The Chemokine-Based Peptide, CXCL9(74-103), Inhibits Angiogenesis by Blocking Heparan Sulfate Proteoglycan-Mediated Signaling of Multiple Endothelial Growth Factors
Growth factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and epidermal growth factor (EGF) are important angiogenesis-mediating factors. They exert their effects not only through their respective receptor tyrosine kinases (RTKs), but they also require molecula...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-10-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/20/5090 |
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| author | Alexandra De Zutter Helena Crijns Nele Berghmans Melissa García-Caballero Lotte Vanbrabant Noëmie Pörtner Vincent Vanheule Paulien Verscheure Mohammad Mairaj Siddiquei Ahmed M. Abu El-Asrar Peter Carmeliet Pieter Van Wielendaele Ingrid De Meester Jo Van Damme Paul Proost Sofie Struyf |
| author_facet | Alexandra De Zutter Helena Crijns Nele Berghmans Melissa García-Caballero Lotte Vanbrabant Noëmie Pörtner Vincent Vanheule Paulien Verscheure Mohammad Mairaj Siddiquei Ahmed M. Abu El-Asrar Peter Carmeliet Pieter Van Wielendaele Ingrid De Meester Jo Van Damme Paul Proost Sofie Struyf |
| author_sort | Alexandra De Zutter |
| collection | DOAJ |
| description | Growth factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and epidermal growth factor (EGF) are important angiogenesis-mediating factors. They exert their effects not only through their respective receptor tyrosine kinases (RTKs), but they also require molecular pairing with heparan sulfate proteoglycans (HSPGs). Angiogenic growth factors and their signaling pathways are commonly targeted in current anti-angiogenic cancer therapies but have unfortunately insufficient impact on patient survival. Considering their obvious role in pathological angiogenesis, HS-targeting drugs have become an appealing new strategy. Therefore, we aimed to reduce angiogenesis through interference with growth factor-HS binding and downstream signaling using a CXCL9-derived peptide with a high affinity for glycosaminoglycans (GAGs), CXCL9(74-103). We showed that CXCL9(74-103) reduced EGF-, VEGF165- and FGF-2-mediated angiogenic processes in vitro, such as endothelial cell proliferation, chemotaxis, adhesion and sprouting, without exerting cell toxicity. CXCL9(74-103) interfered with growth factor signaling in diverse ways, e.g., by diminishing VEGF165 binding to HS and by direct association with FGF-2. The dependency of CXCL9(74-103) on HS for binding to HMVECs and for exerting its anti-angiogenic activity was also demonstrated. In vivo, CXCL9(74-103) attenuated neovascularization in the Matrigel plug assay, the corneal cauterization assay and in MDA-MB-231 breast cancer xenografts. Additionally, CXCL9(74-103) reduced vascular leakage in the retina of diabetic rats. In contrast, CXCL9(86-103), a peptide with low GAG affinity, showed no overall anti-angiogenic activity. Altogether, our results indicate that CXCL9(74-103) reduces angiogenesis by interfering with multiple HS-dependent growth factor signaling pathways. |
| first_indexed | 2024-03-10T06:40:12Z |
| format | Article |
| id | doaj.art-2429a3eef0c44104974d9b4ff4a3d01d |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T06:40:12Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-2429a3eef0c44104974d9b4ff4a3d01d2023-11-22T17:40:07ZengMDPI AGCancers2072-66942021-10-011320509010.3390/cancers13205090The Chemokine-Based Peptide, CXCL9(74-103), Inhibits Angiogenesis by Blocking Heparan Sulfate Proteoglycan-Mediated Signaling of Multiple Endothelial Growth FactorsAlexandra De Zutter0Helena Crijns1Nele Berghmans2Melissa García-Caballero3Lotte Vanbrabant4Noëmie Pörtner5Vincent Vanheule6Paulien Verscheure7Mohammad Mairaj Siddiquei8Ahmed M. Abu El-Asrar9Peter Carmeliet10Pieter Van Wielendaele11Ingrid De Meester12Jo Van Damme13Paul Proost14Sofie Struyf15Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, BelgiumLaboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, BelgiumLaboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, BelgiumLaboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, 3000 Leuven, BelgiumLaboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, BelgiumLaboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, BelgiumLaboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, BelgiumLaboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, BelgiumDepartment