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

• Published in: Cancer 1999-07, Vol.86 (1), p.43-49
• Main Authors: Wimmel, Anja, Rohner, Iris, Ramaswamy, Annette, Heidtmann, Hans‐H., Seitz, Rainer, Kraus, Michael, Schuermann, Marcus
• Format: Article
• Language: English
• Subjects: anticoagulation; Antigens, Neoplasm - analysis; Base Sequence; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - physiopathology; Carcinoma, Small Cell - genetics; Carcinoma, Small Cell - physiopathology; Humans; Lung; lung carcinoma; Lung Neoplasms - genetics; Lung Neoplasms - physiopathology; Medical sciences; Molecular Sequence Data; Pneumology; protein S; Protein S - biosynthesis; Protein S - metabolism; Receptor Protein-Tyrosine Kinases - metabolism; receptor tyrosine kinase; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - analysis; Tumor Cells, Cultured; Tumors of the respiratory system and mediastinum; Tyro3
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/(SICI)1097-0142(19990701)86:1<43::AID-CNCR8>3.0.CO;2-D

BACKGROUND Protein S is a plasma protein that serves as an important cofactor 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 cell 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–dependent clotting test for anticoagulant activity. Immunohistochemistry with anti–protein S polyvalent antiserum was also performed on 31 primary lung carcinoma specimens. RESULTS Protein S mRNA and secreted protein were found in 11 of 12 cell lines 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 carcinoma (SCLC) cell lines. The majority of lung carcinoma cell lines that expressed protein S (13 of 15) also revealed expression of the cognate receptor, Tyro3. Protein S that was present in cell supernatant had anticoagulant activity comparable to that of plasma protein S, suggesting that it is γ‐carboxylated. In lung tumor tissue, protein S antigen was found in 20 of 31 cases examined, predominantly in tumors of the squamous cell and bronchioalveolar cell types. Protein S was found not only in tumor cells but also in cells of the normal bronchial epithelium, in alveolar macrophages, and in endothelium. CONCLUSIONS To the authors' knowledge, their report is the first of the synthesis of an active anticoagulant protein in epithelial cells of human cancer. It suggests that protein S, by binding to a receptor (Tyro3), may influence local anticoagulation events or other, as yet unidentified, aspects of lung tumor development. Cancer 1999;86:43–9. © 1999 American Cancer Society. The synthesis of active anticoagulant protein S in human lung carcinoma is reported. The finding of coexpression of its putative receptor, Tyro3, suggests that protein S may play a functional role in the development of lung carcinoma.