Stimulation of angiostatic platelet factor-4 variant (CXCL4L1/PF-4var) versus inhibition of angiogenic granulocyte chemotactic protein-2 (CXCL6/GCP-2) in normal and tumoral mesenchymal cells.
Chemokines affect inflammation and cancer through leukocyte attraction and angiogenesis. Here, we demonstrate that CXCL4L1/platelet factor-4 variant (PF-4var), a highly angiostatic chemokine, is poorly chemotactic for phagocytes and is inducible in monocytes by inflammatory mediators but remained undetectable in macrophages and neutrophils. In addition, CXCL4L1/PF-4var production by mesenchymal tumor cells was evidenced in vitro and in vivo by specific ELISA and immunohistochemistry. CXCL4L1/PF-4var, but not CXCL4/PF-4, was coinduced with the angiogenic chemokine CXCL6/granulocyte chemotactic protein-2 (GCP-2) by cytokines, e.g., IL-1beta and IL-17, in sarcoma cells, but not in diploid fibroblasts. Furthermore, the induction of CXCL6/GCP-2 in endothelial cells by IL-1beta was enhanced synergistically by TNF-alpha but inhibited by IFN-gamma, which synergized with IL-1beta to produce the angiostatic CXCL10/IFN-gamma-induced protein-10. These findings indicate that the equilibrium between angiostatic and angiogenic factors during inflammation and tumor progression is rather complex and differs depending on the chemokine, cell type, and stimulus. Selective intervention in the chemokine network may drastically disturb this delicate balance of angiogenesis and tissue repair. Application of angiostatic CXCL4L1/PF-4var without attraction of protumoral phagocytes may be beneficial in cancer therapy.
Vandercappellen
Jo
J
Laboratory of Molecular Immunology, Rega Institute, University of Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
Noppen
Samuel
S
Verbeke
Hannelien
H
Put
Willy
W
Conings
René
R
Gouwy
Mieke
M
Schutyser
Evemie
E
Proost
Paul
P
Sciot
Raf
R
Geboes
Karel
K
Opdenakker
Ghislain
G
Van Damme
Jo
J
Struyf
Sofie
S
D043925:Angiogenesis Inducing Agents / Q000037:antagonists & inhibitors*; D043165:Angiostatic Proteins / Q000276:immunology*; D000918:Antibody Specificity / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D054427:Chemokine CXCL6 / Q000037:antagonists & inhibitors*; D002630:Chemotactic Factors / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators; D007700:Kinetics; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D012516:Osteosarcoma / Q000473:pathology*; D010586:Phagocytes / Q000166:cytology* / Q000187:drug effects; D010978:Platelet Factor 4 / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology