Platelet Factor-4 Variant Chemokine CXCL4L1 Inhibits Melanoma and Lung Carcinoma Growth and Metastasis by Preventing Angiogenesis

Abstract

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-; (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. [Cancer Res 2007;67(12):5940-8]

The COOH-Terminal Peptide of Platelet Factor-4 Variant (CXCL4L1/PF-4var47-70) Strongly Inhibits Angiogenesis and Suppresses B16 Melanoma Growth In vivo

“…2D), indicating a stronger angiostatic activity of CXCL4L1/PF-4var 47-70 compared with CXCL4/PF-4 . For comparison, inhibition of endothelial cell migration was obtained at 20 nmol/L CXCL4/PF-4 or 1 nmol/L CXCL4L1/PF-4var, confirming previously published data (18,19). This allowed us to conclude that CXCL4L1/PF-4var is equally angiostatic as the intact chemokine.…”

“…As a control, CXCL4/PF-4 and CXCL4L1/PF-4var were also tested in this assay. The results confirm that CXCL4L1/PF-4var inhibits endothelial cell migration at 1 nmol/L, being therefore a 20-fold more potent inhibitor than CXCL4/PF-4 (18,19). Next, it was found that both PF-4 peptides (from 5 nmol/L onwards) significantly inhibited FGF-2-induced HUVEC motility as observed by time-lapse microscopy ( Fig.…”

“…Struyf et al (19) already showed that intratumoral injection of intact CXCL4L1/PF-4var causes a more pronounced effect than CXCL4/PF-4 in reducing tumor size in different animal models, such as B16 melanoma, A549 adenocarcinoma, and Lewis lung carcinoma. We observed significantly reduced tumor growth in the CXCL4L1/PF-4var 47-70 -treated, but not in the CXCL4/PF-4 47-70 -treated, group (seven injections of 1 μg) from day 9 onwards.…”

“…In a previous study, we showed that CXCL4L1/PF4var is also produced by osteosarcoma cells (18). CXCL4L1/PF-4var was found to be a more potent angiostatic and antitumoral chemokine than CXCL4/PF-4 in different in vitro assays and in vivo models (17,19). Previous reports have shown that shorter COOH-terminal fragments of CXCL4/PF-4 retain their angiostatic properties (20,21).…”

TNF-α and the IFN-γ-inducible protein 10 (IP-10/CXCL-10) delivered by parvoviral vectors act in synergy to induce antitumor effects in mouse glioblastoma

“…10,22,25,[51][52][53][54][55] The antitumor activity of IP-10 alone is usually moderate, but can in some cases be markedly increased by combined therapy, in particular with interleukin-2 and interleukin-12.…”