Non-small cell lung cancer cells produce a functional set of complement factor I and its soluble cofactors.
The complement system is important for protection from invading pathogens, removal of waste products and guidance of the immune response. Furthermore, complement can be also targeted to cancer cells. However, membrane-bound inhibitors over-expressed by certain types of tumor cells restrict the cytotoxic activity of complement. Herein we report that non-small cell lung cancer (NSCLC) cells produce soluble complement inhibitors factor I (FI) and C4b-binding protein (C4BP). FI is a serine protease capable of degrading the activated complement components C3b and C4b, whilst C4BP acts as its cofactor. Furthermore, NSCLC cells express membrane-bound regulators and shed membrane cofactor protein (MCP), which shares cofactor function with C4BP. Secretion of FI from NSCLC cells was higher than previously reported for any non-hepatic source and FI produced by these cells could efficiently support cleavage of C3b and C4b. In vitro functional assays revealed that additional FI significantly decreased C3 deposition and complement-dependent lysis, particularly when cofactors were added. Our results demonstrate that soluble inhibitors produced by NSCLC cells may provide further protection from complement beyond the level ensured by membrane-bound inhibitors and, as such, contribute to the aggressive phenotype of these lung cancer cells.
Okroj
Marcin
M
Lund University, Department of Laboratory Medicine, Section of Clinical Chemistry, University Hospital, S-205 02 Malmö, Sweden.
Hsu
Yi-Fan
YF
Ajona
Daniel
D
Pio
Ruben
R
Blom
Anna M
AM
D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D003167:Complement Activation / Q000276:immunology; D003179:Complement C3b / Q000378:metabolism; D015935:Complement C4b / Q000378:metabolism; D050716:Complement C4b-Binding Protein; D017244:Complement Factor I / Q000096:biosynthesis* / Q000235:genetics; D003602:Cytotoxicity, Immunologic; D015972:Gene Expression Regulation, Neoplastic; D006649:Histocompatibility Antigens / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology*; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012995:Solubility
C055609:C4BPA protein, human; D050716:Complement C4b-Binding Protein; D006649:Histocompatibility Antigens; D012333:RNA, Messenger; D003179:Complement C3b; D015935:Complement C4b; D017244:Complement Factor I