Tumor cell invasion and secondary spread through the blood and lymphatic system, also known as metastasis, is the hallmark of malignant disease and the greatest challenge to cancer treatment. Tumor metastasis requires two important processes, namely, angiogenesis and tumor cell invasion of the basement membrane (BM) and the extracellular matrix (ECM). Circulating tumor cells arrested in the capillary beds of different organs must invade the endothelial cell lining and degrade its underlying basement membrane (BM) in order to escape into the extravascular tissue(s) where they establish metastasis (Liotta L. A. et al. (1983) Tumor invasion and the extracellular matrix, Lab. Invest., 49:639-649).
Major components of the BM and the ECM are glycosaminoglycans, mainly heparan sulphate proteoglycan (HSPG). The basic HSPG structure includes a protein core and several linear heparan sulphate (HS) chains that covalently attached to the protein core. Several cellular enzymes (e.g., collagenase IV, plasminogen activator, cathepsin B, elastase) are thought to be involved in degradation of the BM (Liotta L. A. et al. (1983) Tumor invasion and the extracellular matrix, Lab. Invest., 49:639-649). Among these enzymes is an endo-beta-D-glucuronidase (heparanase) that cleaves HS at specific intrachain sites, i.e., between GlcUA and GlcNAc sites (Vlodavsky I. et al. (1992) Expression of heparanase by platelets and circulating cells of the immune system: Possible involvement in diapedesis and extravasation, Invasion & Metastasis, 12:112-127; Nakajima M. et al. (1988) Heparanase and tumor metastasis J. Cell. Biochem., 36:1 57-167; Vlodavsky I. et al. (1983) Lymphoma cell mediated degradation of sulphated proteoglycans in the subendothelial extracellular matrix: Relationship to tumor cell metastasis, Cancer Res., 43:2704-2711; Vlodavsky I. et al. (1988) Involvement of heparanase in tumor metastasis and angiogenesis, Is. J. Med., 24:464-470). Expression of an HS degrading heparanase was found to correlate with the metastatic potential at mouse lymphoma (Vlodavsky I. et al. (1983) Lymphoma cell mediated degradation of sulphated proteoglycans in the subendothelial extracellular matrix: Relationship to tumor cell metastasis, Cancer Res., 43:2704-2711), fibrosarcoma and melanoma cells (Nakajima M. et al. (1988) Heparanase and tumor metastasis, J. Cell. Biochem., 36:1 57-167). The same is true for human breast, bladder and prostate carcinoma cells (see U.S. Pat. No. 6,190,875). Moreover, elevated levels of heparanase were detected in sera (Nakajima M. et al. (1988) Heparanase and tumor metastasis, J. Cell. Biochem., 36:157-167) and urine (U.S. Pat. No. 6,190,875) of metastatic tumor bearing animals and cancer patients and in tumor biopsies (Vlodavsky I. et al. (1988) Involvement of heparanase in tumor metastasis and angiogenesis, Is. J. Med., 24:464-470). Heparanase has also been implicated in T cell-mediated delayed type hypersensitivity, experimental autoimmune encephalomyelities and adjuvant arthritis, suggesting that heparanase plays a role in cell diapedesis and extravasation associated with inflammation and autoimmune diseases.
Therefore, inhibitors of heparanase are useful for treating various cancers in human and other mammal subjects. An inhibitory effect on heparanase is a valuable biomarker in screening for substances as medicament in cancer treatment, which remains a serious challenges for the medical world.