Journal of the National Cancer Institute Advance Access published online on October 7, 2008
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djn325
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© The Author 2008. Published by Oxford University Press.
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A Central Role for Tumor-derived Monocyte Chemoattractant Protein-1 in Malignant Pleural Effusion
Affiliations of authors: Applied Biomedical Research and Training Centers "Marianthi Simou" and "George P. Livanos," Department of Critical Care and Pulmonary Services, General Hospital "Evangelismos", School of Medicine, National and Kapodistrian University of Athens, Athens, Greece (GTS, I. Psallidas, CM, AK, SK, I. Porfyridis, ZZ, CR, IK); Institute of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece (AM, DG); Department of Hematology & Lymphomas, General Hospital "Evangelismos", Athens, Greece (SV, MK); 2nd Pulmonary Department, "Attikon" University Hospital, School of Medicine, National and Kapodistrian University of Athens, Greece (IK); Division of Allergy, Pulmonary, & Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (MJ, TSB)
Correspondence to: Georgios T. Stathopoulos, MD, PhD, Applied Biomedical Research and Training Centers "Marianthi Simou" and "George P. Livanos", Department of Critical Care and Pulmonary Services, General Hospital "Evangelismos", School of Medicine, National and Kapodistrian University of Athens, 3 Ploutarhou Str., 10675 Athens, Greece (e-mail: gstathop{at}med.uoa.gr, gttstathopoulos{at}yahoo.gr).
Background: Tumor cells in malignant pleural effusions (MPEs) are an important source of monocyte chemoattractant protein (MCP)-1. However, the role of tumor-derived MCP-1 in the pathogenesis and progression of MPE has not been determined.
Methods: B16 mouse skin melanoma cells, which are deficient in MCP-1 expression, and mouse Lewis lung cancer (LLC) cells, which express high levels of MCP-1, were engineered to stably express MCP-1 and short hairpin RNAs (shRNAs) targeting the MCP-1 transcript, respectively. Cells were injected into the pleural cavities of syngeneic immunocompetent mice, and MPE volume and pleural tumors were quantified at necropsy (day 14). MCP-1 and other mediators were determined by cytometric bead array and enzyme-linked immunosorbent assay, and mononuclear and endothelial cells were identified by immunolabeling of F4/80 and factor VIII–related antigen respectively. Mouse survival was assessed using Kaplan–Meier analysis. Vascular permeability in mice with MPE was assessed using albumin-binding Evans blue. Statistical tests were two-sided.
Results: LLC cells expressing shRNA against MCP-1 elaborated less than 5% of the MCP-1 level in cells expressing nonspecific shRNA (control cells), and intrapleural delivery of these cells resulted in less MPE (mean MPE volume = 86 and 585 µL, respectively; difference = 499 µL; 95% confidence interval [CI] = 331 to 669 µL; P < .001), reduced MCP-1 levels in the pleural fluid, and lower mortality than when control cells were delivered. Overexpression of MCP-1 in intrapleurally injected B16 melanoma cells led to increased MPE and reduced survival. In mice with MPE, MCP-1 was a potent inducer of vascular permeability, mononuclear recruitment, and, in pleural tumors, of angiogenesis.
Conclusion: MCP-1 produced by tumor cells is an important determinant of their capacity to induce the formation of MPE and may be a useful target for the treatment of malignant pleural disease.
| CONTEXT AND CAVEATS Prior knowledge High levels of monocyte chemoattractant protein (MCP-1) had been detected in human malignant pleural effusion, but the role of MCP-1 derived from tumor cells in the pathogenesis and progression of MPE was not known. Study design Malignant pleural effusion was studied in a mouse model in which cancer cells were injected into the pleura. Engineering of the injected cancer cells to express high or low levels of MCP-1 allowed the role of the chemokine in pathogenesis of MPE to be assessed. Contribution In the mouse model, the volume of MPE, monocyte and macrophage recruitment, induction of pleural vascular permeability, and neoangiogenesis in tumor cells were dependent on MCP-1 levels in injected cancer cells. Purified MCP-1 was also found to be a direct inducer of vascular hyperpermeablity and inflammation. Implications MCP-1 may prove to be of value as a target for the treatment of malignant pleural disease. Limitations The applicability of the mouse model used in this study to human MPE remains to be determined. From the Editors
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Manuscript received March 5, 2008; revised July 14, 2008; accepted August 8, 2008.
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J Natl Cancer Inst 2008 100: 1417.
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