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.
Highlights
Numerous angiogenic growth factors depend on heparan sulfate for their activity
We identified a novel mechanism for governing angiogenesis effected by ovarian cancer cells
This involves Heparan sulfate (HS) 6-O-sulfation-dependent HBEGF-induced signaling through EGFR, which impacts the concentration of angiogenic cytokines
Summary
Numerous angiogenic growth factors depend on heparan sulfate for their activity. Results: Heparan sulfate 6-O-sulfotransferases induce angiogenesis through HB-EGF/EGFR signaling and angiogenic cytokine expression in ovarian cancer cells. 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. Re-expression of exogenous human Sulf-1 was associated with reduced breast tumor xenograft growth and lower microvessel density [24] and reduction of ovarian cancer cell proliferation in vitro [22]. This suggests that elevated 6-O-sulfation potentiates signaling through a number of receptors and is a tumor growth promoting factor in breast and ovarian cancer. We discovered that HS6STs in ovarian cancer cells regulate HB-EGF-dependent EGFR signaling, which induces FGF2, IL-6, and IL-8 expression in cancer cells, thereby impacting endothelial cell functions in vitro and in vivo
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