and factors predicting resistance. Pituitary 2017; 20:109-115. [PMID: 27778296 DOI: 10.1007/s11102-016-0768-4] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
INTRODUCTION Somatostatin (SST) receptor ligands (SRL), in particular those of first generation (Octreotide and Lanreotide), are widely used in medical treatment of acromegaly, but they assure biochemical control of disease (and the possibility of an improvement of clinical symptoms and tumor shrinkage), only in a subset of patients. DISCUSSION The mechanisms underlying the so called "SRL resistance" are various and involve in particular SST receptor expression and molecular pathways of signal transduction. Different predictors of SRL response have been reported, including clinical and biochemical features (gender, age, growth hormone and insulin-like growth factor-I levels at diagnosis), and tumor characteristic (both at preoperative magnetic resonance imaging study and histopathology) as well as expression of SST receptors. In some cases, only a "partial resistance" to SST can be detected, probably due to the presence of other impaired molecular mechanisms involved in signal transduction, which compromise specific pathways and not others. This may explain some cases of dissociated response between biochemical control and tumor shrinkage.
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Affiliation(s)
- Rosa Maria Paragliola
- Unit of Endocrinology, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, 00168, Rome, Italy
| | - Salvatore Maria Corsello
- Unit of Endocrinology, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, 00168, Rome, Italy
| | - Roberto Salvatori
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Pituitary Center, Johns Hopkins University School of Medicine, 1830 East Monument Street Suite #333, Baltimore, MD, 21287, USA.
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Ritvonen E, Pitkänen E, Karppinen A, Vehkavaara S, Demir H, Paetau A, Schalin-Jäntti C, Karhu A. Impact of AIP and inhibitory G protein alpha 2 proteins on clinical features of sporadic GH-secreting pituitary adenomas. Eur J Endocrinol 2017; 176:243-252. [PMID: 27998919 DOI: 10.1530/eje-16-0620] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Revised: 09/12/2016] [Accepted: 11/22/2016] [Indexed: 02/02/2023]
Abstract
INTRODUCTION In sporadic acromegaly, downregulation of AIP protein of the adenomas associates with invasive tumor features and reduced responsiveness to somatostatin analogues. AIP is a regulator of Gai signaling, but it is not known how the biological function of the Gai pathway is controlled. AIM To study GNAS and AIP mutation status, AIP and Gai-2 protein expressions, Ki-67 proliferation indices and clinical parameters in patients having primary surgery because of acromegaly at a single center between years 2000 and 2010. RESULTS Sixty patients (F/M, 31/29), mean age 49 (median 50), mean follow-up 7.7 years (range 0.6-14.0) underwent primary surgery. Four adenoma specimens (6.8%) harbored an AIP and 21 (35.6%) an activating GNAS (Gsp+) mutation. Altogether 13/56 (23%) adenomas had low AIP protein levels, and 14/56 (25%) low Gai-2 staining. In regression modeling, AIP expression associated with Gai-2 (P = 2.33 × 10-9) and lower Ki-67 (P = 0.04). In pairwise comparison, low AIP protein predicted high GH at last follow-up (mean 7.7 years after surgery, q = 0.045). Extent of treatments given for acromegaly associated with higher preoperative GH (P = 7.94 × 10-4), KNOSP (P = 0.003) and preoperative hypopituitarism (P = 0.03) and remission at last follow-up with change in 3-month postoperative IGF1 (P = 2.07 × 10-7). CONCLUSIONS We demonstrate, for the first time, that AIP protein expression associates with Gai-2 protein intensities in sporadic somatotropinomas, suggesting a joint regulation on somatostatin signaling. Low AIP level associates with higher proliferative activity and predicts high GH concentrations after long-term follow-up. The AIP mutation rate of 6.8% is fairly high, reflecting the genetic composition of the Finnish population.
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Affiliation(s)
- Elina Ritvonen
- EndocrinologyAbdominal Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Esa Pitkänen
- Department of Medical and Clinical Genetics & Genome-Scale BiologyResearch Programs Unit, University of Helsinki, Helsinki, Finland
| | - Atte Karppinen
- Department of NeurosurgeryUniversity of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Satu Vehkavaara
- EndocrinologyAbdominal Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Hande Demir
- Department of Medical and Clinical Genetics & Genome-Scale BiologyResearch Programs Unit, University of Helsinki, Helsinki, Finland
| | - Anders Paetau
- Department of PathologyHUSLAB and University of Helsinki, Helsinki, Finland
| | - Camilla Schalin-Jäntti
- EndocrinologyAbdominal Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Auli Karhu
- Department of Medical and Clinical Genetics & Genome-Scale BiologyResearch Programs Unit, University of Helsinki, Helsinki, Finland
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Abstract
Somatostatin and dopamine receptors are expressed in normal and tumoral somatotroph cells. Upon receptor stimulation, somatostatin and the somatostatin receptor ligands octreotide, lanreotide, and pasireotide, and to a lesser extent, dopamine and the dopamine analogs bromocriptine and cabergoline, suppress growth hormone (GH) secretion from a GH-secreting pituitary somatotroph adenoma. Somatostatin and dopamine receptors are Gαi-protein coupled that inhibit adenylate cyclase activity and cAMP production and reduce intracellular calcium concentration and calcium flux oscillations. Although their main action on somatotroph cells is acute inhibition of GH secretion, they also may inhibit GH production and possibly somatotroph proliferation. These receptors have been reported to create complexes that exhibit functions distinct from that of receptor monomers. Somatostatin suppression of GH is mediated mainly by somatostatin receptor subtype 2 and to a lesser extent by SST5. Human somatostatin receptor subtype 5 has also been shown to harbor mutations associated with GH levels, somatotroph tumor behavior, and somatostatin receptor ligand (SRL) responsiveness. Reviewing current knowledge of somatostatin and dopamine receptor expression and signaling in normal and tumoral somatotroph cells offers insights into mechanisms underlying SRL and dopamine agonist effectiveness in patients with acromegaly.
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Affiliation(s)
- Anat Ben-Shlomo
- Pituitary Center, Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Davis Building, Room 3021, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA.
| | - Ning-Ai Liu
- Pituitary Center, Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Davis Building, Room 3021, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA
| | - Shlomo Melmed
- Pituitary Center, Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Davis Building, Room 3021, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA
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Molecular Characterization of Growth Hormone-producing Tumors in the GC Rat Model of Acromegaly. Sci Rep 2015; 5:16298. [PMID: 26549306 PMCID: PMC4637865 DOI: 10.1038/srep16298] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Accepted: 10/08/2015] [Indexed: 12/14/2022] Open
Abstract
Acromegaly is a disorder resulting from excessive production of growth hormone (GH) and consequent increase of insulin-like growth factor 1 (IGF-I), most frequently caused by pituitary adenomas. Elevated GH and IGF-I levels results in wide range of somatic, cardiovascular, endocrine, metabolic, and gastrointestinal morbidities. Subcutaneous implantation of the GH-secreting GC cell line in rats leads to the formation of tumors. GC tumor-bearing rats develop characteristics that resemble human acromegaly including gigantism and visceromegaly. However, GC tumors remain poorly characterized at a molecular level. In the present work, we report a detailed histological and molecular characterization of GC tumors using immunohistochemistry, molecular biology and imaging techniques. GC tumors display histopathological and molecular features of human GH-producing tumors, including hormone production, cell architecture, senescence activation and alterations in cell cycle gene expression. Furthermore, GC tumors cells displayed sensitivity to somatostatin analogues, drugs that are currently used in the treatment of human GH-producing adenomas, thus supporting the GC tumor model as a translational tool to evaluate therapeutic agents. The information obtained would help to maximize the usefulness of the GC rat model for research and preclinical studies in GH-secreting tumors.
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Abstract
The somatostatin (SRIF) system, which includes the SRIF ligand and receptors, regulates anterior pituitary gland function, mainly inhibiting hormone secretion and to some extent pituitary tumor cell growth. SRIF-14 via its cognate G-protein-coupled receptors (subtypes 1-5) activates multiple cellular signaling pathways including adenylate cyclase/cAMP, MAPK, ion channel-dependent pathways, and others. In addition, recent data have suggested SRIF-independent constitutive SRIF receptor activity responsible for GH and ACTH inhibition in vitro. This review summarizes current knowledge on ligand-dependent and independent SRIF receptor molecular and functional effects on hormone-secreting cells in the anterior pituitary gland.
