MODULATION OF ENDOTHELIAL-CELL PERMEABILITY BY LUNG-CARCINOMA CELLS -A POTENTIAL MECHANISM OF MALIGNANT PLEURAL EFFUSION FORMATION

This study examined the hypothesis that tumor cells metastatic to the pleura secrete a soluble factor(s) that directly increases endothelial cell permeability. Nitrocellulose filters were endothelialzed with bo vine pulmonary artery endothelial cells and exposed to conditioned med ia from either human lung adenocarcinoma (Calu-3), human lung squamous cell carcinoma (SK-MES-1) or control media for 16 h. The diffusional permeability (Pd x 10(-5) cm/sec) to [C-14]albumin was then determined for each monolayer with Ussing-type chambers. Both adenocarcinoma con ditioned media (ACCM) and squamous cell. carcinoma conditioned media ( SCCM) caused a two- to threefold increase in endothelial monolayer per meability. The addition of indomethacin (10 mu g/ml) blocked the obser ved permeability increase in ACCM but not in SCCM, suggesting that the increase in permeability by ACCM was secondary to the production of p rostaglandins. To confirm this, a variety of prostanoids previously sh own to be produced by the Calu-3 cell line were added directly to the endothelial monolayer. Prostaglandin E(2 alpha) (PGF(2 alpha)) in both low (10 ng/ml) and high (100 ng/ml) concentrations for 16 h resulted in a three- to fourfold increase in permeability. Prostaglandin E(2) ( PGE(2)) resulted in a small increase in [C-14]albumin permeability but only at high concentrations (100 ng/ml). PGF(2 alpha) production by t he two tumor cell lines was measured using radioimmunoassay. Baseline adenocarcinoma production of PGF(2 alpha) was 117.5 pmol/10(6) cells a nd fell to 24.2 pmol/10(6) cells hours following incubation with indom ethacin. The decrease in PGF(2 alpha) occurred in parallel with the ch anges in permeability. Concomitant, reversible changes in cell shape a nd F-actin distribution were detected in endothelial cells exposed to ACCM. No significant production of PGF(2 alpha) by the squamous cell c arcinoma cell line was detected. These results suggest that both adeno carcinoma and squamous cell carcinoma secrete a soluble factor(s) that directly increases endothelial cell permeability to albumin and that in the case of adenocarcinoma this soluble factor may be a prostanoid such as PGF(2 alpha).