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CXCR4 and SDF1 expression in human meningiomas: A proliferative role in tumoral meningothelial cells in vitro¹

Department of Oncology, Biology and Genetics, University of Genova (A.B., F.B., A.P., C.P., G.S., T.F.); Section of Neurosurgery DISCAT, University of Genova (A.D.); Section of Pathology, San Martino Hospital, Genova (J.L.R.); and Department of Neuroscience, Ophthalmology and Genetics, Section of Neurosurgery, University of Genova (G.Z., R.S.), Genova, Italy

² Address correspondence to Adriana Bajetto, Ph.D., Department of Oncology, Biology and Genetics, University of Genova, Viale Benedetto XV, 2, 16132 Genova, Italy (adriana.bajetto{at}unige.it).

Chemokines participate in cellular processes associated with tumor proliferation, migration, and angiogenesis. We previously demonstrated that stromal cell-derived factor 1 (SDF1) exerts a mitogenic activity in glioblastomas through the activation of its receptor CXCR4. Here we studied the expression of this chemokine in human meningiomas and its possible role in cell proliferation. Reverse transcriptase-PCR analysis for CXCR4 and SDF1 was performed on 55 human meningiomas (47 WHO grade I, 5 WHO II, and 3 WHO III). Immunolabeling for CXCR4 and SDF1 was performed on paraffin-embedded sections of these tumors. [³H]Thymidine uptake and Western blot analyses were performed on primary meningeal cell cultures of tumors to evaluate the proliferative activity of human SDF1 (hSDF1) in vitro and the involvement of extracellular signal-regulated kinase 1/2 (ERK1/2) activation in this process. CXCR4 mRNA was expressed by 78% of the tumor specimens and SDF1 mRNA by 53%. CXCR4 and SDF1 were often detected in the same tumor tissues and colocalized with epithelial membrane antigen immunostaining. In 9 of 12 primary cultures from meningiomas, hSDF1 induced significant cell proliferation that was strongly reduced by the mitogen-activated protein kinase kinase inhibitor PD98059, involving ERK1/2 activation in the proliferative signal of hSDF1. In fact, CXCR4 stimulation led to ERK1/2 phosphorylation/activation. In addition, the hSDF1-induced cell proliferation was significantly correlated with the MIB1 staining index in the corresponding surgical specimen. In conclusion, we found that human meningiomas express CXCR4 and SDF1 and that hSDF1 induces proliferation in primary meningioma cell cultures through the activation of ERK1/2.

Key Words: cell proliferation • chemokine • CXCR4 • meningioma • SDF1/CXCL12

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