Editors' ChoiceCancer

Heparanase Promotes Exosome Release

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Sci. Signal.  16 Apr 2013:
Vol. 6, Issue 271, pp. ec84
DOI: 10.1126/scisignal.2004245

The enzyme heparanase is an endoglycosidase that cleaves heparan sulfate from cell surfaces and the extracellular matrix. The abundance of heparanase increases in tumors as they become more aggressive, and it is associated with enhanced tumor growth and metastasis. Cancer patients with increased amounts of heparanase have poorer postoperative survival than those with decreased amounts. This association is thought to be mostly a result of remodeling of the extracellular matrix by heparanase; however, Thompson et al. have found another potential route by which heparanase might promote tumor growth. A cultured human myeloma cell line that was transfected to produce increased amounts of heparanase released sixfold more exosomes into the culture medium than did a myeloma cell line with lower amounts of heparanase. Exosomes are membrane-bound vesicles that are released from cells into the extracellular environment, and they can deliver components, such as proteins and nucleic acids, to nearby cells. Incubating heparanase-low cells with recombinant heparanase increased their release of exosomes in a concentration-dependent manner. Similar results were found with lymphoblastoid and breast cancer cell lines. The effect of increased heparanase abundance on exosome release required its enzymatic activity, although the mechanism involved is unclear. In addition, exosomes from heparanase-high myeloma cells had larger amounts of the protumorigenic factors VEGF (vascular endothelial growth factor) and HGF (hepatocyte growth factor) than did exosomes from heparanase-low cells. Finally, exosomes from heparanase-high cells stimulated the invasive capacity of endothelial cells in vitro to a greater extent than did exosomes from heparanase-low cells. Together, these data suggest that heparanase enhances the release of exosomes from tumor cells and alters their composition to potentially promote tumor progression.

C. A. Thompson, A. Purushothaman, V. C. Ramani, I. Vlodavsky, R. D. Sanderson, Heparanase regulates secretion, composition, and function of tumor cell-derived exosomes. J. Biol. Chem. 288, 10093–10099 (2013). [Abstract] [Full Text]