of Ophthalmology, College of Medicine, King Saud University, P.O. Box 245, Riyadh 11411, Saudi ArabiaDepartment of Ophthalmology, College of Medicine, King Saud University, P.O. Box 245, Riyadh 11411, Saudi ArabiaLaboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, 3000 Leuven, BelgiumLaboratory of Medical Biochemistry, University of Antwerp, 2610 Antwerp, BelgiumLaboratory of Medical Biochemistry, University of Antwerp, 2610 Antwerp, BelgiumLaboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, BelgiumLaboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, BelgiumLaboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, BelgiumGrowth factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and epidermal growth factor (EGF) are important angiogenesis-mediating factors. They exert their effects not only through their respective receptor tyrosine kinases (RTKs), but they also require molecular pairing with heparan sulfate proteoglycans (HSPGs). Angiogenic growth factors and their signaling pathways are commonly targeted in current anti-angiogenic cancer therapies but have unfortunately insufficient impact on patient survival. Considering their obvious role in pathological angiogenesis, HS-targeting drugs have become an appealing new strategy. Therefore, we aimed to reduce angiogenesis through interference with growth factor-HS binding and downstream signaling using a CXCL9-derived peptide with a high affinity for glycosaminoglycans (GAGs), CXCL9(74-103). We showed that CXCL9(74-103) reduced EGF-, VEGF165- and FGF-2-mediated angiogenic processes in vitro, such as endothelial cell proliferation, chemotaxis, adhesion and sprouting, without exerting cell toxicity. CXCL9(74-103) interfered with growth factor signaling in diverse ways, e.g., by diminishing VEGF165 binding to HS and by direct association with FGF-2. The dependency of CXCL9(74-103) on HS for binding to HMVECs and for exerting its anti-angiogenic activity was also demonstrated. In vivo, CXCL9(74-103) attenuated neovascularization in the Matrigel plug assay, the corneal cauterization assay and in MDA-MB-231 breast cancer xenografts. Additionally, CXCL9(74-103) reduced vascular leakage in the retina of diabetic rats. In contrast, CXCL9(86-103), a peptide with low GAG affinity, showed no overall anti-angiogenic activity. Altogether, our results indicate that CXCL9(74-103) reduces angiogenesis by interfering with multiple HS-dependent growth factor signaling pathways.https://www.mdpi.com/2072-6694/13/20/5090chemokine-derived peptideheparan sulfategrowth factorsanti-angiogenic activity |
| spellingShingle | Alexandra De Zutter Helena Crijns Nele Berghmans Melissa García-Caballero Lotte Vanbrabant Noëmie Pörtner Vincent Vanheule Paulien Verscheure Mohammad Mairaj Siddiquei Ahmed M. Abu El-Asrar Peter Carmeliet Pieter Van Wielendaele Ingrid De Meester Jo Van Damme Paul Proost Sofie Struyf The Chemokine-Based Peptide, CXCL9(74-103), Inhibits Angiogenesis by Blocking Heparan Sulfate Proteoglycan-Mediated Signaling of Multiple Endothelial Growth Factors Cancers chemokine-derived peptide heparan sulfate growth factors anti-angiogenic activity |
| title | The Chemokine-Based Peptide, CXCL9(74-103), Inhibits Angiogenesis by Blocking Heparan Sulfate Proteoglycan-Mediated Signaling of Multiple Endothelial Growth Factors |
| title_full | The Chemokine-Based Peptide, CXCL9(74-103), Inhibits Angiogenesis by Blocking Heparan Sulfate Proteoglycan-Mediated Signaling of Multiple Endothelial Growth Factors |
| title_fullStr | The Chemokine-Based Peptide, CXCL9(74-103), Inhibits Angiogenesis by Blocking Heparan Sulfate Proteoglycan-Mediated Signaling of Multiple Endothelial Growth Factors |
| title_full_unstemmed | The Chemokine-Based Peptide, CXCL9(74-103), Inhibits Angiogenesis by Blocking Heparan Sulfate Proteoglycan-Mediated Signaling of Multiple Endothelial Growth Factors |
| title_short | The Chemokine-Based Peptide, CXCL9(74-103), Inhibits Angiogenesis by Blocking Heparan Sulfate Proteoglycan-Mediated Signaling of Multiple Endothelial Growth Factors |
| title_sort | chemokine based peptide cxcl9 74 103 inhibits angiogenesis by blocking heparan sulfate proteoglycan mediated signaling of multiple endothelial growth factors |
| topic | chemokine-derived peptide heparan sulfate growth factors anti-angiogenic activity |
| url | https://www.mdpi.com/2072-6694/13/20/5090 |
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