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Logo of jbcThe Journal of Biological Chemistry
 
J Biol Chem. 2011 February 25; 286(8): e99914.
PMCID: PMC3057849

Dual Roles for Heparanase in Myeloma♦

Heparanase Plays a Dual Role in Driving Hepatocyte Growth Factor (HGF) Signaling by Enhancing HGF Expression and Activity

♦ See referenced article, J. Biol. Chem. 2011, 286, 6490–6499

Hepatocyte growth factor is a heparin-binding cytokine that influences the behavior of both endothelial and epithelial cells. HGF is overexpressed by multiple myeloma cells, which aids tumor angiogenesis, cell migration, and cell survival. However, little is known about how this process is regulated in tumor cells. In this Paper of the Week, Vishnu Ramani and colleagues find that heparanase, which cleaves heparan sulfate chains, is responsible for enhancing HGF expression in myeloma cells. In vitro, the addition of recombinant heparanase to myeloma cell lines or transfecting them with heparanase cDNA increased the expression and secretion of HGF along with increased synthesis and shedding of the heparan sulfate proteoglycan syndecan-1. The HGF and shed syndecan-1 form an active complex that stimulates cell signaling via the proto-oncogenic c-met HGF receptor. Interestingly, although heparanase enzyme activity was required for the shedding of syndecan-1 from the cell surface, enzymatic activity was not required for HGF up-regulation. This suggests that heparanase contains two different functional domains, each of which contributes to myeloma cell survival by stimulating the two components of the HGF/syndecan-1 signaling complex.

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Immunohistochemical staining shows greatly increased levels of HGF (brown) in tumors formed in SCID mice from myeloma cells containing high levels of heparanase expression.

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