title: Heparanase regulates secretion, composition, and function of tumor cell-derived exosomes.
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.
authors: Department of Pathology, University of Alabama, Birmingham, Alabama 35294, Israel.
authors: Camilla A
authors: CA
authors: Thompson
authors: Department of Pathology, University of Alabama, Birmingham, Alabama 35294, Israel; University of Alabama (UAB) Comprehensive Cancer Center, University of Alabama, Birmingham, Alabama 35294, Israel.
authors: Anurag
authors: A
authors: Purushothaman
authors: Department of Pathology, University of Alabama, Birmingham, Alabama 35294, Israel.
authors: Vishnu C
authors: VC
authors: Ramani
authors: Cancer and Vascular Biology Research Center, Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
authors: Israel
authors: I
authors: Vlodavsky
authors: Department of Pathology, University of Alabama, Birmingham, Alabama 35294, Israel; University of Alabama (UAB) Comprehensive Cancer Center, University of Alabama, Birmingham, Alabama 35294, Israel. Electronic address: sanderson@uab.edu.
authors: Ralph D
authors: RD
authors: Sanderson
mesh_terms: D045744:Cell Line, Tumor; D018076:DNA, Complementary / Q000378:metabolism; D018450:Disease Progression; D055354:Exosomes / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005966:Glucuronidase / Q000737:chemistry*; D006497:Heparan Sulfate / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D009101:Multiple Myeloma / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000201:enzymology; D053668:Syndecan-1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099175:Heparanase
chemical_list: D018076:DNA, Complementary; D005966:Glucuronidase; D006497:Heparan Sulfate; D017228:Hepatocyte Growth Factor; D053668:Syndecan-1; D042461:Vascular Endothelial Growth Factor A; D000099175:Heparanase