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Affiliation(s)
- Tamar Eigler
- Division of EndocrinologyDiabetes and Metabolism, Department of Medicine, Pituitary Center, Cedars Sinai Medical Center, Davis Building, Room 3066, 8700 Beverly Boulevard, Los Angeles, California 90048, USA
| | - Anat Ben-Shlomo
- Division of EndocrinologyDiabetes and Metabolism, Department of Medicine, Pituitary Center, Cedars Sinai Medical Center, Davis Building, Room 3066, 8700 Beverly Boulevard, Los Angeles, California 90048, USA
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Cuevas-Ramos D, Fleseriu M. Somatostatin receptor ligands and resistance to treatment in pituitary adenomas. J Mol Endocrinol 2014; 52:R223-40. [PMID: 24647046 DOI: 10.1530/jme-14-0011] [Citation(s) in RCA: 113] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Somatostatin (SST), an inhibitory polypeptide with two biologically active forms SST14 and SST28, inhibits GH, prolactin (PRL), TSH, and ACTH secretion in the anterior pituitary gland. SST also has an antiproliferative effect inducing cell cycle arrest and apoptosis. Such actions are mediated through five G-protein-coupled somatostatin receptors (SSTR): SSTR1-SSTR5. In GH-secreting adenomas, SSTR2 expression predominates, and somatostatin receptor ligands (SRLs; octreotide and lanreotide) directed to SSTR2 are presently the mainstays of medical therapy. However, about half of patients show incomplete biochemical remission, but the definition of resistance per se remains controversial. We summarize here the determinants of SRL resistance in acromegaly patients, including clinical, imaging features as well as molecular (mutations, SSTR variants, and polymorphisms), and histopathological (granulation pattern, and proteins and receptor expression) predictors. The role of SSTR5 may explain the partial responsiveness to SRLs in patients with adequate SSTR2 density in the cell membrane. In patients with ACTH-secreting pituitary adenomas, i.e. Cushing's disease (CD), SSTR5 is the most abundant receptor expressed and tumors show low SSTR2 density due to hypercortisolism-induced SSTR2 down-regulation. Clinical studies with pasireotide, a multireceptor-targeted SRL with increased SSTR5 activity, lead to approval of pasireotide for treatment of patients with CD. Other SRL delivery modes (oral octreotide), multireceptor-targeted SRL (somatoprim) or chimeric compounds targeting dopamine D2 receptors and SSTR2 (dopastatin), are briefly discussed.
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Affiliation(s)
- Daniel Cuevas-Ramos
- Department of MedicinePituitary Center, Cedars-Sinai Medical Center, Los Angeles, California, USANorthwest Pituitary Center and Departments of Medicine and Neurological SurgeryOregon Health and Science University, 3181 SW Sam Jackson Park Road (BTE 472), Portland, Oregon 97239, USA
| | - Maria Fleseriu
- Department of MedicinePituitary Center, Cedars-Sinai Medical Center, Los Angeles, California, USANorthwest Pituitary Center and Departments of Medicine and Neurological SurgeryOregon Health and Science University, 3181 SW Sam Jackson Park Road (BTE 472), Portland, Oregon 97239, USA
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AIP inactivation leads to pituitary tumorigenesis through defective Gαi-cAMP signaling. Oncogene 2014; 34:1174-84. [PMID: 24662816 DOI: 10.1038/onc.2014.50] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2013] [Revised: 12/16/2013] [Accepted: 01/01/2014] [Indexed: 01/03/2023]
Abstract
The aryl hydrocarbon receptor interacting protein (AIP) is a tumor-suppressor gene underlying the pituitary adenoma predisposition. Thus far, the exact molecular mechanisms by which inactivated AIP exerts its tumor-promoting action have been unclear. To better understand the role of AIP in pituitary tumorigenesis, we performed gene expression microarray analysis to examine changes between Aip wild-type and knockout mouse embryonic fibroblast (MEF) cell lines. Transcriptional analyses implied that Aip deficiency causes a dysfunction in cyclic adenosine monophosphate (cAMP) signaling, as well as impairments in signaling cascades associated with developmental and immune-inflammatory responses. In vitro experiments showed that AIP deficiency increases intracellular cAMP concentrations in both MEF and murine pituitary adenoma cell lines. Based on knockdown of various G protein α subunits, we concluded that AIP deficiency leads to elevated cAMP concentrations through defective Gαi-2 and Gαi-3 proteins that normally inhibit cAMP synthesis. Furthermore, immunostaining of Gαi-2 revealed that AIP deficiency is associated with a clear reduction in Gαi-2 protein expression levels in human and mouse growth hormone (GH)-secreting pituitary adenomas, thus indicating defective Gαi signaling in these tumors. By contrast, all prolactin-secreting tumors showed prominent Gαi-2 protein levels, irrespective of Aip mutation status. We additionally observed reduced expression of phosphorylated extracellular signal-regulated kinases 1/2 and cAMP response element-binding protein levels in mouse and human AIP-deficient somatotropinomas. This study implies for the first time that a failure to inhibit cAMP synthesis through dysfunctional Gαi signaling underlies the development of GH-secreting pituitary adenomas in AIP mutation carriers.
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Casar-Borota O, Heck A, Schulz S, Nesland JM, Ramm-Pettersen J, Lekva T, Alafuzoff I, Bollerslev J. Expression of SSTR2a, but not of SSTRs 1, 3, or 5 in somatotroph adenomas assessed by monoclonal antibodies was reduced by octreotide and correlated with the acute and long-term effects of octreotide. J Clin Endocrinol Metab 2013; 98:E1730-9. [PMID: 24092823 DOI: 10.1210/jc.2013-2145] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
CONTEXT Reduced expression of somatostatin receptors (SSTRs) in somatotroph adenomas and their potential down-regulation after medical treatment may explain the unsatisfactory response to octreotide in particular acromegalic patients. The expression of SSTRs other than SSTR2a has not been studied in large, unselected cohorts using novel rabbit monoclonal antibodies. OBJECTIVE We aimed to determine the expression of SSTRs 1, 2a, 3, and 5 in somatotroph adenomas, to correlate expression with clinical characteristics and the response to octreotide, and to ascertain whether preoperative octreotide treatment affected SSTR expression. DESIGN, SETTING, PATIENTS The study included 78 adenomas from patients operated on consecutively during 2000 to 2010. After exclusion of 13 patients, immunohistochemical analysis with rabbit monoclonal antibodies against SSTRs 1, 2a, 3, and 5 (clones UMB-7, -1, -5, and -4) was performed on 65 adenomas. INTERVENTION Twenty-eight patients received preoperative octreotide, and 37 patients were operated on without pretreatment. Twenty-six patients were randomized to direct surgery (n = 13) or to octreotide pretreatment (n = 13). MAIN OUTCOME MEASURE SSTR expression was evaluated using a 12-grade scoring system. The responses to the octreotide test dose (GH reduction) and to 6 months of octreotide (IGF-I reduction) were measured. RESULTS The majority of adenomas showed membranous expression of SSTRs 2a and 5. SSTR2a expression was reduced in the pretreated group and correlated with the acute octreotide test results and the effect of octreotide treatment. In a linear regression model with SSTR2a expression as the determinant, the correlation with the acute test response improved after adjustment for medical pretreatment. CONCLUSION Rabbit monoclonal antibodies are reliable markers of SSTRs in somatotroph adenomas. SSTR2a expression correlated with the response to octreotide and was reduced after octreotide treatment, indicating the need for adjustment when SSTR2a expression is correlated with baseline characteristics. Evaluation of SSTR subtypes may be an important aspect of improving the medical treatment for acromegaly.
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Affiliation(s)
- Olivera Casar-Borota
- Section of Specialized Endocrinology, Oslo University Hospital, Rikshospitalet, PO Box 4950 Nydalen, 0424 Oslo, Norway.
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Theodoropoulou M, Stalla GK. Somatostatin receptors: from signaling to clinical practice. Front Neuroendocrinol 2013; 34:228-52. [PMID: 23872332 DOI: 10.1016/j.yfrne.2013.07.005] [Citation(s) in RCA: 276] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Revised: 06/13/2013] [Accepted: 07/12/2013] [Indexed: 02/08/2023]
Abstract
Somatostatin is a peptide with a potent and broad antisecretory action, which makes it an invaluable drug target for the pharmacological management of pituitary adenomas and neuroendocrine tumors. Somatostatin receptors (SSTR1, 2A and B, 3, 4 and 5) belong to the G protein coupled receptor family and have a wide expression pattern in both normal tissues and solid tumors. Investigating the function of each SSTR in several tumor types has provided a wealth of information about the common but also distinct signaling cascades that suppress tumor cell proliferation, survival and angiogenesis. This provided the rationale for developing multireceptor-targeted somatostatin analogs and combination therapies with signaling-targeted agents such as inhibitors of the mammalian (or mechanistic) target of rapamycin (mTOR). The ability of SSTR to internalize and the development of rabiolabeled somatostatin analogs have improved the diagnosis and treatment of neuroendocrine tumors.
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Affiliation(s)
- Marily Theodoropoulou
- Department of Endocrinology, Max Planck Institute of Psychiatry, Kraepelinstrasse 10, 80804 Munich, Germany.
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Gagliano T, Filieri C, Minoia M, Buratto M, Tagliati F, Ambrosio MR, Lapparelli M, Zoli M, Frank G, degli Uberti E, Zatelli MC. Cabergoline reduces cell viability in non functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion. Pituitary 2013; 16:91-100. [PMID: 22350942 DOI: 10.1007/s11102-012-0380-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Dopamine (DA) therapy of non-functioning pituitary adenomas (NFA) can result in tumor stabilization and shrinkage. However, the mechanism of action is still unknown. Previous evidence showed that DA can inhibit pituitary vascular endothelial growth factor expression (VEGF), that may be involved in pituitary tumor growth. The aim of our study was to clarify whether VEGF secretion modulation might mediate the effects of DA agonists on cell proliferation in human NFA. We assessed DA receptor subtype 2 (DR2) expression in 20 NFA primary cultures, where we also investigated the effects of a selective DR2 agonist, cabergoline (Cab), on VEGF secretion and on cell viability. All NFA samples expressed α-subunit and DR2 was expressed in 11 samples. In DR2 expressing tumors, Cab significantly reduced cell viability (-25%; P < 0.05) and VEGF secretion (-20%; P < 0.05). These effects were counteracted by treatment with the DA antagonist sulpiride. Cab antiproliferative effects were blocked by VEGF. Our data demonstrate that Cab, via DR2, inhibits cell viability also by reducing VEGF secretion in a selected group of NFA, supporting that DA agonists can be useful in the medical therapy of DR2 expressing NFA.
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Affiliation(s)
- Teresa Gagliano
- Section of Endocrinology, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Via Savonarola 9, 44100, Ferrara, Italy
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Lan HN, Wang YX, Zheng MZ, Han WW, Zheng X. Using homology modeling, molecular dynamics and molecular docking techniques to identify inhibitor binding regions of somatostatin receptor 1. Chem Res Chin Univ 2013. [DOI: 10.1007/s40242-013-2103-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Cozzi R, Attanasio R. Octreotide long-acting repeatable for acromegaly. Expert Rev Clin Pharmacol 2012; 5:125-43. [PMID: 22390555 DOI: 10.1586/ecp.12.4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Acromegaly remains a therapeutic challenge for the endocrinologist. Among the available therapeutic options, octreotide long-acting repeatable (Sandostatin(®) LAR(®), Novartis) plays a chief role, both as a primary therapy and as an adjuvant treatment after unsuccessful surgery. A plethora of papers and a meta-analysis have demonstrated its efficacy in: control of clinical picture; achievement of safe growth hormone and normal age-matched IGF-I levels (both factors associated with restoration of normal life expectancy) in 60-70% of patients; control of tumor volume (with real shrinkage in over half of cases); and halt or reversal of most acromegaly-associated comorbidities. Treatment is well tolerated in most patients and can be safely prolonged for many years if required.
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Affiliation(s)
- Renato Cozzi
- Division of Endocrinology, Ospedale Niguarda, Via Canonica 81, I-20154 Milan, Italy.
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22
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Altered expression of somatostatin receptors in pancreatic islets from NOD mice cultured at different glucose concentrations in vitro and in islets transplanted to diabetic NOD mice in vivo. EXPERIMENTAL DIABETES RESEARCH 2011; 2011:623472. [PMID: 21912536 PMCID: PMC3167186 DOI: 10.1155/2011/623472] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/11/2011] [Accepted: 07/02/2011] [Indexed: 11/17/2022]
Abstract
Somatostatin acts via five receptors (sst1–5). We investigated if the changes in pancreatic islet sst expression in diabetic NOD mice compared to normoglycemic mice are a consequence of hyperglycemia or the ongoing immune reaction in the pancreas. Pancreatic islets were isolated from NOD mice precultured for 5 days and further cultured for 3 days at high or low glucose before examined. Islets were also isolated from NOD mice and transplanted to normal or diabetic mice in a number not sufficient to cure hyperglycemia. After three days, the transplants were removed and stained for sst1–5 and islet hormones. Overall, changes in sst islet cell expression were more common in islets cultured in high glucose concentration in vitro as compared to the islet transplantation in vivo to diabetic mice. The beta and PP cells exhibited more frequent changes in sst expression, while the alpha and delta cells were relatively unaffected by the high glucose condition. Our findings suggest that the glucose level may alter sst expressed in islets cells; however, immune mechanisms may counteract such changes in islet sst expression.
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Abstract
Somatostatin analogs (SA) are widely used in acromegaly, either as first-line or adjuvant treatment after surgery. First-line treatment with these drugs is generally used in the patients with macroadenomas or in those with clinical conditions so severe as to prevent unsafe reactions during anesthesia. Generally, the response to SA takes into account both control of GH and IGF-I excess, with consequent improvement of clinical symptoms directly related to GH and IGF-I excess, and tumor shrinkage. This latter effect is more prominent in the patients treated first-line and bearing large macroadenomas, but it is also observed in patients with microadenomas, even with little clinical implication. Predictors of response are patients' gender, age, initial GH and IGF-I levels, and tumor mass, as well as adequate expression of somatostatin receptor types 2 and 5, those with the highest affinity for octreotide and lanreotide. Only sporadic cases of somatostatin receptor gene mutation or impaired signaling pathways have been described in GH-secreting tumors so far. The response to SA also depends on treatment duration and dosage of the drug used, so that a definition of resistance based on short-term treatments using low doses of long-acting SA is limited. Current data suggest that response to these drugs is better analyzed taking together biochemical and tumoral effects because only the absence of both responses might be considered as a poor response or resistance. This latter evidence seems to occur in 25% of treated patients after 12 months of currently available long-acting SA.
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Affiliation(s)
- Annamaria Colao
- Department of Clinical and Molecular Endocrinology and Oncology, University “Federico II,” Naples, Italy.
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24
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Bai LY, Liang AX, Zhang J, Yang FF, Han L, Huo LJ, Yang LG. Effects of immunization against a DNA vaccine encoding somatostatin gene (pGM-CSF/SS) by attenuated Salmonella typhimurium on growth, reproduction and lactation in female mice. Theriogenology 2011; 75:155-63. [DOI: 10.1016/j.theriogenology.2010.08.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2009] [Revised: 08/01/2010] [Accepted: 08/01/2010] [Indexed: 12/14/2022]
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Tagliati F, Gentilin E, Buratto M, Molè D, degli Uberti EC, Zatelli MC. Magmas, a gene newly identified as overexpressed in human and mouse ACTH-secreting pituitary adenomas, protects pituitary cells from apoptotic stimuli. Endocrinology 2010; 151:4635-42. [PMID: 20719856 DOI: 10.1210/en.2010-0441] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Pituitary tumors are mostly benign, being locally invasive in 5-35% of cases. Deregulation of several genes has been suggested as a possible alteration underlying the development and progression of pituitary tumors. We here report the identification of a cDNA, corresponding to Magmas gene (mitochondria-associated protein involved in granulocyte-macrophage colony-stimulating factor signal transduction), which is highly expressed in two different ACTH-secreting mouse pituitary adenoma cell lines as compared with normal pituitary as well as in two thirds of 64 examined pituitary adenomas as compared with human normal pituitary. Tim 16, the mitochondrial protein encoded by Magmas, was indeed expressed in a mouse ACTH-secreting pituitary adenoma cell line, AtT-20 D16v-F2 cells, in a subcellular compartment likely corresponding to mitochondria. Magmas silencing determined a reduced rate of DNA synthesis, an accumulation in G1 phase, and a concomitant decrease in S phase in At-T20 D16v-F2 cells. Moreover, Magmas-silenced cells displayed basal caspase 3/7 activity and DNA fragmentation levels similar to control cells, which both increased under proapoptotic stimuli. Our data demonstrate that Magmas is overexpressed in mouse and human ACTH-secreting pituitary adenomas. Moreover, our results show that Magmas protects pituitary cells from apoptosis, suggesting its possible involvement in neoplastic transformation.
