FGF2 binding, signaling, and angiogenesis are modulated by heparanase in metastatic melanoma cells

Jane Reiland, Doty Kempf, Madhuchhanda Roy, Yvonne Denkins, Dario Marchetti

Research output: Contribution to journalArticlepeer-review

72 Scopus citations


Heparanase (HPSE) and fibroblast growth factor-2 (FGF2) are critical regulators of melanoma angiogenesis and metastasis. Elevated HPSE expression contributes to melanoma progression; however, further augmentation of HPSE presence can inhibit tumorigenicity. HPSE enzymatically cleaves heparan sulfate glycosaminoglycan chains (HS) from proteoglycans. HS act as both low-affinity FGF2 receptors and coreceptors in the formation of high-affinity FGF2 receptors. We have investigated HPSE's ability to modulate FGF2 activity through HS remodeling. Extensive HPSE degradation of human metastatic melanoma cells (70W) inhibited FGF2 binding. Unexpectedly, treatment of 70W cells with low HPSE concentrations enhanced FGF2 binding. In addition, HPSE-unexposed cells did not phosphorylate extracellular signal-related kinase (ERK) or focal adhesion kinase (FAK) in response to FGF2. Conversely, in cells treated with HPSE, FGF2 stimulated ERK and FAK phosphorylation. Secondly, the presence of soluble HPSE-degraded HS enhanced FGF2 binding and ERK phosphorylation at low HS concentrations. Higher concentrations of soluble HS inhibited FGF2 binding, but FGF2 signaling through ERK remained enhanced. Soluble HS were unable to support FGF2-stimulated FAK phosphorylation irrespective of HPSE treatment. Finally, cell exposure to HPSE or to HPSE-degraded HS modulated FGF2-induced angiogenesis in melanoma. In conclusion, these effects suggest relevant mechanisms for the HPSE modulation of melanoma growth factor responsiveness and tumorigenicity.

Original languageEnglish (US)
Pages (from-to)596-606
Number of pages11
Issue number7
StatePublished - 2006


  • Angiogenesis
  • FGF2 binding
  • Heparan sulfate
  • Heparanase
  • Malignant melanoma

ASJC Scopus subject areas

  • Cancer Research


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