title: Ovarian cancer cell heparan sulfate 6-O-sulfotransferases regulate an angiogenic program induced by heparin-binding epidermal growth factor (EGF)-like growth factor/EGF receptor signaling.
abstract: Heparan sulfate (HS) is a component of cell surface and extracellular matrix proteoglycans that regulates numerous signaling pathways by binding and activating multiple growth factors and chemokines. The amount and pattern of HS sulfation are key determinants for the assembly of the trimolecular, HS-growth factor-receptor, signaling complex. Here we demonstrate that HS 6-O-sulfotransferases 1 and 2 (HS6ST-1 and HS6ST-2), which perform sulfation at 6-O position in glucosamine in HS, impact ovarian cancer angiogenesis through the HS-dependent HB-EGF/EGFR axis that subsequently modulates the expression of multiple angiogenic cytokines. Down-regulation of HS6ST-1 or HS6ST-2 in human ovarian cancer cell lines results in 30-50% reduction in glucosamine 6-O-sulfate levels in HS, impairing HB-EGF-dependent EGFR signaling and diminishing FGF2, IL-6, and IL-8 mRNA and protein levels in cancer cells. These cancer cell-related changes reduce endothelial cell signaling and tubule formation in vitro. In vivo, the development of subcutaneous tumor nodules with reduced 6-O-sulfation is significantly delayed at the initial stages of tumor establishment with further reduction in angiogenesis occurring throughout tumor growth. Our results show that in addition to the critical role that 6-O-sulfate moieties play in angiogenic cytokine activation, HS 6-O-sulfation level, determined by the expression of HS6ST isoforms in ovarian cancer cells, is a major regulator of angiogenic program in ovarian cancer cells impacting HB-EGF signaling and subsequent expression of angiogenic cytokines by cancer cells.
authors.affiliation: Institute of Cancer Sciences, Faculty of Medical and Human Sciences, The University of Manchester, Manchester M20 4BX, United Kingdom.
authors.forename: Claire L
authors.initials: CL
authors.lastname: Cole
authors.affiliation: Institute of Cancer Sciences, Faculty of Medical and Human Sciences, The University of Manchester, Manchester M20 4BX, United Kingdom.
authors.forename: Graham
authors.initials: G
authors.lastname: Rushton
authors.affiliation: Institute of Cancer Sciences, Faculty of Medical and Human Sciences, The University of Manchester, Manchester M20 4BX, United Kingdom.
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Jayson
authors.affiliation: Institute of Cancer Sciences, Faculty of Medical and Human Sciences, The University of Manchester, Manchester M20 4BX, United Kingdom. Electronic address: egle.avizienyte@ics.manchester.ac.uk.
authors.forename: Egle
authors.initials: E
authors.lastname: Avizienyte
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D004187:Disaccharides / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005944:Glucosamine / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D010051:Ovarian Neoplasms / Q000378:metabolism*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D015398:Signal Transduction; D015238:Sulfotransferases / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; D004187:Disaccharides; D015850:Interleukin-6; D016209:Interleukin-8; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D016222:Fibroblast Growth Factor 2; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; C485757:HS6ST2 protein, human; D015238:Sulfotransferases; C404189:heparan sulfate 6-O-sulfotransferase; D005944:Glucosamine
keywords: Angiogenesis; Epidermal Growth Factor Receptor (EGFR); HB-EGF; Heparan Sulfate; IL-6; IL-8; Sulfotransferase; Tumor Microenvironment