title: Dopamine receptor type 2 (DRD2) and somatostatin receptor type 2 (SSTR2) agonists are effective in inhibiting proliferation of progenitor/stem-like cells isolated from nonfunctioning pituitary tumors.
abstract: The role of progenitor/stem cells in pituitary tumorigenesis, resistance to pharmacological treatments and tumor recurrence is still unclear. This study investigated the presence of progenitor/stem cells in non-functioning pituitary tumors (NFPTs) and tested the efficacy of dopamine receptor type 2 (DRD2) and somatostatin receptor type 2 (SSTR2) agonists to inhibit in vitro proliferation. They found that 70% of 46 NFPTs formed spheres co-expressing stem cell markers, transcription factors (DAX1, SF1, ERG1) and gonadotropins. Analysis of tumor behavior showed that spheres formation was associated with tumor invasiveness (OR = 3,96; IC: 1.05-14.88, p = 0.036). The in vitro reduction of cell proliferation by DRD2 and SSTR2 agonists (31 ± 17% and 35 ± 13% inhibition, respectively, p < 0.01 vs. basal) occurring in about a half of NFPTs cells was conserved in the corresponding spheres. Accordingly, these drugs increased cyclin-dependent kinase inhibitor p27 and decreased cyclin D3 expression in spheres. In conclusion, they provided further evidence for the existence of cells with a progenitor/stem cells-like phenotype in the majority of NFPTs, particularly in those with invasive behavior, and demonstrated that the antiproliferative effects of dopaminergic and somatostatinergic drugs were maintained in progenitor/stem-like cells.
authors.affiliation: Endocrine Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.|Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
authors.forename: E
authors.identifier: 0000-0002-4424-7895
authors.initials: E
authors.lastname: Peverelli
authors.affiliation: Endocrine Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.|Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Giardino
authors.affiliation: Endocrine Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.|Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Treppiedi
authors.affiliation: Stem Cell Laboratory, Department of Pathophysiology and Transplantation, University of Milan, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, Ystem Srl, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Meregalli
authors.affiliation: Stem Cell Laboratory, Department of Pathophysiology and Transplantation, University of Milan, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, Ystem Srl, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Belicchi
authors.affiliation: Division of Pathology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy.|Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi" (INGM), Milan, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Vaira
authors.affiliation: Endocrinology Service, Department of Biomedical Science for Health, University of Milan, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Corbetta
authors.affiliation: Laboratory of Experimental Endocrinology, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Verdelli
authors.affiliation: Endocrine Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.|Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Verrua
authors.affiliation: Endocrine Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.|Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
authors.forename: A L
authors.initials: AL
authors.lastname: Serban
authors.affiliation: Neurosurgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan.
authors.forename: M
authors.initials: M
authors.lastname: Locatelli
authors.affiliation: Neurosurgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan.
authors.forename: G
authors.initials: G
authors.lastname: Carrabba
authors.affiliation: Department of Clinical Sciences and Community Health, University of Milano, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Gaudenzi
authors.affiliation: Endocrine Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.|Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Malchiodi
authors.affiliation: Stem Cell Laboratory, Department of Pathophysiology and Transplantation, University of Milan, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, Ystem Srl, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Cassinelli
authors.affiliation: Endocrine Unit, IRCCS Istituto Clinico Humanitas, Department of Biomedical Sciences, Humanitas University, Rozzano, Italy.
authors.forename: A G
authors.initials: AG
authors.lastname: Lania
authors.affiliation: Division of Pathology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy.|Department of Biomedical, Surgical and Dental Sciences, University of Milan Medical School.
authors.forename: S
authors.initials: S
authors.lastname: Ferrero
authors.affiliation: Division of Pathology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy.|Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Bosari
authors.affiliation: Department of Clinical Sciences and Community Health, University of Milano, Milan, Italy.|Endocrine and Metabolic Research Laboratory, Istituto Auxologico Italiano-IRCCS, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Vitale
authors.affiliation: Stem Cell Laboratory, Department of Pathophysiology and Transplantation, University of Milan, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, Ystem Srl, Milan, Italy.
authors.forename: Y
authors.initials: Y
authors.lastname: Torrente
authors.affiliation: Endocrine Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.|Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Spada
authors.affiliation: Endocrine Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.|Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Mantovani
mesh_terms: D000328:Adult; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D056743:Cyclin D3 / Q000096:biosynthesis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D057137:DAX-1 Orphan Nuclear Receptor / Q000096:biosynthesis; D015259:Dopamine Agents / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D000072237:ERG1 Potassium Channel / Q000096:biosynthesis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006062:Gonadotropins / Q000096:biosynthesis; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects; D010911:Pituitary Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000072260:RNA Splicing Factors / Q000096:biosynthesis; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000235:genetics*; D017481:Receptors, Somatostatin / Q000819:agonists / Q000235:genetics*; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology
chemical_list: D056743:Cyclin D3; D057137:DAX-1 Orphan Nuclear Receptor; C581293:DRD2 protein, human; D015259:Dopamine Agents; D000072237:ERG1 Potassium Channel; D006062:Gonadotropins; C539965:NR0B1 protein, human; D000072260:RNA Splicing Factors; D017448:Receptors, Dopamine D2; D017481:Receptors, Somatostatin; C107467:SF1 protein, human; C574734:SSTR2 protein, human; D050760:Cyclin-Dependent Kinase Inhibitor p27
keywords: dopamine; drug resistance; pituitary adenomas; somatostatin; tumor stem cells