Production of experimental malignant pleural effusions is dependent on invasion of the pleura and expression of vascular endothelial growth factor/vascular permeability factor by human lung cancer cells

We determined the molecular mechanisms that regulate the pathogenesis of ma lignant pleural effusion (PE) associated with advanced stage of human, nons mall-cell lung cancer. Intravenous injection of human PC14 and PC14PE6 (ade nocarcinoma) or H226 (squamous cell carcinoma) cells into nude mice yielded numerous lung lesions. PC14 and PC14PE6 lung lesions invaded the pleura an d produced PE containing a high level of vascular endothelial growth factor (VEGF)-localized vascular hyperpermeability. Lung lesions produced by H226 cells were confined to the lung parenchyma with no PE. The level of expres sion of VEGF mRNA and protein by the cell lines directly correlated with ex tent of PE formation. Transfection of PC14PE6 cells with antisense VEGF165 gene did not inhibit invasion into the pleural space but reduced pi formati on. H226 cells transfected with either sense VEGF 165 or sense VEGF 121 gen es induced localized vascular hyperpermeability and produced pi only after direct implantation into the thoracic cavity. The production of PE was thus associated with the ability of tumor cells to invade the pleura, a propert y associated with expression of high levels of urokinase-type plasminogen a ctivator and low levels of TIMP-2. Collectively, the data demonstrate that the production of malignant PE requires tumor cells to invade the pleura an d express high levels of VEGF/VPF.