2. Academic Validation
  3. The Chemokine-Based Peptide, CXCL9(74-103), Inhibits Angiogenesis by Blocking Heparan Sulfate Proteoglycan-Mediated Signaling of Multiple Endothelial Growth Factors

The Chemokine-Based Peptide, CXCL9(74-103), Inhibits Angiogenesis by Blocking Heparan Sulfate Proteoglycan-Mediated Signaling of Multiple Endothelial Growth Factors

  • Cancers (Basel). 2021 Oct 12;13(20):5090. doi: 10.3390/cancers13205090.
Alexandra De Zutter 1,  Helena Crijns 1,  Nele Berghmans 1,  Melissa García-Caballero 2,  Lotte Vanbrabant 1,  Noëmie Pörtner 1,  Vincent Vanheule 1,  Paulien Verscheure 1,  Mohammad Mairaj Siddiquei 3,  Ahmed M Abu El-Asrar 3,  Peter Carmeliet 2,  Pieter Van Wielendaele 4,  Ingrid De Meester 4,  Jo Van Damme 1,  Paul Proost 1,  Sofie Struyf 1
Affiliations

Affiliations

  • 1 Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium.
  • 2 Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, 3000 Leuven, Belgium.
  • 3 Department of Ophthalmology, College of Medicine, King Saud University, P.O. Box 245, Riyadh 11411, Saudi Arabia.
  • 4 Laboratory of Medical Biochemistry, University of Antwerp, 2610 Antwerp, Belgium.
PMID: 34680238 DOI: 10.3390/cancers13205090
Abstract

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.

Keywords

anti-angiogenic activity; chemokine-derived peptide; growth factors; heparan sulfate.

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