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Title: De CXCR3-chemokineliganden CXCL4, CXCL4L1 en afgeleide peptides: Signaaltransductie en rol in angiogene aandoeningen
Other Titles: The CXCR3 chemokine ligands CXCL4, CXCL4L1 and derived peptides: Signal transduction and role in angiogenic disorders
Authors: Van Raemdonck, Katrien
Issue Date: 6-Oct-2014
Abstract: The days of chemokines being merely ‘chemotactic cytokinesÂ’ that direct immune cells travelling through the body and to sites of inflammation, have long passed. Chemokines are now considered multifunctional players involved in a myriad of physiological and pathological processes. A considerable subset of chemokines has been involved in the regulation of angiogenesis, or the formation of new blood vessels from an existing vascular network. Besides its physiological role during embryogenesis, a derailed stimulation of angiogenesis also characterizes many different diseases. Tumor progression, for example, is tightly associated with intratumoral neovascularization ensuring sufficient oxygen supply to the expanding malignant tissue. Our study has focused on the platelet-derived chemokines PF-4/CXCL4 and PF-4var/CXCL4L1. These two highly similar proteins bind the CXCR3 receptor, either presented as CXCR3A, mostly promoting leukocyte migration and proliferation upon ligand binding, or presented as CXCR3B, triggering angiostatic signaling in endothelial cells. CXCL4 in fact acts in various CXCR3-dependent and -independent manners. However, little is known about the mode of action of CXCL4L1.This doctoral project has aimed to improve fundamental understanding of both CXCL4 and CXCL4L1 biology and their therapeutic applicability. To this end, we have first studied signaling of these platelet-derived CXCR3 chemokine ligands in various CXCR3A- or CXCR3B-expressing cells, including transfected CHO cells, activated human T lymphocytes and human blood and lymphatic microvascular endothelial cells. In summary, our results demonstrate that both CXCL4 and CXCL4L1 activate signaling pathways associated with migration via CXCR3A. Additionally, we revealed that the angiostatic effect of both platelet CXC chemokines is reflected by a reduction of ERK activation in microvascular endothelial cells treated with mitogenic stimuli, e.g. the angiogenic chemokine SDF-1/CXCL12. Interestingly, the observed ability of CXCL4L1 in particular, to counteract CXCL12-induced ERK activation, can also be extended to lymphatic microvascular endothelial cells. CXCL4L1 could thus inhibit lymphangiogenesis as well, which may have important implications for its anti-tumoral effect as the lymphatic vasculature is considered an escape route for metastatic tumor cells.In addition, we have also evaluated the function of endogenous CXCL4 in the pathogenesis of the angiogenic disorder proliferative diabetic retinopathy (PDR). Despite its angiostatic function, elevated vitreous CXCL4 concentrations correlated with active neovascularization in the diabetic eye, suggesting CXCL4 is part of an inadequate compensatory feedback mechanism, presumably triggered by excessive angiogenic stimuli. On the other hand, increasing levels of CXCL4 associate inversely with fibrotic complications of PDR. Finally, we focused on the anti-tumoral potential of CXCL4- and CXCL4L1-derived carboxy-terminal peptides, CXCL4(47-70) and CXCL4L1(47-70), respectively. In vitro, we confirmed the anti-proliferative effect of both peptides on human lymphatic and blood microvascular endothelial cells. The peptides were demonstrated to be efficient inhibitors of EGF, an important growth factor also for malignant epithelial cells. We therefore explored the anti-tumoral potential of CXCL4(47-70) and CXCL4L1(47-70) in an EGF-dependent breast tumor model, using human MDA-MB-231 tumor cells. Despite the observed in vitro angiostatic activity, little effect on the tumoral vasculature was observed in MDA-MB-231 tumor-bearing mice, treated intratumorally with either peptide. Nevertheless, CXCL4(47-70)-treated mice did present smaller tumors. We suspect this reduced tumor growth to be dependent not on angiostatic activity, but to be attributable to changes in the inflammatory microenvironment. CXCL4(47-70)-treated tumors indeed showed higher expression of various inflammatory markers, such as interferon. Taken together, the unexpected outcome of this study has highlighted the tumor model-dependent responsiveness to chemokine-based therapy. CXCL4, CXCL4L1 and derived peptides display anti-tumoral activity that relies on their angiostatic potential, lymphangiostatic effect as well as the attraction of anti-tumoral, inflammatory leukocytes. The net result of treatment with these chemokines is at the moment rather unpredictable. In summary, our data support the therapeutic potential of CXCL4, CXCL4L1 and their carboxy-terminal derived peptides, yet stress the necessity for better understanding of their structure/function relationship.
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Laboratory of Molecular Immunology (Rega Institute)

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