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Stromal-Derived Factor-1/CXCL12-CXCR 4 Axis Is Involved in the Dissemination of NSCLC Cells into Pleural Space

Third Department of Internal Medicine, Kagoshima University Faculty of Medicine; and Department of Respiratory Medicine, National Minami-kyushu Hospital, Kagoshima, Japan

Address correspondence to: Dr. Wataru Matsuyama, M.D., Ph.D., Third Department of Internal Medicine, Kagoshima University Faculty of Medicine, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan. E-mail: vega{at}xa2.so-net.ne.jp

Malignant pleural effusion (PE) is one of the poor prognostic factors in non–small cell lung cancer (NSCLC), and the detailed mechanism of the malignant PE formation is not fully elucidated. Recently, CXCR4, a receptor for chemokine stromal-derived factor-1 (SDF-1) that can induce chemotaxis of cells, was reported to be expressed on NSCLC. In this study, we hypothesized that the SDF-1/CXCR4 axis may be involved in the dissemination of malignant cells into pleural space, and investigated its expression, function, and signaling pathway using NSCLC cell lines and clinical samples from 43 patients with NSCLC with malignant PE. We found functional expression of CXCR4 on NSCLC cell lines, and also found that SDF-1 could induce migration via phosphatidylinositol 3 (PI-3) kinase– and p44/42 mitogen-activated protein kinase–dependent manner. The SDF-1 levels in malignant PE were significantly higher than those in transudate PE and showed a significant positive correlation with PE volumes. The sensitivity and specificity for prediction of recurrence of malignant PE was 61.5% and 83.3%, respectively (cutoff SDF-1 = 2,500 ng/ml), and better than those using pH of PE. Cancer cells in malignant PE expressed CXCR4, and mesothelial cells of the pleura stained positive for SDF-1. The SDF-1/CXCR4 axis is involved in the dissemination of NSCLC cells into pleural space.

Abbreviations: Dulbecco's modified Eagle medium, DMEM • fetal calf serum, FCS • non–small cell lung cancer, NSCLC • phosphate-buffered saline, PBS • pleural effusion, PE • phosphatidylinositol 3, PI 3 • stromal-derived factor-1, SDF-1