Impact of heparanase and the tumor microenvironment on cancer progression: Basic aspects and clinical implications
In order to metastasize, malignant cells must acquire the ability to invade tissues (metastasis) and to attract blood vessels (angiogenesis). We have shown that the heparanase enzyme can render malignant cells with both abilities. We have generated a technology for the development of unique inhibitors of heparanase which are non-anticoagulant derivatives of heparin, and found that these compounds were effective in preventing tumor growth and metastasis in vivo. Applying heparanase transgenic and knockout mice, we are also stdying the involvement of heparanase in inflammation driven cancer, and in diabetic nephropathy.
Our overall objective is to elucidate heparanase regulation and mode of action in tumor progression, paving the way for future anti-heparanase therapeutic modalities with minimal side effects. Specifically, we focus on: I) heparanase gene silencing in vivo, as an approach to i) eliminate both enzymatic and non-enzymatic activities of heparanase; and ii) elucidate the role of host- and tumor-derived heparanase in cancer metastasis and angiogenesis; II) inhibition heparanase enzymatic activity, applying: i) non-anticoagulant species of heparin; ii) peptides which inhibit proper processing and/or interaction of the enzyme with its substrate; and iii) neutralizing antibodies; and III) structure-function analysis of the heparanase protein for rational design of inhibitory molecules directed against specific domains involved in enzymatic and non-enzymatic functions of the heparanase protein.