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Angiostatic, tumor inflammatory and anti-tumor effects of CXCL447-70 and CXCL4L147–70 in an EGF-dependent breast cancer model

2014; Impact Journals LLC; Volume: 5; Issue: 21 Linguagem: Inglês

10.18632/oncotarget.2538

1949-2553

Katrien Van Raemdonck, Nele Berghmans, Vincent Vanheule, Antonella Bugatti, Paul Proost, Ghislain Opdenakker, Marco Presta, Jo Van Damme, Sofie Struyf,

Immune cells in cancer

// Katrien Van Raemdonck 1 , Nele Berghmans 1 , Vincent Vanheule 1 , Antonella Bugatti 2 , Paul Proost 1 , Ghislain Opdenakker 3 , Marco Presta 2 , Jo Van Damme 1 , Sofie Struyf 1 1 Laboratory of Molecular Immunology, KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Leuven, Belgium 2 Laboratory of Experimental Oncology and Immunology, University of Brescia, Department of Molecular and Translational Medicine Brescia, Italy 3 Laboratory of Immunobiology, KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Leuven, Belgium Correspondence to: Sofie Struyf, e-mail: Sofie.Struyf@rega.kuleuven.be Keywords: chemokines, CXCL4, CXCL4L1, EGF, CCL5, angiogenesis Received: June 12, 2014 Accepted: September 29, 2014 Published: October 21, 2014 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.