title: Overexpression of stromal cell-derived factor 1 and its receptor CXCR4 induces autocrine/paracrine cell proliferation in human pituitary adenomas.
abstract: OBJECTIVE
  Hypothalamic or locally produced growth factors and cytokines control pituitary development, functioning, and cell division. We evaluated the expression of the chemokine stromal cell-derived factor 1 (SDF1) and its receptor CXCR4 in human pituitary adenomas and normal pituitary tissues and their role in cell proliferation.
  
  
  METHODS
  The expression of SDF1 and CXCR4 in 65 human pituitary adenomas and 4 human normal pituitaries was determined by reverse transcription-PCR, immunohistochemistry, and confocal immunofluorescence. The proliferative effect of SDF1 was evaluated in eight fibroblast-free human pituitary adenoma cell cultures.
  
  
  RESULTS
  CXCR4 mRNA was expressed in 92% of growth hormone (GH)-secreting pituitary adenomas (GHoma) and 81% of nonfunctioning pituitary adenomas (NFPA), whereas SDF1 was identified in 63% and 78% of GHomas and NFPAs, respectively. Immunostaining for CXCR4 and SDF1 showed a strong homogenous labeling in all tumoral cells in both GHomas and NFPAs. In normal tissues, CXCR4 and SDF1 were expressed only in a subset of anterior pituitary cells, with a lower expression of SDF1 compared with its cognate receptor. CXCR4 and SDF1 were not confined to a specific cell population in the anterior pituitary but colocalized with discrete subpopulations of GH-, prolactin-, and adrenocorticorticotropic hormone-secreting cells. Conversely, most of the SDF1-containing cells expressed CXCR4. In six of eight pituitary adenoma primary cultures, SDF1 induced a statistically significant increase in DNA synthesis that was prevented by the treatment with the CXCR4 antagonist AMD3100 or somatostatin.
  
  
  CONCLUSIONS
  CXCR4 and SDF1 are overexpressed in human pituitary adenomas and CXCR4 activation may contribute to pituitary cell proliferation and, possibly, to adenoma development in humans.
authors.affiliation: Laboratory of Pharmacology, Department of Oncology, Biology and Genetics, University of Genova, Viale Benedetto XV 2, Genoa, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Barbieri
authors.forename: Adriana
authors.initials: A
authors.lastname: Bajetto
authors.forename: Ralf
authors.initials: R
authors.lastname: Stumm
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pattarozzi
authors.forename: Carola
authors.initials: C
authors.lastname: Porcile
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Zona
authors.forename: Alessandra
authors.initials: A
authors.lastname: Dorcaratto
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Ravetti
authors.forename: Francesco
authors.initials: F
authors.lastname: Minuto
authors.forename: Renato
authors.initials: R
authors.lastname: Spaziante
authors.forename: Gennaro
authors.initials: G
authors.lastname: Schettini
authors.forename: Diego
authors.initials: D
authors.lastname: Ferone
authors.forename: Tullio
authors.initials: T
authors.lastname: Florio
mesh_terms: D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000096:biosynthesis*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D018613:Microscopy, Confocal; D010911:Pituitary Neoplasms / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D019718:Receptors, CXCR4 / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D012333:RNA, Messenger; D019718:Receptors, CXCR4