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Tumor Necrosis Factor- Promotes Malignant Pleural Effusion

¹ Applied Biomedical Research and Training Center "Marianthi Simou"; ² Department of Critical Care and Pulmonary Services, General Hospital "Evangelismos," School of Medicine, National and Kapodistrian University of Athens; ³ Department of Hematology and Lymphomas, General Hospital "Evangelismos"; ⁴ 2nd Pulmonary Department, "Attikon" University Hospital, School of Medicine, National and Kapodistrian University of Athens; ⁵ Oncology Unit, 3rd University Department of Internal Medicine, General Hospital "Sotiria," School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; ⁶ Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; ⁷ Institute of Physical Chemistry, Laboratory of Natural Products Synthesis and Bioorganic Chemistry, National Centre for Scientific Research "Demokritos," Aghia Paraskevi, Greece; and ⁸ Biomedical Sciences Research Center "Alexander Fleming," Vari, Greece

Requests for reprints: Georgios T. Stathopoulos, Department of Critical Care and Pulmonary Services, General Hospital "Evangelismos," School of Medicine, National and Kapodistrian University of Athens, 3 Ploutarhou Street, 10675 Athens, Greece. Phone: 30-210-723-5521 or 30-210-462-5236; Fax: 30-210-723-9127 or 30-210-462-5236; E-mail: gstathop{at}med.uoa.gr.

Tumor necrosis factor (TNF)- is present in the microenvironment of human tumors, including malignant pleural effusion (MPE). Although the cytokine is produced in the pleural cavity by both tumor and host cells, its effects on MPE formation are unknown. In these studies, we sought to determine the role of TNF- in the pathogenesis of MPE and to assess the therapeutic effects of its neutralization in a preclinical model. For this, MPEs were generated in immunocompetent mice using intrapleural injection of mouse lung adenocarcinoma cells. The roles of tumor- and host-derived TNF- were assessed using combined experimentation with TNF- gene–deficient mice and in vivo TNF- neutralization. To expand the scope of preclinical data, TNF- and vascular endothelial growth factor (VEGF) expression were determined in human cancer cell lines and human MPE. In the MPE model, TNF- of host and tumor origin was present. TNF- neutralization significantly limited tumor dissemination, effusion formation, vascular hyperpermeability, TNF- and VEGF expression, and angiogenesis, thereby improving survival. In contrast, these variables were not different between TNF- gene–sufficient and TNF- gene–deficient mice. In mouse cancer cells, TNF- functioned via nuclear factor-B– and neutral sphingomyelinase–dependent pathways to induce TNF- and VEGF, respectively. These results were recapitulated in human cancer cells, and a correlation was detected between TNF- and VEGF content of human MPE. We conclude that tumor-derived TNF- is important in the development of MPE in mice, and provide preclinical evidence supporting the efficacy of TNF- blockade against malignant pleural disease. [Cancer Res 2007;67(20):9825–34]

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