title: Angiostatic and chemotactic activities of the CXC chemokine CXCL4L1 (platelet factor-4 variant) are mediated by CXCR3.
abstract: We investigated possible cellular receptors for the human CXC chemokine platelet factor-4 variant/CXCL4L1, a potent inhibitor of angiogenesis. We found that CXCL4L1 has lower affinity for heparin and chondroitin sulfate-E than platelet factor-4 (CXCL4) and showed that CXCL10 and CXCL4L1 could displace each other on microvascular endothelial cells. Labeled CXCL4L1 also bound to CXCR3A- and CXCR3B-transfectants and was displaced by CXCL4L1, CXCL4, and CXCL10. The CXCL4L1 anti-angiogenic activity was blocked by anti-CXCR3 antibodies (Abs) in the Matrigel and cornea micropocket assays. CXCL4L1 application in CXCR3(-/-) or in wild-type mice treated with neutralizing anti-CXCR3 Abs, resulted in reduced inhibitory activity of CXCL4L1 on tumor growth and vascularization of Lewis lung carcinoma. Furthermore, CXCL4L1 and CXCL4 chemoattracted activated T cells, human natural killer cells, and human immature dendritic cells (DCs). Migration of DCs toward CXCL4 and CXCL4L1 was desensitized by preincubation with CXCL10 and CXCL11, inhibited by pertussis toxin, and neutralized by anti-CXCR3 Abs. Chemotaxis of T cells, natural killer cells, and DCs is likely to contribute to the antitumoral action. However, the in vivo data indicate that the angiostatic property of CXCL4L1 is equally important in retarding tumor growth. Thus, both CXCR3A and CXCR3B are implicated in the chemotactic and vascular effects of CXCL4L1.
authors.affiliation: Rega Institute, K.U. Leuven, Leuven, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Struyf
authors.forename: Laura
authors.initials: L
authors.lastname: Salogni
authors.forename: Marie D
authors.initials: MD
authors.lastname: Burdick
authors.forename: Jo
authors.initials: J
authors.lastname: Vandercappellen
authors.forename: Mieke
authors.initials: M
authors.lastname: Gouwy
authors.forename: Sam
authors.initials: S
authors.lastname: Noppen
authors.forename: Paul
authors.initials: P
authors.lastname: Proost
authors.forename: Ghislain
authors.initials: G
authors.lastname: Opdenakker
authors.forename: Marc
authors.initials: M
authors.lastname: Parmentier
authors.forename: Craig
authors.initials: C
authors.lastname: Gerard
authors.forename: Silvano
authors.initials: S
authors.lastname: Sozzani
authors.forename: Robert M
authors.initials: RM
authors.lastname: Strieter
authors.forename: Jo
authors.initials: J
authors.lastname: Van Damme
mesh_terms: D020533:Angiogenesis Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D002630:Chemotactic Factors / Q000378:metabolism* / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology; D003713:Dendritic Cells / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D010978:Platelet Factor 4 / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D054367:Receptors, CXCR3 / Q000378:metabolism*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; C515187:CXCR3 protein, human; D002630:Chemotactic Factors; C064936:PF4V1 protein, human; D054367:Receptors, CXCR3; D010978:Platelet Factor 4