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Affiliation(s)
- Federico Tagliati
- Section of Endocrinology, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Via Savonarola 9, I-44100 Ferrara, Italy
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Zatelli MC, Gentilin E, Daffara F, Tagliati F, Reimondo G, Carandina G, Ambrosio MR, Terzolo M, Degli Uberti EC. Therapeutic concentrations of mitotane (o,p'-DDD) inhibit thyrotroph cell viability and TSH expression and secretion in a mouse cell line model. Endocrinology 2010; 151:2453-61. [PMID: 20392828 DOI: 10.1210/en.2009-1404] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Mitotane therapy is associated with many side effects, including thyroid function perturbations mimicking central hypothyroidism, possibly due to laboratory test interference or pituitary direct effects of mitotane. We investigated whether increasing concentrations of mitotane in the therapeutic range might interfere with thyroid hormone assays and evaluated the effects of mitotane on a mouse TSH-producing pituitary cell line. TSH, free T(4), and free T(3) levels do not significantly change in sera from hypo-, hyper-, or euthyroid patients after addition of mitotane at concentrations in the therapeutic window. In the mouse TalphaT1 cell line, mitotane inhibits both TSH expression and secretion, blocks TSH response to TRH, and reduces cell viability, inducing apoptosis at concentrations in the therapeutic window. TRH is not capable of rescuing TalphaT1 cells from the inhibitory effects of mitotane on TSH expression and secretion, which appear after short time treatment and persist over time. Our results demonstrate that mitotane does not interfere with thyroid hormone laboratory tests but directly reduces both secretory activity and cell viability on pituitary TSH-secreting mouse cells. These data represent a possible explanation of the biochemical picture consistent with central hypothyroidism in patients undergoing mitotane therapy and open new perspectives on the direct pituitary effects of this drug.
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Affiliation(s)
- Maria Chiara Zatelli
- Section of Endocrinology, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Via Savonarola 9, 44121 Ferrara, Italy
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Ben-Shlomo A, Melmed S. Pituitary somatostatin receptor signaling. Trends Endocrinol Metab 2010; 21:123-33. [PMID: 20149677 PMCID: PMC2834886 DOI: 10.1016/j.tem.2009.12.003] [Citation(s) in RCA: 149] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2009] [Revised: 12/09/2009] [Accepted: 12/10/2009] [Indexed: 12/27/2022]
Abstract
Somatotropin-release inhibitory factor (SRIF) is a major regulator of pituitary function, mostly inhibiting hormone secretion and to a lesser extent pituitary cell growth. Five SRIF receptor subtypes (SSTR1-5) are ubiquitously expressed G-protein coupled receptors. In the pituitary, SSTR1, 2, 3 and 5 are expressed, with SSTR2 and SSTR5 predominating. As new SRIF analogs have recently been introduced for treatment of pituitary disease, we evaluate the current knowledge of cell-specific pituitary SRIF receptor signaling and highlight areas of future research for comprehensive understanding of these mechanisms. Elucidating pituitary SRIF receptor signaling enables understanding of pituitary hormone secretion and cell growth, and also encourages future therapeutic development for pituitary disorders.
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Affiliation(s)
- Anat Ben-Shlomo
- Pituitary Center, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California 90048, USA
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Feelders RA, Hofland LJ, van Aken MO, Neggers SJ, Lamberts SWJ, de Herder WW, van der Lely AJ. Medical therapy of acromegaly: efficacy and safety of somatostatin analogues. Drugs 2009; 69:2207-26. [PMID: 19852525 DOI: 10.2165/11318510-000000000-00000] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Acromegaly is a chronic disease with signs and symptoms due to growth hormone (GH) excess. The most frequent cause of acromegaly is a GH-producing pituitary adenoma. Chronic GH excess is accompanied by long-term complications of the locomotor (arthrosis) and cardiovascular (atherosclerosis, cardiomyopathy) systems and is, when untreated, associated with an increased mortality. The aim of treatment of acromegaly is to improve symptoms, to achieve local tumour mass control, and to decrease morbidity and mortality. Treatment options include surgery, medical therapy and radiotherapy. Transsphenoidal surgery is the first choice of treatment when a definitive cure can be achieved, particularly in the case of microadenomas and when decompression of surrounding structures (optic chiasm, ophthalmic motor nerves) is indicated. Primary medical therapy has been increasingly applied in recent years, especially when a priori chances of surgical cure are low (because of adenoma size and localization) and in patients with advanced age and/or serious co-morbidity. In addition, preoperative primary medical therapy may result in tumour shrinkage, facilitating tumour resection, and may reduce perioperative complications due to GH excess. Within the spectrum of medical therapy, long-acting somatostatin analogues (somatostatins) are considered as first-line treatment. Treatment with somatostatin analogues results in GH control in approximately 60% of patients. In addition, somatostatin analogues induce tumour shrinkage in 30-50% of patients, particularly when applied as primary therapy. Prolonged treatment with somatostatin analogues appears to be safe and is usually well tolerated. The currently available somatostatin analogues, octreotide and lanreotide, seem to be equally effective; however, this should still be evaluated in prospective, randomized trials evaluating efficacy with respect to GH control and tumour shrinkage. In patients with an insufficient clinical and biochemical response to somatostatin analogues, combination therapy with dopamine receptor agonists or the GH receptor antagonist pegvisomant usually leads to disease control. New developments in the medical therapy of acromegaly include the universal somatostatin receptor agonist pasireotide, which has a broader affinity for all somatostatin receptor (sst) subtypes compared with the currently available somatostatin analogues with preferential affinity for the sst2 receptor, and chimeric compounds that interact with both somatostatin and dopamine receptors with synergizing effects on GH secretion.
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Affiliation(s)
- Richard A Feelders
- Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands.
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Zatelli MC, Minoia M, Molè D, Cason V, Tagliati F, Margutti A, Bondanelli M, Ambrosio MR, degli Uberti E. Growth hormone excess promotes breast cancer chemoresistance. J Clin Endocrinol Metab 2009; 94:3931-8. [PMID: 19622619 DOI: 10.1210/jc.2009-1026] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT GH and IGF-I are known to promote breast carcinogenesis. Even if breast cancer (BC) incidence is not increased in female acromegalic patients, mortality is greater as compared with general population. OBJECTIVE The objective of the study was to evaluate whether GH/IGF-I excess might influence BC response to chemotherapy. DESIGN We evaluated GH and IGF-I effects on cell proliferation of a BC cell line, MCF7 cells, in the presence of doxorubicin (Doxo), frequently used in BC chemotherapy, and the possible mechanisms involved. RESULTS GH and IGF-I induce MCF7 cell growth in serum-free conditions and protect the cells from the cytotoxic effects of Doxo. GH effects are direct and not mediated by IGF-I because they are apparent also in the presence of an IGF-I receptor blocking antibody and disappear in the presence of the GH antagonist pegvisomant. The expression of the MDR1 gene, involved in resistance to chemotherapeutic drugs, was not induced by GH. In addition, c-fos transduction was reduced by Doxo, which prevented GH stimulatory effects. Pegvisomant inhibited basal and GH-induced c-fos promoter transcriptional activity. Autocrine GH action is ruled out by the lack of endogenous GH expression in this MCF7 cell strain. CONCLUSIONS These data indicate that GH can directly induce resistance to chemotherapeutic drugs with a mechanism that might involve GH-induced early gene transcription and support the hypothesis that GH excess can hamper BC treatment, possibly resulting in an increased mortality.
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Affiliation(s)
- Maria Chiara Zatelli
- Section of Endocrinology, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, 44100 Ferrara, Italy
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Erchegyi J, Cescato R, Grace CRR, Waser B, Piccand V, Hoyer D, Riek R, Rivier JE, Reubi JC. Novel, potent, and radio-iodinatable somatostatin receptor 1 (sst1) selective analogues. J Med Chem 2009; 52:2733-46. [PMID: 19351180 DOI: 10.1021/jm801314f] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The proposed sst(1) pharmacophore (J. Med. Chem. 2005, 48, 523-533) derived from the NMR structures of a family of mono- and dicyclic undecamers was used to design octa-, hepta-, and hexamers with high affinity and selectivity for the somatostatin sst(1) receptor. These compounds were tested for their in vitro binding properties to all five somatostatin (SRIF) receptors using receptor autoradiography; those with high SRIF receptor subtype 1 (sst(1)) affinity and selectivity were shown to be agonists when tested functionally in a luciferase reporter gene assay. Des-AA(1,4-6,10,12,13)-[DTyr(2),DAgl(NMe,2naphthoyl)(8),IAmp(9)]-SRIF-Thr-NH(2) (25) was radio-iodinated ((125)I-25) and specifically labeled sst(1)-expressing cells and tissues. 3D NMR structures were calculated for des-AA(1,4-6,10,12,13)-[DPhe(2),DTrp(8),IAmp(9)]-SRIF-Thr-NH(2) (16), des-AA(1,2,4-6,10,12,13)-[DAgl(NMe,2naphthoyl)(8),IAmp(9)]-SRIF-Thr-NH(2) (23), and des-AA(1,2,4-6,10,12,13)-[DAgl(NMe,2naphthoyl)(8),IAmp(9),Tyr(11)]-SRIF-NH(2) (27) in DMSO. Though the analogues have the sst(1) pharmacophore residues at the previously determined distances from each other, the positioning of the aromatic residues in 16, 23, and 27 is different from that described earlier, suggesting an induced fit mechanism for sst(1) binding of these novel, less constrained sst(1)-selective family members.
