Cancer Suppression: Heparanase Enzyme

The enzyme heparanase is responsible for release and activation of various growth-promoting molecules, and degradation of non-cellular components in tissue matrices. As a result, it plays a dominant role in the process of tissue regeneration, and is effective in promoting tumor growth, metastasis and angiogenesis in vivo.

In the setting of wound healing, traumatic tissue disruption destroys the cellular elements of the tissue, but at the same time initiates the heparanase-mediated healing process. In the setting of tissue engraftment (e.g., organ transplantation), heparanase is responsible for releasing and activating pro-angiogenic molecules, which promote the formation of new blood vessels and their growth into the newly transplanted organ.

Suppressing tumor metastasis and growth by heparanase inhibition

Cancer metastasis most often heralds the cancer patient's imminent death. In order to metastasize, malignant cells must acquire two abilities: the ability to invade new tissues and the ability to grow new blood vessels (angiogenesis) in order to sustain them in their new "habitat". We have found that heparanase can render cancer cells with both these abilities. A variety of glycol-split derivatives of heparin and other poly-sugar moieties have been identified with a strategic partner. These act as unique heparanase-inhibiting molecules and have been found to be effective in suppressing tumor growth, metastasis and angiogenesis in vivo.

Suppression of diabetic nephropathy (DN) by heparanase inhibition

Nephropathy is the major life-threatening complication of diabetes. Heparanase, preferentially over-expressed in diabetic kidney, plays an important role in the pathogenesis of DN, ultimately associated with kidney dysfunction. In support of a causal involvement of heparanase in DN are findings showing that: i) heparanase null mice fail to develop albuminuria and renal damage in response to diabetes, and ii) albuminuria is inhibited in diabetic mice treated with heparanase inhibitors.

Heparanase & Inflammation

Upregulation of heparanase is noted in various inflammatory conditions, often associated with degradation of heparan sulfate (HS) and release of HS-bound chemokines and cytokines. Over-expression and gene silencing approaches revealed an essential involvement of heparanase in inflammatory reactions. Heparanase is therefore an attractive target for preventive and therapeutic approaches against inflammatory bowel disease, psoriasis, rheumatoid arthritis and sepsis.

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Inventor - Professor Israel Vlodavsky