Hypoxia increases susceptibility of non-small cell lung cancer cells to complement attack.
The complement system can be specifically targeted to tumor cells due to molecular changes on their surfaces that are recognized by complement directly or via naturally occurring antibodies. However, tumor cells often overexpress membrane-bound complement inhibitors protecting them from complement attack. We have previously shown that non-small cell lung cancer (NSCLC) cells, additionally to membrane-bound inhibitors, produce substantial amounts of soluble regulators such as factor I (FI) and factor H (FH). Since low oxygen concentration is associated with rapidly growing solid tumors, we studied how NSCLC cells protect themselves from complement attack under hypoxic conditions. Unexpectedly, mRNA levels and secretion of both FI and FH were significantly decreased already after 24 h exposure to hypoxia while cell viability measured by XTT assay and annexin V/7-AAD staining was affected only marginally. Furthermore, we observed decrease of mRNA level and loss of membrane-bound complement inhibitor CD46 and increased deposition of early (C3b) and terminal (C9) complement components on hypoxic NSCLC cells. All three complement pathways (classical, lectin and alternative) were employed to deposit C3b on cell surface. Taken together, our results imply that under hypoxic conditions NSCLC give up some of their available defense mechanisms and become more prone to complement attack.
Okroj
Marcin
M
Department of Laboratory Medicine, Section of Medical Protein Chemistry, University Hospital, UMAS, Lund University, entrance 46, 205 02 Malmö, Sweden.
Corrales
Leticia
L
Stokowska
Anna
A
Pio
Ruben
R
Blom
Anna M
AM
D018958:CD55 Antigens / Q000032:analysis; D018957:CD59 Antigens / Q000032:analysis; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology / Q000628:therapy*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival; D003167:Complement Activation; D017242:Complement Factor H / Q000235:genetics; D003165:Complement System Proteins / Q000276:immunology*; D005340:Fibrinogen / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology / Q000628:therapy*; D051916:Membrane Cofactor Protein / Q000032:analysis
C497857:CD46 protein, human; D018958:CD55 Antigens; D018957:CD59 Antigens; D051916:Membrane Cofactor Protein; C051590:CD59 protein, human; D017242:Complement Factor H; D005340:Fibrinogen; D003165:Complement System Proteins