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Affiliation(s)
- Judit Erchegyi
- The Clayton Foundation Laboratories for Peptide Biology, La Jolla, California 92037, USA
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Saveanu A, Jaquet P. Somatostatin-dopamine ligands in the treatment of pituitary adenomas. Rev Endocr Metab Disord 2009; 10:83-90. [PMID: 18651224 DOI: 10.1007/s11154-008-9086-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2008] [Accepted: 06/12/2008] [Indexed: 01/18/2023]
Abstract
Somatostatin receptors (sst1-5) and dopamine receptor 2 (D2DR) are well expressed and co-localized in several human pituitary adenomas, suggesting possible functional interactions in the control of hormonal hypersecretion and tumor cell growth. The present review describes the expression and functionality of these receptors in the different classes of human pituitary adenomas. The sst2 agonists, octreotide and lanreotide, control GH hypersecretion and tumor growth in about 65% of somatotropinomas. The D2DR agonists, bromocriptine and cabergoline, control about 90% of prolactinomas. Such drugs are much less effective in the control of the others pituitary adenomas also expressing ssts and D2DR receptors. The second part summarizes the current knowledge on new chimeric compounds with sst2, sst5, and D2DR affinity. Such ligands bearing distinct ssts and DRD2 pharmacophores may synergistically produce an increased control of secretion and/or of proliferation in the different types of pituitary adenomas. The mechanisms of action of such chimeric molecules through increased binding affinities, prolonged bioavailability, ligand-induced modulation of receptors heterodimerization, are discussed.
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Affiliation(s)
- Alexandru Saveanu
- CRN2M UMR 6231, Centre National de la Recherche Scientifique, Universite de la Mediterranee, Faculté de Médecine Nord, Marseille, France.
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Current therapy and drug pipeline for the treatment of patients with acromegaly. Adv Ther 2009; 26:383-403. [PMID: 19444656 DOI: 10.1007/s12325-009-0029-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2009] [Indexed: 01/09/2023]
Abstract
INTRODUCTION Acromegaly is a multisystem disease resulting from chronic exposure to supraphysiological levels of growth hormone (GH), and is associated with significant morbidity and excess mortality. The etiology is almost exclusively an underlying pituitary adenoma. Current therapeutic interventions include surgery, radiotherapy, and medical therapy. RESULTS Despite surgery, around 50% of patients fail to achieve the biochemical targets shown to correlate with normalization of mortality rates. Radiotherapy is efficacious in controlling tumor growth and GH secretion; still, achievement of biochemical targets may take up to a decade and a number of safety issues have been raised with this treatment modality. Medical therapy, therefore, has an important role as adjuvant therapy in patients who fail to achieve control with surgery, or while awaiting the effects of radiotherapy to be realized. Furthermore, medical therapy is increasingly being used as primary therapy. Current medical therapies include dopaminergic agonists, somatostatin analogs, and GH receptor (GHR) antagonists. Dopaminergic agonists achieve biochemical targets in up to 30% of patients, and somatostatin analogs in around 60%. The currently available GHR antagonist pegvisomant effectively controls insulin-like growth factor-I levels in over 90% of patients; however, it has no effect on the tumor itself and has considerable financial implications. Research into optimizing the somatostatin and dopaminergic systems has led to promising advances in agonist development. Moieties with selectivity for various combinations of somatostatin receptor subtype receptors have been examined, along with molecules that additionally show high affinity for the dopaminergic D2 receptor. Of the molecules studied in vitro, only pasireotide (SOM230) and BIM-23A760 are currently undergoing further development. Other innovations to improve convenience of currently available drugs are also being investigated. CONCLUSION Significant advances in under standing of the somatostatin and dopaminergic system have aided drug development. This may lead to new clinically available therapies enabling control of acromegaly in a larger proportion of patients, and at an earlier stage in their disease management.
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Discovery of novel non-peptidic β-alanine piperazine amide derivatives and their optimization to achiral, easily accessible, potent and selective somatostatin sst1 receptor antagonists. Bioorg Med Chem Lett 2009; 19:1305-9. [DOI: 10.1016/j.bmcl.2009.01.072] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2008] [Revised: 01/20/2009] [Accepted: 01/22/2009] [Indexed: 10/21/2022]
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Casarini APM, Jallad RS, Pinto EM, Soares IC, Nonogaki S, Giannella-Neto D, Musolino NR, Alves VAF, Bronstein MD. Acromegaly: correlation between expression of somatostatin receptor subtypes and response to octreotide-lar treatment. Pituitary 2009; 12:297-303. [PMID: 19330452 DOI: 10.1007/s11102-009-0175-1] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
About one-third of acromegalics are resistant to the clinically available somatostatin analogs (SA). The resistance is related to density reduction or different expression of somatostatin receptor subtypes (SSTR). This study analyzes SSTR's expression in somatotrophinomas, comparing to SA response, hormonal levels, and tumor volume. We analyzed 39 somatotrophinomas; 49% were treated with SA. The most expressed SSTR was SSTR5, SSTR3, SSTR2, SSTR1, and SSTR4, respectively. SSTR1 and SSTR2 had higher expression in patients that had normalized GH and IGF-I. SSTR3 was more expressed in patients with tumor reduction. There was a positive correlation between the percentage of tumor reduction and SSTR1, SSTR2 and SSTR3 expression. Also, a positive correlation between SSTR2 mRNA expression and the immunohistochemical reactivity of SSTR2 was found. Our study confirmed the association between the SA response to GH and IGF-I and the SSTR2. Additionally, this finding was also demonstrated in relation to SSTR1.
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Affiliation(s)
- Ana Paula M Casarini
- Neuroendocrine Unit, Division of Endocrinology and Metabolism, University of Sao Paulo Medical School, Av. 9 de Julho 3858 01406-100, Sao Paulo, SP, Brazil.
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35
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Li M, Wang X, Li W, Li F, Yang H, Wang H, Brunicardi FC, Chen C, Yao Q, Fisher WE. Somatostatin receptor-1 induces cell cycle arrest and inhibits tumor growth in pancreatic cancer. Cancer Sci 2008; 99:2218-23. [PMID: 18823376 DOI: 10.1111/j.1349-7006.2008.00940.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Functional somatostatin receptors (SSTR) are lost in human pancreatic cancer. Transfection of SSTR-1 inhibited pancreatic cancer cell proliferation in vitro. We hypothesize that stable transfection of SSTR-1 may inhibit pancreatic cancer growth in vivo possibly through cell cycle arrest. In this study, we examined the expression of SSTR-1 mRNA in human pancreatic cancer tissue specimens, and investigated the effect of SSTR-1 overexpression on cell proliferation, cell cycle, and tumor growth in a subcutaneous nude mouse model. We found that SSTR-1 mRNA was downregulated in the majority of pancreatic cancer tissue specimens. Transfection of SSTR-1 caused cell cycle arrest at the G(0)/G(1) growth phase, with a corresponding decline of cells in the S (mitotic) phase. The overexpression of SSTR-1 significantly inhibited subcutaneous tumor size by 71% and 43% (n = 5, P < 0.05, Student's t-test), and inhibited tumor weight by 69% and 47% (n = 5, P < 0.05, Student's t-test), in Panc-SSTR-1 and MIA-SSTR-1 groups, respectively, indicating the potent inhibitory effect of SSTR-1 on pancreatic cancer growth. Our data demonstrate that overexpression of SSTR-1 significantly inhibits pancreatic cancer growth possibly through cell cycle arrest. This study suggests that gene therapy with SSTR-1 may be a potential adjuvant treatment for pancreatic cancer.
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Affiliation(s)
- Min Li
- Michael E DeBakey Department of Surgery, Molecular Surgeon Research Center, Baylor College of Medicine, Houston, Texas, USA.
