Heparanase, the sole heparan sulfate degrading endoglycosidase, regulates multiple biological activities that enhance tumor growth, angiogenesis and metastasis. Much of the impact of heparanase on tumor progression is related to its function in mediating tumor-host crosstalk, priming the tumor microenvironment to better support tumor progression. Heparanase expression is enhanced in almost all cancers examined including various carcinomas, sarcomas and hematological malignancies. Numerous clinical association studies have consistently demonstrated that upregulated heparanase expression correlates with increased tumor size, tumor angiogenesis, enhanced metastasis and poor prognosis. Notably, heparanase is ranked among the most frequently recognized tumor antigens in patients with pancreatic, colorectal or breast cancer, favoring heparanase-based immunotherapy. Development of heparanase inhibitors focused on carbohydrate-based compounds of which 4 are being evaluated in clinical trials for various types of cancer, including myeloma, pancreatic carcinoma and hepatocellular carcinoma. Owing to their heparin-like nature, these compounds may exert off target effects. Newly generated heparanase neutralizing monoclonal antibodies profoundly attenuated myeloma and lymphoma tumor growth and dissemination in preclinical models, likely by targeting heparanase in the tumor microenvironment.
KEYWORDSHeparanase; immunotherapy; lymphoma; neutralizing monoclonal antibody; tumor microenvironment
Heparanase and cancerHeparan sulfate (HS) proteoglycans (HSPGs) are ubiquitous macromolecules associated with the cell surface and extracellular matrix (ECM) of a wide range of tissues.1 The HS chains bind to and assemble ECM proteins, thus playing important roles in ECM integrity, barrier function and cell-ECM interactions.1 HSPGs not only provide a storage depot for heparin-binding molecules (i.e., growth factors, chemokines, enzymes) in the tumor microenvironment, but also decisively regulate their accessibility, function and mode of action. It is therefore not surprising that a HS degrading enzyme (i.e., heparanase) is critically involved in tumor growth, angiogenesis and metastasis. Mammalian cells express a single dominant functional heparanase, an endoglycosidase that cleaves HS, leading to disassembly of the ECM and release of HS-bound bioactive molecules, thereby affecting tumor progression, angiogenesis and inflammation.2-4 The heparanase mRNA encodes a 65 kDa pro-enzyme that is cleaved by cathepsin L into 8 and 50 kDa subunits that non-covalently associate to form the active enzyme.5 Heparanase is up-regulated in essentially all human tumors examined, most often associating with reduced patients' survival post operation, increased tumor metastasis and higher vessel density.2,6,7 A causal role of heparanase in tumor metastasis was demonstrated by the increased lung, liver and bone colonization of cancer cells following over-expression of the heparanase gene, and by a marked decrease in the metastatic potential of cells s...