title: GCP-2/CXCL6 synergizes with other endothelial cell-derived chemokines in neutrophil mobilization and is associated with angiogenesis in gastrointestinal tumors.
abstract: The precise role of chemokines in neovascularization during inflammation or tumor growth is not yet fully understood. We show here that the chemokines granulocyte chemotactic protein-2 (GCP-2/CXCL6), interleukin-8 (IL-8/CXCL8), and monocyte chemotactic protein-1 (MCP-1/CCL2) are co-induced in microvascular endothelial cells after stimulation with pro-inflammatory stimuli. In contrast with its weak proliferative effect on endothelial cells, GCP-2 synergized with MCP-1 in neutrophil chemotaxis. This synergy may represent a mechanism for tumor development and metastasis by providing efficient leukocyte infiltration in the absence of exogenous immune modulators. To mimic endothelial cell-derived GCP-2 in vivo, GCP-2 was intravenously injected and shown to provoke a dose-dependent systemic response, composed of an immediate granulopenia, followed by a profound granulocytosis. By immunohistochemistry, GCP-2 was further shown to be expressed by endothelial cells from human patients with gastrointestinal (GI) malignancies. GCP-2 staining correlated with leukocyte infiltration into the tumor and with the expression of the matrix metalloproteinase-9 (MMP-9/gelatinase B). Together with previous findings, these data suggest that the production of GCP-2 by endothelial cells within the tumor can contribute to tumor development through neovascularization due to endothelial cell chemotaxis and to tumor cell invasion and metastasis by attracting and activating neutrophils loaded with proteases that promote matrix degradation.
authors.affiliation: Laboratory of Molecular Immunology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium.
authors.forename: Klara
authors.initials: K
authors.lastname: Gijsbers
authors.forename: Mieke
authors.initials: M
authors.lastname: Gouwy
authors.forename: Sofie
authors.initials: S
authors.lastname: Struyf
authors.forename: Anja
authors.initials: A
authors.lastname: Wuyts
authors.forename: Paul
authors.initials: P
authors.lastname: Proost
authors.forename: Ghislain
authors.initials: G
authors.lastname: Opdenakker
authors.forename: Freddy
authors.initials: F
authors.lastname: Penninckx
authors.forename: Nadine
authors.initials: N
authors.lastname: Ectors
authors.forename: Karel
authors.initials: K
authors.lastname: Geboes
authors.forename: Jo
authors.initials: J
authors.lastname: Van Damme
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis; D054427:Chemokine CXCL6; D018925:Chemokines / Q000502:physiology*; D019743:Chemokines, CXC / Q000502:physiology*; D002633:Chemotaxis; D004730:Endothelium, Vascular / Q000503:physiopathology; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000098:blood supply* / Q000276:immunology / Q000503:physiopathology*; D006801:Humans; D007150:Immunohistochemistry; D016209:Interleukin-8 / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D009504:Neutrophils / Q000502:physiology*
chemical_list: C111835:CCL2 protein, human; C515503:CXCL6 protein, human; D018932:Chemokine CCL2; D054427:Chemokine CXCL6; D018925:Chemokines; D019743:Chemokines, CXC; D016209:Interleukin-8