title: Phenotypical and Pharmacological Characterization of Stem-Like Cells in Human Pituitary Adenomas.
abstract: The presence and functional role of tumor stem cells in benign tumors, and in human pituitary adenomas in particular, is a debated issue that still lacks a definitive formal demonstration. Fifty-six surgical specimens of human pituitary adenomas were processed to establish tumor stem-like cultures by selection and expansion in stem cell-permissive medium or isolating CD133-expressing cells. Phenotypic and functional characterization of these cells was performed (1) ex vivo, by immunohistochemistry analysis on paraffin-embedded tissues; (2) in vitro, attesting marker expression, proliferation, self-renewal, differentiation, and drug sensitivity; and (3) in vivo, using a zebrafish model. Within pituitary adenomas, we identified rare cell populations expressing stem cell markers but not pituitary hormones; we isolated and expanded in vitro these cells, obtaining fibroblast-free, stem-like cultures from 38 pituitary adenoma samples. These cells grow as spheroids, express stem cell markers (Oct4, Sox2, CD133, and nestin), show sustained in vitro proliferation as compared to primary cultures of differentiated pituitary adenoma cells, and are able to differentiate in hormone-expressing pituitary cells. Besides, pituisphere cells, apparently not tumorigenic in mice, engrafted in zebrafish embryos, inducing pro-angiogenic and invasive responses. Finally, pituitary adenoma stem-like cells express regulatory pituitary receptors (D2R, SSTR2, and SSTR5), whose activation by a dopamine/somatostatin chimeric agonist exerts antiproliferative effects. In conclusion, we provide evidence that human pituitary adenomas contain a subpopulation fulfilling biological and phenotypical signatures of tumor stem cells that may represent novel therapeutic targets for therapy-resistant tumors.
authors: Pharmacology Section, Department of Internal Medicine, University of Genova, Viale Benedetto XV, 2, 16132, Genoa, Italy.
authors: Roberto
authors: R
authors: Würth
authors: Pharmacology Section, Department of Internal Medicine, University of Genova, Viale Benedetto XV, 2, 16132, Genoa, Italy.|Centre of Excellence for Biomedical Research (CEBR), University of Genova, Genoa, Italy.
authors: Federica
authors: F
authors: Barbieri
authors: Pharmacology Section, Department of Internal Medicine, University of Genova, Viale Benedetto XV, 2, 16132, Genoa, Italy.
authors: Alessandra
authors: A
authors: Pattarozzi
authors: Department of Clinical Sciences and Community Health, University of Milano, Milan, Italy.
authors: Germano
authors: G
authors: Gaudenzi
authors: Pharmacology Section, Department of Internal Medicine, University of Genova, Viale Benedetto XV, 2, 16132, Genoa, Italy.|Centre of Excellence for Biomedical Research (CEBR), University of Genova, Genoa, Italy.
authors: Federico
authors: F
authors: Gatto
authors: Department of Neurosciences, University of Genova, Genoa, Italy.|Department of Neurosurgery, IRCCS-AOU San Martino-IST, Genoa, Italy.
authors: Pietro
authors: P
authors: Fiaschi
authors: Department of Pathology, IRCCS-AOU San Martino-IST, Genoa, Italy.
authors: Jean-Louis
authors: JL
authors: Ravetti
authors: Department of Neurosciences, University of Genova, Genoa, Italy.|Department of Neurosurgery, IRCCS-AOU San Martino-IST, Genoa, Italy.
authors: Gianluigi
authors: G
authors: Zona
authors: Laboratory of Gene Transfer, IRCCS-AOU San Martino-IST, Genoa, Italy.
authors: Antonio
authors: A
authors: Daga
authors: Department of Clinical Sciences and Community Health, University of Milano, Milan, Italy.|Endocrine and Metabolic Research Laboratory, Istituto Auxologico Italiano-IRCCS, Milan, Italy.
authors: Luca
authors: L
authors: Persani
authors: Pharmacology Section, Department of Internal Medicine, University of Genova, Viale Benedetto XV, 2, 16132, Genoa, Italy.|Centre of Excellence for Biomedical Research (CEBR), University of Genova, Genoa, Italy.
authors: Diego
authors: D
authors: Ferone
authors: Department of Clinical Sciences and Community Health, University of Milano, Milan, Italy.|Endocrine and Metabolic Research Laboratory, Istituto Auxologico Italiano-IRCCS, Milan, Italy.
authors: Giovanni
authors: G
authors: Vitale
authors: Pharmacology Section, Department of Internal Medicine, University of Genova, Viale Benedetto XV, 2, 16132, Genoa, Italy. tullio.florio@unige.it.|Centre of Excellence for Biomedical Research (CEBR), University of Genova, Genoa, Italy. tullio.florio@unige.it.
authors: Tullio
authors: http://orcid.org/0000-0002-2394-996X
authors: T
authors: Florio
mesh_terms: D000071916:AC133 Antigen / Q000378:metabolism; D000236:Adenoma / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D006801:Humans; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000166:cytology*; D010902:Pituitary Gland / Q000473:pathology*; D010911:Pituitary Neoplasms / Q000378:metabolism / Q000473:pathology*; D013004:Somatostatin; D014407:Tumor Cells, Cultured
chemical_list: D000071916:AC133 Antigen; D013004:Somatostatin
keywords: Cancer stem cells; Cell proliferation; Pituitary adenoma; Somatostatin receptors; Spherogenesis