PURPOSE: 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. EXPERIMENTAL DESIGN: 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.
PURPOSE: 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. EXPERIMENTAL DESIGN:C5aR expression was investigated in humancancer 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 humancancers. 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: Alok K Shah; Gunter Hartel; Ian Brown; Clay Winterford; Renhua Na; Kim-Anh Lê Cao; Bradley A Spicer; Michelle A Dunstone; Wayne A Phillips; Reginald V Lord; Andrew P Barbour; David I Watson; Virendra Joshi; David C Whiteman; Michelle M Hill Journal: Mol Cell Proteomics Date: 2018-08-10 Impact factor: 5.911
Authors: Edimara S Reis; Dimitrios C Mastellos; Daniel Ricklin; Alberto Mantovani; John D Lambris Journal: Nat Rev Immunol Date: 2017-09-18 Impact factor: 53.106
Authors: Daniel Ajona; Carolina Zandueta; Leticia Corrales; Haritz Moreno; María J Pajares; Sergio Ortiz-Espinosa; Elena Martínez-Terroba; Naiara Perurena; Fernando J de Miguel; Eloisa Jantus-Lewintre; Carlos Camps; Silvestre Vicent; Jackeline Agorreta; Luis M Montuenga; Ruben Pio; Fernando Lecanda Journal: Am J Respir Crit Care Med Date: 2018-05-01 Impact factor: 21.405
Authors: Gustavo Ferrín; Manuel Rodríguez-Perálvarez; Patricia Aguilar-Melero; Isidora Ranchal; Camilo Llamoza; Clara I Linares; Sandra González-Rubio; Jordi Muntané; Javier Briceño; Pedro López-Cillero; José Luis Montero-Álvarez; Manuel de la Mata Journal: PLoS One Date: 2015-03-19 Impact factor: 3.240