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Dalm VASH, Hofland LJ, Lamberts SWJ. Future clinical prospects in somatostatin/cortistatin/somatostatin receptor field. Mol Cell Endocrinol 2008; 286:262-77. [PMID: 17942217 DOI: 10.1016/j.mce.2007.09.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2007] [Revised: 08/13/2007] [Accepted: 09/07/2007] [Indexed: 01/31/2023]
Abstract
Somatostatin receptors (sst), somatostatin (SS) and cortistatin (CST) are widely expressed in the various systems in the human and rodent organisms and are "responsible" for maintaining homeostasis, which is essential for survival. Because of their broad expression pattern sst, SS and CST interactions may play regulatory roles in both physiology and pathophysiology in mammalian organisms. SS analogue treatment strategies as well as the use of SS analogues for diagnostic purposes have been established in diseases of different origins. This review focuses on the currently determined role for SS analogues in today's clinical practice and the potential clinical prospects for SS, CST and sst interactions in the future, with a focus on neuroendocrine and non-neuroendocrine tumours and immune-mediated diseases. Moreover, the role of new SS analogues and new insights in sst physiology will be discussed.
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Affiliation(s)
- V A S H Dalm
- Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
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Gahete MD, Durán-Prado M, Luque RM, Martínez-Fuentes AJ, Vázquez-Martínez R, Malagón MM, Castaño JP. Are somatostatin and cortistatin two siblings in regulating endocrine secretions? In vitro work ahead. Mol Cell Endocrinol 2008; 286:128-34. [PMID: 18215456 DOI: 10.1016/j.mce.2007.11.013] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2007] [Revised: 11/17/2007] [Accepted: 11/17/2007] [Indexed: 10/22/2022]
Abstract
Somatostatin (SRIF) and cortistatin (CST) are two cyclic peptides sharing remarkable structural, pharmacological and functional similarities. Both peptides bind all somatostatin receptors subtypes (sst1-5) with comparable affinities, which may explain the considerable similitude between their actions, particularly on endocrine targets. However, the expression patterns of both peptides do not overlap in human tissues, and they are regulated by different stimuli, suggesting that SRIF and CST can exert unique roles. In fact, CST can bind other receptors, different to ssts (e.g. ghrelin receptor, GHS-R and the MrgX2 receptor), which may be involved in those differential actions. In this review, we have summarized the limited knowledge gathered so far regarding the in vitro actions exerted by CST in different endocrine systems under normal and pathophysiological conditions, and have compared them with the well established functions known for SRIF on these systems. Available data suggests that CST substantially reproduces, but not fully mimics the "in vitro" effects of SRIF on pituitary secretions of human and animal models. Conversely, the functions of CST in the majority of peripheral endocrine (and non-endocrine) tissues are still unknown. Notwithstanding this, the differential tissue expression pattern of SRIF, CST and their receptors suggests that CST may act as a mere natural SRIF analogue in a number of tissues but in some endocrine tissues it may play a predominant, unique regulatory role with potential pathophysiological relevance. The challenge is now to find the genuine differences between these seemingly identical endocrine siblings.
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Affiliation(s)
- Manuel D Gahete
- Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain
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Zatelli MC, Ambrosio MR, Bondanelli M, degli Uberti EC. In vitro testing of new somatostatin analogs on pituitary tumor cells. Mol Cell Endocrinol 2008; 286:187-91. [PMID: 18243520 DOI: 10.1016/j.mce.2007.12.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2007] [Revised: 12/03/2007] [Accepted: 12/17/2007] [Indexed: 12/16/2022]
Abstract
Somatostatin has been discovered as a somatotroph release inhibitory factor (SRIF), and, indeed, it has been demonstrated that SRIF and its analogs can inhibit pituitary tumor hormone secretion and control neoplastic bulk. Several in vitro studies have contributed to the current knowledge of the mechanisms by which SRIF and its analogs may influence pituitary adenomas, opening the way to new possible therapeutic strategies. This review focuses on the results obtained by testing several SRIF analogs in vitro on pituitary adenomas, concerning both secretory activity and cell viability. These studies provide the basis for further investigations, both at basic and clinical level, of the application of SRIF analogs in the pituitary field.
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Affiliation(s)
- Maria Chiara Zatelli
- Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Ferrara, Italy.
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39
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Saveanu A, Jaquet P, Brue T, Barlier A. Relevance of coexpression of somatostatin and dopamine D2 receptors in pituitary adenomas. Mol Cell Endocrinol 2008; 286:206-13. [PMID: 18241980 DOI: 10.1016/j.mce.2007.12.008] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2007] [Revised: 12/10/2007] [Accepted: 12/12/2007] [Indexed: 02/06/2023]
Abstract
Dopamine and somatostatin are both involved in the negative control of normal pituitary cells. Dopamine subtype 2 receptor (D2DR) and somatostatin receptor (sst) agonists, mainly directed to sst2, are used in the treatment of pituitary adenomas. Nevertheless, a majority of corticotroph and gonadotroph adenomas and a third of somatotroph adenomas are still not sufficiently controlled by these treatments. D2DR and sst1, 2, 3 and 5 are present in most pituitary adenomas. These receptors may interact by heterodimerization as shown for sst1-sst5, sst5-D2DR, sst2-sst3 and sst2-D2DR suggesting possible additive effects. D2DR and sst2 agonist cotreatment showed limited additivity on GH secretion in acromegaly. Moreover, new chimeric compounds with sst2, D2DR and sst5 affinity have shown an increased control of secretion and/or proliferation of different types of pituitary adenomas in cell culture. Together with the multi-sst ligand drugs recently developed, these dopamine-somatostatin ligands represent a new opportunity in the combinatory treatment of pituitary adenomas.
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Affiliation(s)
- A Saveanu
- Laboratory Interactions Cellulaires Neuroendocriniennes, UMR 6544 CNRS, Institut Fédératif Jean Roche, Faculté de Médecine Nord, Université de la Méditerranée, Marseille, France.
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40
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Thermos K. Novel signals mediating the functions of somatostatin: the emerging role of NO/cGMP. Mol Cell Endocrinol 2008; 286:49-57. [PMID: 18384933 DOI: 10.1016/j.mce.2008.02.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2007] [Revised: 02/11/2008] [Accepted: 02/12/2008] [Indexed: 11/16/2022]
Abstract
The neuropeptide somatostatin is a cyclic tetradecapeptide, which is widely distributed in the peripheral and central nervous system. It mediates a plethora of physiological actions and functions as a neurotransmitter, neuromodulator or trophic factor. Somatostatin activates six receptor subtypes that are expressed differentially in different tissues and are coupled to diverse signalling pathways. In order to elucidate the functional role of the individual receptor subtypes, many investigations focused on the assignment of each receptor to a particular signalling pathway. Signalling pathways involving enzyme (adenylate cyclase, phospholipases, phosphatases) and ion channel systems in native and recombinant receptor systems have been extensively studied. A one to one situation (receptor/pathway) has yet to be established, thus justifying the diverse actions of somatostatin. Recently, a NO/cGMP pathway has been shown to mediate the functions of somatostatin and its receptors. This review will present the findings that support the emerging role of NO/cGMP as a novel signal in SRIF's actions in retinal physiology and somatotroph release.
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Affiliation(s)
- Kyriaki Thermos
- University of Crete, Faculty of Medicine, Department of Basic Sciences, Laboratory of Pharmacology, Heraklion, Crete, Greece.
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Yang SK, Chen C. Involvement of somatostatin receptor subtypes in membrane ion channel modification by somatostatin in pituitary somatotropes. Clin Exp Pharmacol Physiol 2007; 34:1221-7. [PMID: 17892506 DOI: 10.1111/j.1440-1681.2007.04806.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
1. Growth hormone (GH) secretion from pituitary somatotropes is mainly regulated by two hypothalamic hormones, GH-releasing hormone (GHRH) and somatotrophin releasing inhibitory factor (SRIF). 2. Somatotrophin releasing inhibitory factor inhibits GH secretion via activation of specific membrane receptors, somatostatin receptors (SSTRs) and signalling transduction systems in somatotropes. 3. Five subtypes of SSTRs, namely SSTR1, 2, 3, 4 and 5, have been identified, with the SSTR2 subtype divided into SSTR2A and SSTR2B. All SSTRs are G-protein-coupled receptors. 4. Voltage-gated Ca(2+) and K(+) channels on the somatotrope membrane play an important role in regulating GH secretion and SRIF modifies both channels to reduce intracellular free Ca(2+) concentration and GH secretion. 5. Using specific SSTR subtype-specific agonists, it has been found that reduction in Ca(2+) currents by SRIF is mediated by SSTR2 and an increase in K(+) currents is mediated by both SSTR2 and SSTR4 in rat somatotropes.
