Cellular and molecular specificity of pituitary gland physiology

The anterior pituitary gland has the ability to respond to complex signals derived from central and peripheral systems. Perception of these signals and their integration are mediated by cell interactions and cross-talk of multiple signaling transduction pathways and transcriptional regulatory networks that cooperate for hormone secretion, cell plasticity, and ultimately specific pituitary responses that are essential for an appropriate physiological response. We discuss the physiopathological and molecular mechanisms related to this integrative regulatory system of the anterior pituitary gland and how it contributes to modulate the gland functions and impacts on body homeostasis.Fil: Perez Castro, Carolina Ines. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires; ArgentinaFil: Renner, Ulrich. Max Planck Institut Für Psychiatrie; AlemaniaFil: Haedo, Mariana Raquel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires; ArgentinaFil: Stalla, Gunter K.. Max Planck Institut Für Psychiatrie; AlemaniaFil: Arzt, Eduardo Simon. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires; Argentin

Pituitary tumors: Cell type-specific roles for BMP-4

BMP-4 plays a crucial role not only in the formation of the anterior pituitary during embryo development but also in the pathogenesis of pituitary tumors in adults. In tumor cells, BMP-4 promotes prolactin secretion and lactotroph cell proliferation through a Smad-estrogen receptor crosstalk but it inhibits ACTH production and cell proliferation of corticotrophs. In addition, BMP-4 increases GH secretion in rat pituitary tumor somatolactotroph GH3 cells and FSHβ subunit gene transcription in the murine gonadotroph cell line, LβT2. Therefore, BMP-4 has a differential role on different types of pituitary tumors: it promotes pituitary prolactinoma while it inhibits corticotroph pathogenesis in Cushing's disease. The modulation of BMP-4 also plays an important role in the therapeutic mechanism of action of bromocriptine, somatostatin analogs and retinoic acid.Fil: Labeur, Marta. Max Planck Institute of Psychiatry; AlemaniaFil: Páez Pereda, Marcelo. Max Planck Institute of Psychiatry; AlemaniaFil: Haedo, Mariana Raquel. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular. Laboratorio de Fisiología y Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Arzt, Eduardo Simon. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular. Laboratorio de Fisiología y Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Stalla, Günter K.. Max Planck Institute of Psychiatry; Alemani

Autocrine IL-6 mediates pituitary tumor senescence

Cellular senescence is a stable proliferative arrest state. Pituitary adenomas are frequent and mostly benign, but the mechanism for this remains unknown. IL-6 is involved in pituitary tumor progression and is produced by the tumoral cells. In a cell autonomous fashion, IL-6 participates in oncogene-induced senescence in transduced human melanocytes. Here we prove that autocrine IL-6 participates in pituitary tumor senescence. Endogenous IL-6 inhibition in somatotroph MtT/S shRNA stable clones results in decreased SA-β-gal activity and p16INK4a but increased pRb, proliferation and invasion. Nude mice injected with IL-6 silenced clones develop tumors contrary to MtT/S wild type that do not, demonstrating that clones that escape senescence are capable of becoming tumorigenic. When endogenous IL-6 is silenced, cell cultures derived from positive SA-β-gal human tumor samples decrease the expression of the senescence marker. Our results establish that IL-6 contributes to maintain senescence by its autocrine action, providing a natural model of IL-6 mediated benign adenoma senescence.Fil: Sapochnik, Melanie Denise. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Haedo, Mariana Raquel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Fuertes, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Ajler, Pablo. Hospital Italiano; ArgentinaFil: Carrizo, Guillermo. Hospital Italiano; ArgentinaFil: Cervio, Andrés. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Sevlever, Gustavo. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Stalla, Günter K.. Max Planck Institute of Psychiatry; AlemaniaFil: Arzt, Eduardo Simon. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular. Laboratorio de Fisiología y Biología Molecular; Argentin

