title: Enhancement of human cancer cell motility and invasiveness by anaphylatoxin C5a via aberrantly expressed C5a receptor (CD88).
abstract: OBJECTIVE
  The anaphylatoxin C5a is a chemoattractant that induces leukocyte migration via C5a receptor (C5aR). There is emerging evidence that C5a is generated in the cancer microenvironment. We therefore sought C5aR expression and a direct influence of the C5a-C5aR axis on cancer cells.
  
  
  METHODS
  C5aR expression was investigated in human cancer tissues and cell lines. Effects of C5a stimulation on cancer cells were studied by cytoskeletal rearrangement, time-lapse analysis, Matrigel chamber assay, and invasion in nude mouse in a comparison of C5aR-expressing cancer cells with control cells.
  
  
  RESULTS
  C5aR was aberrantly expressed in various human cancers. Several cancer cell lines also expressed C5aR. C5a triggered cytoskeletal rearrangement and enhanced cell motility three-fold and invasiveness 13-fold of C5aR-expressing cancer cells. Such enhancement by C5a was not observed in control cells. Cancer cell invasion was still enhanced in the absence of C5a concentration gradient and even after the removal of C5a stimulation, suggesting that random cell locomotion plays an important role in C5a-triggered cancer cell invasion. C5a increased the release of matrix metalloproteinases (MMP) from cancer cells by two- to 11-fold, and inhibition of MMP activity abolished the C5a-enhancing effect on cancer cell invasion. Compared with control cells, C5aR-expressing cells spread 1.8-fold more broadly at implanted nude mouse skin sites only when stimulated with C5a.
  
  
  CONCLUSIONS
  These results illustrate a novel activity of the C5a-C5aR axis that promotes cancer cell invasion through motility activation and MMP release. Targeting this signaling pathway may provide a useful therapeutic option for cancer treatment.
authors.affiliation: Department of Molecular Pathology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Nitta
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Wada
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kawano
authors.forename: Yoji
authors.initials: Y
authors.lastname: Murakami
authors.forename: Atsushi
authors.initials: A
authors.lastname: Irie
authors.forename: Keisuke
authors.initials: K
authors.lastname: Taniguchi
authors.forename: Ken
authors.initials: K
authors.lastname: Kikuchi
authors.forename: Gen
authors.initials: G
authors.lastname: Yamada
authors.forename: Kentaro
authors.initials: K
authors.lastname: Suzuki
authors.forename: Jiro
authors.initials: J
authors.lastname: Honda
authors.forename: Masayo
authors.initials: M
authors.lastname: Wilson-Morifuji
authors.forename: Norie
authors.initials: N
authors.lastname: Araki
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Eto
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
authors.forename: Takahisa
authors.initials: T
authors.lastname: Imamura
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects* / Q000235:genetics; D015936:Complement C5a / Q000494:pharmacology*; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D059008:Time-Lapse Imaging; D014183:Transplantation, Heterologous
chemical_list: D000814:Aniline Compounds; C470794:N-((4-dimethylaminophenyl)methyl)-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide; D044087:Receptor, Anaphylatoxin C5a; D013764:Tetrahydronaphthalenes; D015936:Complement C5a; D020782:Matrix Metalloproteinases