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Affiliation(s)
- Seung-Kwon Yang
- Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia
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Yang SK, Parkington HC, Epelbaum J, Keating DJ, Chen C. Somatostatin decreases voltage-gated Ca2+ currents in GH3 cells through activation of somatostatin receptor 2. Am J Physiol Endocrinol Metab 2007; 292:E1863-70. [PMID: 17327372 DOI: 10.1152/ajpendo.00047.2007] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
The secretion of growth hormone (GH) is inhibited by hypothalamic somatostatin (SRIF) in somatotropes through five subtypes of the somatostatin receptor (SSTR1-SSTR5). We aimed to characterize the subtype(s) of SSTRs involved in the Ca2+ current reduction in GH3 somatotrope cells using specific SSTR subtype agonists. We used nystatin-perforated patch clamp to record voltage-gated Ca2+ currents, using a holding potential of -80 mV in the presence of K+ and Na+ channel blockers. We first established the presence of T-, L-, N-, and P/Q-type Ca2+ currents in GH3 cells using a variety of channel blockers (Ni+, nifedipine, omega-conotoxin GVIA, and omega-agatoxin IVA). SRIF (200 nM) reduced L- and N-type but not T- or P/Q-type currents in GH3 cells. A range of concentrations of each specific SSTR agonist was tested on Ca2+ currents to find the maximal effective concentration. Activation of SSTR2 with 10(-7) and 10(-8) M L-797,976 decreased the voltage-gated Ca2+ current and abolished any further decrease by SRIF. SSTR1, SSTR3, SSTR4, and SSTR5 agonists at 10(-7) M did not modify the voltage-gated Ca2+ current and did not affect the Ca2+ current response to SRIF. These results indicate that SSTR2 is involved mainly in regulating voltage-gated Ca2+ currents by SRIF, which contributes to the decrease in intracellular Ca2+ concentration and GH secretion by SRIF.
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Affiliation(s)
- Seung-Kwon Yang
- Prince Henry's Institute of Medical Research, PO Box 5152, Clayton, Victoria 3168, Australia
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Zatelli MC, Ambrosio MR, Bondanelli M, Uberti ECD. Control of pituitary adenoma cell proliferation by somatostatin analogs, dopamine agonists and novel chimeric compounds. Eur J Endocrinol 2007; 156 Suppl 1:S29-S35. [PMID: 17413185 DOI: 10.1530/eje.1.02352] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The antisecretory effects of somatostatin (SRIH) and its analogs are widely recognized and provide the basis for treatment of hormonal hypersecretion in patients with pituitary adenomas, especially in the settings of acromegaly. Dopamine (DA) agonists have also been used for medical treatment of prolactin and/or GH hypersecretion, and recent evidence points to an even greater antisecretory effect for a chimeric molecule, having high affinity for both SRIH and DA receptors. Evidence for an antiproliferative effect of these compounds has also been provided. This review focuses on the antiproliferative effects of SRIH and its analogs, of DA and chimeric compounds on pituitary adenomas, and on the clinical consequences on tumor volume of pharmacological treatment of pituitary adenomas with these drugs.
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van der Hoek J, Lamberts SWJ, Hofland LJ. Preclinical and clinical experiences with the role of somatostatin receptors in the treatment of pituitary adenomas. Eur J Endocrinol 2007; 156 Suppl 1:S45-S51. [PMID: 17413188 DOI: 10.1530/eje.1.02350] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The patho-physiological role of somatostatin receptor subtypes (sst) in neuro endocrine diseases has gained enhanced scientific interest in the past few years. The development of novel somatotropin-release inhibiting factor analogs, both sst-specific and universal ligands, seem promising as a tool to further increase fundamental insights in sst function. Eventually, this research should result in novel medical therapeutic opportunities in patients suffering from neuro-endocrine diseases. In the present review, the functional role of sst in all types of pituitary adenomas, based on recent preclinical and clinical studies, is being discussed.
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Taboada GF, Luque RM, Bastos W, Guimarães RFC, Marcondes JB, Chimelli LMC, Fontes R, Mata PJP, Filho PN, Carvalho DP, Kineman RD, Gadelha MR. Quantitative analysis of somatostatin receptor subtype (SSTR1-5) gene expression levels in somatotropinomas and non-functioning pituitary adenomas. Eur J Endocrinol 2007; 156:65-74. [PMID: 17218727 DOI: 10.1530/eje.1.02313] [Citation(s) in RCA: 161] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
OBJECTIVE It is believed that the variable effectiveness of somatostatin analogs in post-surgical management of somatotropinomas and non-functioning pituitary adenomas (NFPA) may be due in part to variable expression of somatostatin receptor isoforms (SSTR1-5), within and between pituitary tumor types. DESIGN AND METHODS Quantitative real-time RT-PCR was used to compare absolute mRNA copy numbers for all five SSTR isoforms in 23 somatotropinomas and 19 NFPA. RESULTS Somatostatin receptor subtype 5 mRNA was present at the highest level in somatotropinomas, followed by SSTR2>SSTR3>>SSTR1>>>SSTR4. In contrast, SSTR3 mRNA was present at the highest level in NFPA, followed by SSTR2, while SSTR1, SSTR4, and SSTR5 transcripts were only detectable in select tumors. Among somatotropinomas, a positive correlation was found between SSTR2 mRNA levels and the percent decrease of GH (%GH) after 3 and 6 months of therapy with octreotide long acting repeatable (LAR) (r=0.51 and r=0.66; P=0.05 and P=0.008). Also the percent decrease of IGF-I (%IGF-I) after 3 months of octreotide LAR was negatively correlated with SSTR5 and %IGF-I after 6 months of octreotide LAR was positively correlated with SSTR2. CONCLUSIONS The present report is a large series examining SSTR mRNA levels in somatotropinomas and NFPA. These initial findings suggest that detailed knowledge of the SSTR mRNA expression profile in somatotropinomas can help to predict the hormonal response to therapy with LAR. Also, it appears that SSTR3 in NFPA may be a potential target for SSTR3 preferential or universal ligands such as pasireotide.
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Affiliation(s)
- Giselle F Taboada
- Serviços de Endocrinologia, Neurocirurgia, Anatomia Patológica, Hospital Universitário Clementino Fraga Filho, Rio de Janeiro, Brazil
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Casarini AP, Pinto EM, Jallad RS, Giorgi RR, Giannella-Neto D, Bronstein MD. Dissociation between tumor shrinkage and hormonal response during somatostatin analog treatment in an acromegalic patient: preferential expression of somatostatin receptor subtype 3. J Endocrinol Invest 2006; 29:826-30. [PMID: 17114915 DOI: 10.1007/bf03347378] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION About a third of acromegalic patients is resistant to available SS analogs (SA), octreotide (OCT) and lanreotide (LAN). Such resistance is related to reduction of SS receptor (SSTR) density or to a different expression of SSTR subtypes. There are 5 known SSTR subtypes. SSTR2 and SSTR5 are usually expressed in GH-secreting pituitary tumors, and both SA bind preferentially to SSTR2 and, to a lesser extent, to SSTR5. We herein describe an acromegalic patient who presented impressive tumor shrinkage without hormonal normalization during primary therapy with SA. MATERIAL AND METHODS This 23-yr-old male acromegalic patient was treated with slow-release LAN (LAN-SR), 30 mg every 10 days for six months, followed by OCT-LAR, 30 mg every 28 days for an additional six months with a 75% tumor volume reduction but without GH and IGF-I normalization. Subsequently, he underwent pituitary surgery and expression of SSTR in the removed tumor was performed by real time RT-PCR by the 2-deltaCt method, using GAPDH as internal control. All PCR products were confirmed by automated sequencing. RESULTS SSTR expression revealed an unusual profile, with almost exclusively expression of SSTR3. CONCLUSIONS These unusual clinical and receptor subtypes profile suggest an important role of SSTR3 on tumor shrinkage. The low affinity of LAN and OCT for this SSTR subtype could be compensated by its high expression in this GH-secreting pituitary macroadenoma.
