The Angiopoietin/Tie2 Axis Mediates Malignant Pleural Effusion Formation

AbstractPURPOSE: Angiopoietins and their receptor, Tie2, participate in angiogenesis, regulation of vascular permeability, and inflammation, all central to the pathogenesis of malignant pleural effusions (MPEs). In the present study, we aimed to examine the role of the angiopoietin/Tie2 axis in MPE pathogenesis. EXPERIMENTAL DESIGN: MPE was induced by intrapleural injection of murine adenocarcinoma cells in C57BL/6 mice. Animals were given twice-weekly intraperitoneal injections of 40 mg/kg MuTekdeltaFc or vehicle. MuTekdeltaFc is a soluble Tie2 (sTie2) receptor that binds murine angiopoietins thereby disrupting their interaction with Tie2 receptors expressed on tissues. Animals were killed on day 14. RESULTS: Angiopoietin/Tie2 axis blockade significantly reduced pleural fluid volume and pleural tumor foci. The mean ± SEM pleural fluid volumes were 617 ± 48 μl and 316 ± 62 μl for the control and treated groups, respectively (P = .001), whereas the mean ± SEM tumor foci were 7.3 ± 1.0 and 3.0 ± 0.52 for the control and treated groups, respectively (P = .001). In addition, tumor-associated cachexia, tumor angiogenesis, pleural vascular permeability, recruitment of inflammatory cells to the pleural cavity, and local elaboration of vascular endothelial growth factor and interleukin 6 were also downregulated, and tumor cell apoptosis was induced in animals treated with the inhibitor. CONCLUSIONS: Our results indicate that the angiopoietin/Tie2 axis is an important component of MPE pathogenesis. Further studies are required to determine whether therapeutic interventions targeting this pathway could be beneficial for patients with MPE