Anaphylatoxin C5a indirectly fosters
cancer cells through recruitment of myeloid-derived suppressor cells (MDS) for inhibiting antitumor CD8+ T cells and induction of neovascularization. We recently found activation of
cancer cells by C5a directly via the C5a-receptor (C5aR; CD88) to enhance invasiveness. Thus, C5a possibly contributes to
cancer progression rather than elimination. C5a generation in
cancer tissues has been reported; however, the mechanism is not fully elucidated.
Cancer cell expression of
complement regulatory molecules suggests inefficient C5a generation through activation of the
complement system in response to
cancer cells. To explore another C5a generation mechanism in
cancer tissues, we examined
cancer cells for C5a-releasing activity from C5. C5a was present in C5-supplemented
culture media of
cancer cells including C5aR-expressing cells, and the media enhanced C5aR-expressing
cancer cell invasion, which was abolished by anti-C5a antibody. The C5a-releasing activity was absent in the supernatants of the media and was inhibited by
aprotinin, a
serine protease inhibitor, and decanoyl-
Arg-Val-Lys-Arg-chloromethylketone but not by inhibitors specific for
cysteine,
acid, or
metal proteases. These results indicated C5a release from C5 by a
cancer cell membrane-bound
serine protease that can cleave
peptide bonds at the carboxy-terminal site of paired
basic amino acid residues.
Cancer cell C5a release from the
complement-immobilized plasma supported feasibility of this
cancer cell
protease-dependent C5a generation in
cancer tissues. The new mechanism of C5a generation suggests self-activation of C5aR-expressing
cancer cells to enhance invasiveness and induction of MDS recruitment and neovascularization to create a microenvironment favorable for
cancer progression.