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. 2008 Oct 15;100(20):1464-76.
doi: 10.1093/jnci/djn325. Epub 2008 Oct 7.

A central role for tumor-derived monocyte chemoattractant protein-1 in malignant pleural effusion

Georgios T Stathopoulos  1 , Ioannis Psallidas, Ardiana Moustaki, Charalampos Moschos, Androniki Kollintza, Sophia Karabela, Ilias Porfyridis, Spyridoula Vassiliou, Marilena Karatza, Zongmin Zhou, Myungsoo Joo, Timothy S Blackwell, Charis Roussos, Daniel Graf, Ioannis Kalomenidis
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A central role for tumor-derived monocyte chemoattractant protein-1 in malignant pleural effusion

Georgios T Stathopoulos et al. J Natl Cancer Inst. .

Abstract

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 muL, respectively; difference = 499 muL; 95% confidence interval [CI] = 331 to 669 muL; 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.

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