Abstract
CXCL4 and CXCL4L1, platelet-derived CXC chemokines, and their carboxy-terminal peptides CXCL4(47-70) and CXCL4L1(47-70) previously displayed angiostatic and anti-tumoral activity in a melanoma model. Here, we found CXCL4(47-70) and CXCL4L1(47-70) to inhibit lymphatic endothelial cell proliferation in vitro. Furthermore, the angiostatic potential of CXCL4(47-70) and CXCL4L1(47-70) was tested against different angiogenic stimuli (FGF1, FGF2, FGF8, EGF and VEGF). Besides reducing FGF2-induced vascular endothelial cell growth, CXCL4(47-70) and CXCL4L1(47-70) efficiently counteracted EGF. Consequently, we considered their anti-tumoral potential in EGF-dependent MDA-MB-231 breast tumors. In tumor-bearing mice, CXCL4(47-70) reduced tumor growth better than CXCL4L1(47-70). In CXCL4(47-70)-treated tumors significantly more intratumoral monocytes/macrophages and dendritic cells were present and higher expression levels of CCL5 and IFN- γ were detected by qPCR on tumor lysates. Because neither peptide was able to specifically bind CXCR3A or CXCR3B, differential glycosaminoglycan binding and direct interaction with cytokines (EGF and CCL5) might explain any differences in anti-tumoral effects. Notably, CCL5-induced monocyte chemotaxis in vitro was increased by addition of CXCL4(47-70) or CXCL4L1(47-70). Finally, CXCL4(47-70) and CXCL4L1(47-70) inhibited proliferation of MDA-MB-231 cells. Our results suggest a tumor type-dependent responsiveness to either CXCL4(47-70) or CXCL4L1(47-70) treatment, defined by anti-proliferative, angiostatic and inflammatory actions, and substantiate their therapeutic potential.
Highlights
Angiogenesis, the formation of an ever more branching network of blood vessels from a pre-existing vascular network, has been established as a requisite for successful tumor growth and cancer progression [1, 2]
A distinction should be made between angiogenic and angiostatic chemokines. The latter group comprises the CXCR3 ligands, namely CXCL9/Monokine induced by interferon-γ (Mig), CXCL10/Interferon-γ-induced protein 10 (IP-10), CXCL11/Interferon-inducible T-cell α chemoattractant (I-TAC), CXCL4/Platelet factor-4 (PF-4)
We demonstrated MDA-MB-231 tumor cells to be sensitive to the anti-proliferative effect of CXCL447–70 and CXCL4L147–70 in vitro
Summary
Angiogenesis, the formation of an ever more branching network of blood vessels from a pre-existing vascular network, has been established as a requisite for successful tumor growth and cancer progression [1, 2]. Classic anti-angiogenic therapeutics have encountered important hurdles and interest in less obvious targets, including inflammatory mediators such as the chemokines, increases [3,4,5,6,7]. These chemotactic cytokines play an important role in immunity as they control activation and migration of particular subsets of leukocytes. A distinction should be made between angiogenic (mostly CC and ELR-positive CXC chemokines) and angiostatic chemokines (mostly ELRnegative CXC chemokines) The latter group comprises the CXCR3 ligands, namely CXCL9/Monokine induced by interferon-γ (Mig), CXCL10/Interferon-γ-induced protein 10 (IP-10), CXCL11/Interferon-inducible T-cell α chemoattractant (I-TAC), CXCL4/Platelet factor-4 (PF-4)
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