Research Papers:

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

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

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Oncotarget. 2014; 5:10916-10933. https://doi.org/10.18632/oncotarget.2538

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Katrien Van Raemdonck1, Nele Berghmans1, Vincent Vanheule1, Antonella Bugatti2, Paul Proost1, Ghislain Opdenakker3, Marco Presta2, Jo Van Damme1, Sofie Struyf1

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: [email protected]

Keywords: chemokines, CXCL4, CXCL4L1, EGF, CCL5, angiogenesis

Received: June 12, 2014     Accepted: September 29, 2014     Published: October 21, 2014


CXCL4 and CXCL4L1, platelet-derived CXC chemokines, and their carboxy-terminal peptides CXCL447–70 and CXCL4L147–70 previously displayed angiostatic and anti-tumoral activity in a melanoma model. Here, we found CXCL447–70 and CXCL4L147–70 to inhibit lymphatic endothelial cell proliferation in vitro. Furthermore, the angiostatic potential of CXCL447–70 and CXCL4L147–70 was tested against different angiogenic stimuli (FGF1, FGF2, FGF8, EGF and VEGF). Besides reducing FGF2-induced vascular endothelial cell growth, CXCL447–70 and CXCL4L147–70 efficiently counteracted EGF. Consequently, we considered their anti-tumoral potential in EGF-dependent MDA-MB-231 breast tumors. In tumor-bearing mice, CXCL447–70 reduced tumor growth better than CXCL4L147–70. In CXCL447–70-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 CXCL447–70 or CXCL4L147–70. Finally, CXCL447–70 and CXCL4L147–70 inhibited proliferation of MDA-MB-231 cells. Our results suggest a tumor type-dependent responsiveness to either CXCL447–70 or CXCL4L147–70 treatment, defined by anti-proliferative, angiostatic and inflammatory actions, and substantiate their therapeutic potential.

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