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The Heparanase/Syndecan‐1 Axis in Cancer Progression

Although oncogenic mutations are considered the primary drivers of tumor initiation, latter steps in cancer progression including angiogenesis, invasion and metastasis are greatly influenced by the activity of growth factors and their signaling receptors. Heparan sulfate proteoglycans, with their negative charge and high degree of structural diversity, facilitate growth factor binding to their high affinity receptors thus acting to fine‐tune signaling events within the tumor microenvironment. The syndecan‐1 heparan sulfate proteoglycan is highly expressed on the surface of many types of tumor cells and can be shed from the cell surface and remain biologically active. Syndecan‐1 regulates multiple functions including tumor cell attachment, growth, invasion and angiogenesis. Heparanase‐1 (HPSE) is the only known endoglucuronidase that can degrade heparan sulfate and its upregulated expression is associated with aggressive tumor behavior. While studying HPSE, we made the surprising discovery that this enzyme dramatically enhances shedding of syndecan‐1 from the surface of myeloma and breast cancer cells. It does this by upregulating the expression of syndecan‐1 sheddases and by shortening the heparan sulfate chains thus allowing better access of the sheddases to the syndecan‐1 core protein. Utilizing multiple myeloma cells as a model, we demonstrated that VEGF and HGF that are bound to the shed syndecan‐1 can present growth factors thereby stimulating angiogenesis and osteolysis. Interestingly, once shed from the myeloma cell surface, a cryptic domain within the syndecan‐1 core protein becomes available and clusters with VEGFR2 and VLA‐4 to activate Rac signaling thereby enhancing myeloma invasion. Beyond the role of the syndecan‐1/HPSE axis in regulating growth factor activity and cell invasion, we discovered that by shortening syndecan‐1 heparan sulfate chains, HPSE dramatically enhances biogenesis of tumor exosomes. The released exosomes, carrying high levels of HPSE as cargo, can deliver exosomal HPSE to recipient cells and regulate their behavior including enhancing tumor chemoresistance. Moreover, when myeloma cells are exposed to chemotherapeutic drugs bortezomib or melphalan, heparanase expression is significantly upregulated further accelerating exosome biogenesis. These therapy‐induced “chemoexosomes” hold the potential to further support tumor survival and progression. When chemoexosomes carrying a high level of HPSE as cargo were exposed to myeloma cells under spheroid forming conditions, the myeloma cells formed more and larger spheroids that had elevated levels of stem cell markers ALDH1A1, GLI1 and SOX2. The stemness inducing ability of myeloma chemoexosomes was diminished in the presence of HPSE inhibitors or when HPSE expression was knocked down in cells secreting the exosomes. These data indicate a direct role of chemoexosome‐mediated transfer of HPSE in enhancing the stem cell phenotype of myeloma cells that could facilitate eventual tumor regrowth and patient relapse. Taken together, these data demonstrate that HPSE enzymatic remodeling of syndecan‐1 plays important roles in regulating tumor progression and may also impact tumor response to therapy.