Cytokines and genes in pituitary tumorigenesis: RSUME role in cell biology

Cytokines of the IL-6 or gp130 family regulate many cellular responses and play regulatory roles in numerous tissues, and are placed as auto-paracrine regulators of pituitary function acting in normal and tumoral anterior pituitary cells. Especially, IL-6 has a regulatory role in the hormone secretion and growth of the anterior pituitary and is involved in adenoma pathogenesis. Recently, IL-6 has been shown to mediate oncogene-induced senescence (OIS). IL-6 might participate in such a process in adenomas pituitary as well. From pituitary tumoral gp130 overexpressing cells, an unknown protein, RSUME, has been cloned. RSUME is induced by hypoxia in pituitary tumors and regulate pathways involved in angiogenic and tumorigenic processes (NF-κB/IκB and HIF-1α pathways). Thus, it could have an important role in the development of the pituitary tumors. Copyright © 2010 S. Karger AG, Basel.Fil: Fuertes, Mariana. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gerez, Juan Atilio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; ArgentinaFil: Haedo, Mariana Raquel. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Giacomini, Damiana Paula. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Páez Pereda, Marcelo. Affectis Pharmaceuticals; AlemaniaFil: Labeur, Marta. Max Planck Institute of Psychiatry; AlemaniaFil: Stalla, Günter K. Max Planck Institute of Psychiatry; AlemaniaFil: Arzt, Eduardo Simon. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Novel Medical Therapies for Pituitary Tumors

Despite considerable progress, there is still no medical treatment available for some kinds of pituitary tumors, in particular hormone inactive adenomas and corticotroph pituitary tumors. Surgical removal or at least debulking of the tumor is the only option to treat these kinds of tumors apart from rarely applied radiotherapy. Moreover, treatment resistance is present in a considerable proportion of patients bearing pituitary tumors, for which medical treatment regimens are already available (prolactinomas, somatotroph adenomas). Thus, novel or improved medical treatment strategies would be desirable. Here, we summarize preclinical and clinical findings about the hormone and growth-suppressive action of various drugs, which will probably lead to novel future medical treatment concepts for pituitary tumors.Fil: Theodoropoulou, M.. Max Planck Institute of Psychiatry; AlemaniaFil: Labeur, M.. Max Planck Institute of Psychiatry; AlemaniaFil: Páez Pereda, Marcelo. Max Planck Institute of Psychiatry; AlemaniaFil: Haedo, Mariana Raquel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Perone, Marcelo Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Renner, U.. Max Planck Institute of Psychiatry; AlemaniaFil: Arzt, Eduardo Simon. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Stalla, G.K.. Max Planck Institute of Psychiatry; Alemani

Effect of SOM230 (Pasireotide) on corticotropic cells: Action in dogs with Cushing's disease

SOM230 (pasireotide) is a multiligand somatostatin (SRIF) analog able to bind to somatostatin receptor (SSTR) subtypes 1, 2, 3 and 5, and trigger antisecretory and antiproliferative signaling cascades. Canines have become in vivo models to test the pharmacological treatment of corticotropinomas because they frequently develop Cushing's disease in a spontaneous manner, due to adrenocorticotropic hormone (ACTH)-producing pituitary adenomas. Different levels of expression of SSTR2 and SSTR5 have been shown in both mouse AtT20 cells and canine tumoral corticotropinoma cells. The objective of this study was to evaluate whether SOM230 controls both tumor cell growth and hormone synthesis, therefore controlling the disease. SOM230 was tested in dogs suffering from Cushing's disease (10 animals were treated continuously during 6 months, and another 10 were treated with 3 cycles consisting of 2 months of treatment followed by a 2-month rest period). A significant decrease in ACTH, urinary cortisol creatinine ratio, adenoma size (magnetic nuclear resonance) and improvement of clinical signs were obtained, without side effects. AtT20 cells treated with SOM230 suppressed pro-opiomelanocortin (POMC) promoter activity through SSTR2, via the G i α-subunit, and reduced Nur77/Nurr1 transcriptional activity. We conclude that SOM230, in addition to its well-described antisecretory effects, inhibits, as shown in AtT20 cells, ACTH synthesis at the POMC transcriptional level, an effect mediated mainly through SSTR2, and limits tumor growth. The controlled Cushing's disease in the dogs that received the treatment indicates that SOM230 has a potential therapeutic use in humans suffering from Cushing's disease.Fil: Castillo, Victor. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias; ArgentinaFil: Theodoropoulou, Marily. Max Planck Institute of Psychiatry; AlemaniaFil: Stalla, Johanna. Max Planck Institute of Psychiatry; AlemaniaFil: Gallelli, Maria Florencia. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cabrera Blatter, Maria Fernanda. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias; ArgentinaFil: Haedo, Mariana Raquel. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular. Laboratorio de Fisiología y Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Labeur, Marta. Max Planck Institute of Psychiatry; AlemaniaFil: Schmid, Herbert A.. Novartis Institutes for Biomedical Research; SuizaFil: Stalla, Günter K.. Max Planck Institute of Psychiatry; AlemaniaFil: Arzt, Eduardo Simon. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular. Laboratorio de Fisiología y Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin