Platelet factor-4 variant chemokine CXCL4L1 inhibits melanoma and lung carcinoma growth and metastasis by preventing angiogenesis.
The platelet factor-4 variant, designated PF-4var/CXCL4L1, is a recently described natural non-allelic gene variant of the CXC chemokine platelet factor-4/CXCL4. PF-4var/CXCL4L1 was cloned, and the purified recombinant protein strongly inhibited angiogenesis. Recombinant PF-4var/CXCL4L1 was angiostatically more active (at nanomolar concentration) than PF-4/CXCL4 in various test systems, including wound-healing and migration assays for microvascular endothelial cells and the rat cornea micropocket assay for angiogenesis. Furthermore, PF-4var/CXCL4L1 more efficiently inhibited tumor growth in animal models of melanoma and lung carcinoma than PF-4/CXCL4 at an equimolar concentration. For B16 melanoma in nude mice, a significant reduction in tumor size and the number of small i.t. blood vessels was obtained with i.t. applied PF-4var/CXCL4L1. For A549 adenocarcinoma in severe combined immunodeficient mice, i.t. PF-4var/CXCL4L1 reduced tumor growth and microvasculature more efficiently than PF-4/CXCL4 and prevented metastasis to various organs better than the angiostatic IFN-inducible protein 10/CXCL10. Finally, in the syngeneic model of Lewis lung carcinoma, PF-4var/CXCL4L1 inhibited tumor growth equally well as monokine induced by IFN-gamma (Mig)/CXCL9, also known to attract effector T lymphocytes. Taken together, PF-4var/CXCL4L1 is a highly potent antitumoral chemokine preventing development and metastasis of various tumors by inhibition of angiogenesis. These data confirm the clinical potential of locally released chemokines in cancer therapy.
Struyf
Sofie
S
Laboratory of Molecular Immunology, Rega Institute, Leuven, Belgium.
Burdick
Marie D
MD
Peeters
Elke
E
Van den Broeck
Karolien
K
Dillen
Chris
C
Proost
Paul
P
Van Damme
Jo
J
Strieter
Robert M
RM
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010978:Platelet Factor 4 / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D051381:Rats
C064936:PF4V1 protein, human; D010978:Platelet Factor 4