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J. Biol. Chem. 288 (14): 10093-10099

© 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

Background: Heparanase drives the progression of many tumor types.

Results: Heparanase enhances exosome secretion and alters exosome composition and function.

Conclusion: Heparanase promotes tumor progression by regulating exosome secretion and composition.

Significance: Therapeutic inhibition of heparanase may decrease exosome secretion and slow tumor progression.

Heparanase Regulates Secretion, Composition, and Function of Tumor Cell-derived Exosomes*{diamondsuit}

Camilla A. Thompson{ddagger}, Anurag Purushothaman{ddagger}§, Vishnu C. Ramani{ddagger}, Israel Vlodavsky, , and Ralph D. Sanderson{ddagger}§1

From the {ddagger}Department of Pathology and
§University of Alabama (UAB) Comprehensive Cancer Center, University of Alabama, Birmingham, Alabama 35294 and
the Cancer and Vascular Biology Research Center, Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel

ABSTRACT Back to Top

Abstract: Emerging evidence indicates that exosomes play a key role in tumor-host cross-talk and that exosome secretion, composition, and functional capacity are altered as tumors progress to an aggressive phenotype. However, little is known regarding the mechanisms that regulate these changes. Heparanase is an enzyme whose expression is up-regulated as tumors become more aggressive and is associated with enhanced tumor growth, angiogenesis, and metastasis. We have discovered that in human cancer cells (myeloma, lymphoblastoid, and breast cancer), when expression of heparanase is enhanced or when tumor cells are exposed to exogenous heparanase, exosome secretion is dramatically increased. Heparanase enzyme activity is required for robust enhancement of exosome secretion because enzymatically inactive forms of heparanase, even when present in high amounts, do not dramatically increase exosome secretion. Heparanase also impacts exosome protein cargo as reflected by higher levels of syndecan-1, VEGF, and hepatocyte growth factor in exosomes secreted by heparanase-high expressing cells as compared with heparanase-low expressing cells. In functional assays, exosomes from heparanase-high cells stimulated spreading of tumor cells on fibronectin and invasion of endothelial cells through extracellular matrix better than did exosomes secreted by heparanase-low cells. These studies reveal that heparanase helps drive exosome secretion, alters exosome composition, and facilitates production of exosomes that impact both tumor and host cell behavior, thereby promoting tumor progression.

Key Words: Cancer • Cancer Biology • Heparan Sulfate • Multiple Myeloma • Proteoglycan • Heparanase

Received for publication December 14, 2012. Revision received February 2, 2013.

1 To whom correspondence should be addressed: Dept. of Pathology, University of Alabama at Birmingham, 602 WTI, 1720 Second Ave. S., Birmingham, Alabama 35294. E-mail: sanderson{at}

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