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


CONCLUSIONS
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.
Stathopoulos
Georgios T
GT
Applied Biomedical Research and Training Center Marianthi Simou, Department of Critical Care and Pulmonary Services, General Hospital Evangelismos, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. gstathop@med.uoa.gr
Psallidas
Ioannis
I
Moustaki
Ardiana
A
Moschos
Charalampos
C
Kollintza
Androniki
A
Karabela
Sophia
S
Porfyridis
Ilias
I
Vassiliou
Spyridoula
S
Karatza
Marilena
M
Zhou
Zongmin
Z
Joo
Myungsoo
M
Blackwell
Timothy S
TS
Roussos
Charis
C
Graf
Daniel
D
Kalomenidis
Ioannis
I
D000818:Animals; D002199:Capillary Permeability; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000235:genetics / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D008546:Melanoma, Experimental / Q000098:blood supply / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000473:pathology; D010957:Plasmids / Q000235:genetics; D016066:Pleural Effusion, Malignant / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D012878:Skin Neoplasms / Q000098:blood supply / Q000235:genetics / Q000276:immunology / Q000473:pathology; D014162:Transfection
D018932:Chemokine CCL2; D034741:RNA, Small Interfering