Angiostatic, tumor inflammatory and anti-tumor effects of CXCL4(47-70) and CXCL4L1(47-70) in an EGF-dependent breast cancer model.
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.
Laboratory of Molecular Immunology, KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Leuven, Belgium.
Katrien
K
Van Raemdonck
Laboratory of Molecular Immunology, KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Leuven, Belgium.
Nele
N
Berghmans
Laboratory of Molecular Immunology, KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Leuven, Belgium.
Vincent
V
Vanheule
Laboratory of Experimental Oncology and Immunology, University of Brescia, Department of Molecular and Translational Medicine Brescia, Italy.
Antonella
A
Bugatti
Laboratory of Molecular Immunology, KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Leuven, Belgium.
Paul
P
Proost
Laboratory of Immunobiology, KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Leuven, Belgium.
Ghislain
G
Opdenakker
Laboratory of Experimental Oncology and Immunology, University of Brescia, Department of Molecular and Translational Medicine Brescia, Italy.
Marco
M
Presta
Laboratory of Molecular Immunology, KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Leuven, Belgium.
Jo
J
Van Damme
Laboratory of Molecular Immunology, KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Leuven, Belgium.
Sofie
S
Struyf
D043165:Angiostatic Proteins / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis; D003029:Coagulants / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D018836:Inflammation Mediators / Q000494:pharmacology*; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic; D010446:Peptide Fragments / Q000494:pharmacology*; D010978:Platelet Factor 4; D023041:Xenograft Model Antitumor Assays
D043165:Angiostatic Proteins; D000970:Antineoplastic Agents; D003029:Coagulants; D016207:Cytokines; D018836:Inflammation Mediators; C064936:PF4V1 protein, human; D010446:Peptide Fragments; D010978:Platelet Factor 4; D004815:Epidermal Growth Factor