A. Wimmel et al., Synthesis and secretion of the anticoagulant protein S and coexpression ofthe Tyro3 receptor in human lung carcinoma cells, CANCER, 86(1), 1999, pp. 43-49
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.