title: Stromal-derived factor-1alpha/CXCL12-CXCR 4 axis is involved in the dissemination of NSCLC cells into pleural space.
abstract: 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-1alpha (SDF-1alpha) that can induce chemotaxis of cells, was reported to be expressed on NSCLC. In this study, we hypothesized that the SDF-1alpha/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-1alpha could induce migration via phosphatidylinositol 3 (PI-3) kinase- and p44/42 mitogen-activated protein kinase-dependent manner. The SDF-1alpha 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-1alpha = 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-1alpha. The SDF-1alpha/CXCR4 axis is involved in the dissemination of NSCLC cells into pleural space.
authors.affiliation: Third Department of Internal Medicine, Kagoshima University Faculty of Medicine, National Minami-kyushu Hospital, Kagoshima 890-8520, Japan.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Oonakahara
authors.forename: Wataru
authors.initials: W
authors.lastname: Matsuyama
authors.forename: Ikkou
authors.initials: I
authors.lastname: Higashimoto
authors.forename: Masaharu
authors.initials: M
authors.lastname: Kawabata
authors.forename: Kimiyoshi
authors.initials: K
authors.lastname: Arimura
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Osame
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002118:Calcium / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010994:Pleura / Q000166:cytology; D035422:Pleural Cavity / Q000378:metabolism / Q000473:pathology*; D016066:Pleural Effusion, Malignant; D019718:Receptors, CXCR4 / Q000378:metabolism*; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000502:physiology*; D013223:Statistics as Topic
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D004791:Enzyme Inhibitors; D019718:Receptors, CXCR4; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium