Overexpression of stromal cell-derived factor 1 and its receptor CXCR4 induces autocrine/paracrine cell proliferation in human pituitary adenomas.
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.
Barbieri
Federica
F
Laboratory of Pharmacology, Department of Oncology, Biology and Genetics, University of Genova, Viale Benedetto XV 2, Genoa, Italy.
Bajetto
Adriana
A
Stumm
Ralf
R
Pattarozzi
Alessandra
A
Porcile
Carola
C
Zona
Gianluigi
G
Dorcaratto
Alessandra
A
Ravetti
Jean-Louis
JL
Minuto
Francesco
F
Spaziante
Renato
R
Schettini
Gennaro
G
Ferone
Diego
D
Florio
Tullio
T
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
C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D012333:RNA, Messenger; D019718:Receptors, CXCR4