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Affiliation(s)
- A P Casarini
- Laboratory Cellular and Molecular Endocrinology (LIM25), Hospital of Clínicas, University of Sao Paulo Medical School, Sao Paulo, Brazil
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Tagliati F, Zatelli MC, Bottoni A, Piccin D, Luchin A, Culler MD, Degli Uberti EC. Role of complex cyclin d1/cdk4 in somatostatin subtype 2 receptor-mediated inhibition of cell proliferation of a medullary thyroid carcinoma cell line in vitro. Endocrinology 2006; 147:3530-8. [PMID: 16601140 DOI: 10.1210/en.2005-1479] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Somatostatin (SRIH) inhibits cell proliferation by interacting with five distinct SRIH receptor subtypes (SSTRs) activating several pathways in many tissues. We previously demonstrated that SRIH, by activating Src homology-2-containing protein, inhibits cell proliferation of the human medullary thyroid carcinoma cell line, TT, which expresses all SSTRs. However, the effects of SRIH on cell cycle proteins have not been investigated so far. We therefore evaluated the effects of SRIH and a selective SSTR2 agonist on cell cycle protein expression, mainly focusing on cyclin D1 and its associated kinases. Our data show that SRIH and the selective SSTR2 agonist, BIM-23120, reduce cell proliferation and DNA synthesis as well as induce a delay of the cell cycle in G(2)/M phase. Moreover, treatment with both SRIH and BIM-23120 decreases cyclin D1 levels, with a parallel increase in phosphocyclin D1 levels, suggesting protein degradation. Moreover, our data show an increase in glycogen synthase kinase-3beta activity, which triggers phosphorylation-dependent cyclin D1 degradation. Indeed, we observed a reduction in cyclin D1 protein half-life under treatment with SRIH or the SSTR2 selective agonist. A reduction in cdk4 protein levels is also observed with a parallel reduction in Rb phosphorylation levels at Ser-780. Our data indicate that the subtype 2 receptor-mediated antiproliferative effect of SRIH on TT cell proliferation may be exerted through a decrease in cyclin D1 levels.
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Affiliation(s)
- Federico Tagliati
- Section of Endocrinology, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Via Savonarola 9, 44100 Ferrara, Italy
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Wu P, Mao JD, Yan JY, Rui J, Zhao YC, Li XH, Xu GQ. Correlation between the expressions of gastrin, somatostatin and cyclin and cyclin-depend kinase in colorectal cancer. World J Gastroenterol 2006; 11:7211-7. [PMID: 16437675 PMCID: PMC4725074 DOI: 10.3748/wjg.v11.i45.7211] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To explore the correlation between the expressions of gastrin (GAS), somatostatin (SS) and cyclin, cyclin-dependent kinase (CDK) in colorectal cancer, and to detect the specific regulatory sites where gastrointestinal hormone regulates cell proliferation. METHODS Seventy-nine resected large intestine carcinomatous specimens were randomly selected. Immunohistochemical staining for GAS, SS, cyclin D1, cyclin E, cyclin A, cyclin B1, CDK2 and CDK4 was performed according to the standard streptavidin-biotin-peroxidase (S-P) method. According to the semi-quantitative integral evaluation, SS and GAS were divided into high, middle and low groups. Cyclin D1, cyclin E, cyclin A, cyclin B1, CDK2, CDK4 expressions in the three GAS and SS groups were assessed. RESULTS The positive expression rate of cyclin D1 was significantly higher in high (78.6%, 11/14) and middle GAS groups (73.9%, 17/23) than in low GAS group (45.2%, 19/42) (P<0.05, c2(high vs low) = 4.691; P<0.05, c2(middle vs low) = 4.945). The positive expression rate of cyclin A was significantly higher in high (100%, 14/14) and middle GAS groups (82.6%, 19/23) than in low GAS group (54.8%, 23/42) (P<0.01, c2(high vs low) = 9.586; P<0.05, c2(middle vs low) = 5.040). The positive expression rate of CDK2 was significantly higher in high (92.9%, 13/14) and middle GAS groups (87.0%, 20/23) than in low GAS group (50.0%, 21/42) (P<0.01, c2(high vs low) = 8.086; P<0.01, c2(middle vs low) = 8.715). The positive expression rate of CDK4 was significantly higher in high (78.6%, 11/14) and middle GAS groups (78.3%, 18/23) than in low GAS group (42.9%, 18/42) (P<0.05, c2(high vs low) = 5.364; P<0.01, c2(middle vs low) = 7.539). The positive expression rate of cyclin E was prominently higher in low SS group (53.3%, 24/45) than in high (9.1%, 1/11) and middle (21.7%, 5/23) SS groups (P<0.05, c2(high vs low) = 5.325; P<0.05, c2(middle vs low) = 6.212). The positive expression rate of CDK2 was significantly higher in low SS group (77.8%, 35/45) than in high SS group (27.3%, 3/11) (P<0.01, c2(high vs low) = 8.151). There was a significant positive correlation between the integral ratio of GAS to SS and the semi-quantitative integral of cyclin D1, cyclin E, cyclin A, CDK2, CDK4 (P<0.05, (D1)r(s) = 0.252; P<0.01, (E)r(s) = 0.387; P<0.01, (A)r(s) = 0.466; P<0.01, (K2)r(s) = 0.519; P<0.01, (K4)r(s) = 0.434). CONCLUSION The regulation and control of gastrin, SS in colorectal cancer cell growth may be directly related to the abnormal expressions of cyclins D1, A, E, and CDK2, CDK4. The regulatory site of GAS in the cell cycle of colorectal carcinoma may be at the G(1), S and G(2) phases. The regulatory site of SS may be at the entrance of S phase.
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Affiliation(s)
- Pei Wu
- Department of General Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu 241001, Anhui Province, China.
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Gola M, Doga M, Bonadonna S, Mazziotti G, Vescovi PP, Giustina A. Neuroendocrine tumors secreting growth hormone-releasing hormone: Pathophysiological and clinical aspects. Pituitary 2006; 9:221-9. [PMID: 17036195 DOI: 10.1007/s11102-006-0267-0] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Hypothalamic GHRH is secreted into the portal system, binds to specific surface receptors of the somatotroph cell and elicits intracellular signals that modulate pituitary GH synthesis and/or secretion. Moreover, GHRH is synthesized and expressed in multiple extrapituitary tissues. Excessive peripheral production of GHRH by a tumor source would therefore be expected to cause somatotroph cell hyperstimulation, increased GH secretion and eventually pituitary acromegaly. Immunoreactive GHRH is present in several tumors, including carcinoid tumors, pancreatic cell tumors, small cell lung cancers, endometrial tumors, adrenal adenomas, and pheochromocytomas which have been reported to secrete GHRH. Acromegaly in these patients, however, is uncommon. The distinction of pituitary vs. extrapituitary acromegaly is extremely important in planning effective management. Regardless of the cause, GH and IGF-1 are invariably elevated and GH levels fail to suppress (<1 microg/l) after an oral glucose load in all forms of acromegaly. Dynamic pituitary tests are not helpful in distinguishing acromegalic patients with pituitary tumors from those harbouring extrapituitary tumors. Plasma GHRH levels are usually elevated in patients with peripheral GHRH-secreting tumors, and are normal or low in patients with pituitary acromegaly. Unique and unexpected clinical features in an acromegalic patient, including respiratory wheezing or dyspnea, facial flushing, peptic ulcers, or renal stones sometimes are helpful in alerting the physician to diagnosing non pituitary endocrine tumors. If no facility to measure plasma GHRH is available, and in the absence of MRI evidence of pituitary adenoma, a CT scan of the thorax and abdominal ultrasound could be performed to exclude with good approximation the possibility of an ectopic GHRH syndrome. Surgical resection of the tumor secreting ectopic GHRH should be the logical approach to a patient with ectopic GHRH syndrome. Standard chemotherapy directed at GHRH-producing carcinoid tumors is generally unsuccessful in controlling the activated GH axis. Somatostatin analogs provide an effective option for medical management of carcinoid patients, especially those with recurrent disease. In fact, long-acting somatostatin analogs may be able to control not only the ectopic hormonal secretion syndrome, but also, in some instances, tumor growth. Therefore, although cytotoxic chemotherapy, pituitary surgery, or irradiation still remain available therapeutic options, long-acting somatostatin analogs are now preferred as a second-line therapy in patients with carcinoid tumors and ectopic GHRH-syndrome.
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Affiliation(s)
- Monica Gola
- Endocrine Section, Department of Internal Medicine, University of Brescia, Brescia, Italy
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50
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Zatelli MC, Piccin D, Ambrosio MR, Bondanelli M, degli Uberti EC. Antiproliferative effects of somatostatin analogs in pituitary adenomas. Pituitary 2006; 9:27-34. [PMID: 16703406 DOI: 10.1007/s11102-006-7822-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The antisecretory effects of somatostatin (SRIF) and its analogs are widely recognised and provide the basis for treatment of hormonal hypersecretion in pituitary adenomas, especially in the settings of acromegaly. Evidence for an antiproliferative effect of these compounds has also been provided. This review focuses on the mechanisms transducing the antiproliferative effects of SRIF and its analogs on pituitary adenomas, and on the clinical consequences on tumor volume of pharmacological treatment of pituitary adenomas with these drugs.
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Affiliation(s)
- Maria Chiara Zatelli
- Section of Endocrinology, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, 44100, Ferrara, Italy
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