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

Abstract

We determined the molecular mechanisms that regulate the pathogenesis of malignant pleural effusion (PE) associated with advanced stage of human, non-small-cell lung cancer. Intravenous injection of human PC14 and PC14PE6 (adenocarcinoma) or H226 (squamous cell carcinoma) cells into nude mice yielded numerous lung lesions. PC14 and PC14PE6 lung lesions invaded the pleura and 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 expression of VEGF mRNA and protein by the cell lines directly correlated with extent of PE formation. Transfection of PC14PE6 cells with antisense VEGF165 gene did not inhibit invasion into the pleural space but reduced PE formation. H226 cells transfected with either sense VEGF 165 or sense VEGF 121 genes induced localized vascular hyperpermeability and produced PE 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 property associated with expression of high levels of urokinase-type plasminogen activator and low levels of TIMP-2. Collectively, the data demonstrate that the production of malignant PE requires tumor cells to invade the pleura and express high levels of VEGF/VPF.

Human chondrosarcoma secretes vascular endothelial growth factor to induce tumor angiogenesis and stores basic fibroblast growth factor for regulation of its own growth

“…Levels of VEGF and bFGF proteins were calculated as nanograms of VEGF or picograms of bFGF/10 6 cells as described. 26,27 These CM were used in proliferation assays and migration assays. Preliminary experiments confirmed that the VEGF ELISA kit detected both VEGF 121 and VEGF 165 .…”

Sensitization of Tumor-Associated Endothelial Cell Apoptosis by the Novel Vascular-Targeting Agent ZD6126 in Combination with Cisplatin

“…Cells from the human lung adenocarcinoma cell line PC14PE6 were kindly donated by Dr. Isaiah J. Fidler (20). The cells were maintained in RPMI 1640 supplemented with 10% fetal bovine serum and penicillin-streptomycin and were cultured in a humidified CO 2 incubator at 37°C.…”

“…For production of lung metastases, human lung adenocarcinoma PC14PE6 cells (1 ϫ 10 6 ) were suspended in 0.2 mL of PBS and injected into the tail vein of nude mice (20). For evaluation of apoptosis of tumor and endothelial cells, animals received cisplatin (6 mg/kg i.v.…”

Bevacizumab in the treatment of non-small-cell lung cancer

“…VEGF is also known as vascular permeability factor, and can induce vascular leakage and may be involved brain edema (Ferrara et al, 2003). Malignant pleural effusions from lung cancer have high levels of VEGF, and VEGF secretion has also been associated with the development of ascites (Senger et al, 1983;Yanagawa et al, 1999;Yano et al, 2000a). The direct role VEGF has in angiogenesis and other malignant processes made it an attractive target for the development of new therapeutic agents.…”