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Overexpression of Stromal Cell–Derived Factor 1 and Its Receptor CXCR4 Induces Autocrine/Paracrine Cell Proliferation in Human Pituitary Adenomas

Authors' Affiliations: ¹ Laboratory of Pharmacology, Department of Oncology, Biology and Genetics, ² Division of Neurosurgery, Department of Neuroscience, Ophthalmology and Genetics, ³ Section of Neurosurgery DISCAT, and ⁴ Department of Endocrinological and Medical Sciences and Center of Excellence for Biomedical Research, University of Genova; ⁵ Section of Pathology, San Martino Hospital; ⁶ Gruppo per lo Studio e la Cura dei Tumori Cerebrali, Genova, Italy; and ⁷ Institute of Pharmacology and Toxicology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany

Requests for reprints: Tullio Florio, Department of Oncology, Biology and Genetics, University of Genova, Viale Benedetto XV, 2, 16132 Genova, Italy. Phone: 39-010-3538806; Fax: 39-010-3538806; E-mail: tullio.florio{at}unige.it.

Purpose: 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.

Experimental Design: 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.