Synthesis and secretion of the anticoagulant protein S and coexpression ofthe Tyro3 receptor in human lung carcinoma cells

BACKGROUND. Protein S is a plasma protein that serves as an important cofac tor for activated protein C in the blood anticoagulation system. Protein S also acts as a mitogen on distinct cell types and is a ligand for Tyro3, a member of the Axl family of oncogenic receptor tyrosine kinases. This lends support to the hypothesis that protein S might also be involved in tumor c ell regulation. METHODS. The expression of protein S and receptor Tyro3 was examined in 22 lung carcinoma cell lines and normal bronchial epithelial cells by reverse transcriptase-polymerase chain reaction. Secreted protein S was identified by Western blot analysis of cell supernatants and tested in a protein S-dep endent clotting test for anticoagulant activity. Immunohistochemistry with anti-protein S polyvalent antiserum was also performed on 31 primary lung c arcinoma specimens. RESULTS. Protein S mRNA and secreted protein were found in 11 of 12 cell li nes of nonsmall cell lung carcinoma (NSCLC) origin and in normal bronchial epithelial cells, but they were found in only 4 of 10 small cell lung carci noma (SCLC) cell lines. The majority of lung carcinoma cell lines that expr essed protein S (13 of 15) also revealed expression of the cognate receptor , Tyro3. Protein S that was present in cell supernatant had anticoagulant a ctivity comparable to that of plasma protein S, suggesting that it is gamma -carboxylated. In lung tumor tissue, protein S antigen was found in 20 of 3 1 cases examined, predominantly in tumors of the squamous cell and bronchio alveolar cell types. Protein S was found not only in tumor cells but also i n cells of the normal bronchial epithelium, in alveolar macrophages, and in endothelium. CONCLUSIONS. To the authors' knowledge, their report is the first of the sy nthesis of an active anticoagulant protein in epithelial cells of human can cer. It suggests that protein S, by binding to a receptor (Tyro3), may infl uence local anticoagulation events or other, as yet unidentified, aspects o f lung tumor development. Cancer 1999;86:43-9. (C) 1999 American Cancer Soc iety.