Tumor Biology Research Unit

Heparanase Enzyme: a critical determinant

of extra cellular matrix remodeling

in cancer progression and normal development

Perhaps the most important characteristic of malignant tumors is their ability to spread to other parts of the body and form secondary growths (or metastases), as well as to recruit continuously new blood vessels in order to sustain themselves and grow. Moreover, the new blood vessels embedded in the tumor serve as a gateway for cancer cells to enter the blood circulation and metastasize to distant organs.

Both metastasis and new blood vessel formation are invasive processes that depend on the ability of cells to penetrate extra cellular matrix barriers. Extra cellular matrix is a macromolecular milieu surrounding cellular elements in tissues and organs. It serves as the main physical obstacle for cell invasion. Long polysaccharide chains of heparan sulfate are responsible for the integrity and barrier function of the extra cellular matrix. Prof. Israel Vlodavsky, who heads the Tumor Biology Research Unit in the Sharett Oncology Institute, initiated in 1979 studies on the control of cell growth and differentiation by the extra cellular matrix. Back in 1983, he and his team (Ruth Atzmon, Rivka Ishai-Michaeli and Rafael Fridman) have characterized the activity of the enzyme (heparanase) that degrades heparan sulfate in extra cellular matrix, thus enabling cancer cells to get through the extracellular matrix barriers, invade adjacent tissues, disseminate and form metastases.

The next step was to develop inhibitors for the enzyme effective in laboratory animals. The results were impressive: the heparanase inhibitors decreased the number of metastases in mice by 90%. However, the inhibitors caused some undesirable side effects. In order to develop safe and effective substances for inhibiting heparanase, large quantities of the enzyme were needed. Attempts to decipher the amino acid sequence of heparanase and to isolate the gene responsible for the enzyme’s production lasted for more than a decade. In 1999, Vlodavsky succeeded in defining the gene encoding for heparanase enzyme. This achievement opened several important avenues of investigation, which are currently underway in the Tumor Biology Research Unit of the Hadassah Medical Center.

Heparanase in cancer progression. Degradation of heparan sulfate in the extra cellular matrix by heparanase emerges as a fundamental mechanism of tumor invasiveness, neovascularization and metastasis. Heparanase upregulation has been documented in a variety of human tumors, correlating with increased vascularization and poor postoperative survival. Heparanase enzymatic activity results in disassembly of extracellular barriers for tumor spread and release of angiogenic factors stored in extracellular matrix depots. Heparanase-targeting approaches (i.e., gene silencing, inhibition of heparanase enzymatic activity) are being established in our lab and their therapeutic potential is investigated, applying a variety of in vitro and in vivo experimental systems.

Heparanase in normal development and pathophysiology. In parallel with the decisive role of heparanase in cancer progression, we investigate the enzyme’ contribution to normal cell and tissue function as well as pathophisiological processes. Among the processes involving heparanase activity are wound repair, tissue regeneration, immune surveillance, embryonic implantation and development, bone formation, hair growth as well as kidney dysfunction and amyloid and prion diseases.

Regulation of the heparanase gene and protein. Given heparanase involvement in diverse biological processes associated with extracellular matrix remodeling and cell migration, tight regulation of heparanase gene expression and enzymatic activity must take place, to ensure specificity of action in a particular time and location. Research is underway to characterize the interplay between genetic and epigenetic (i.e., methylation) elements responsible for transcriptional control of the heparanase gene and to study post-translational regulation, focusing on proteolytic activation of the heparanase pro-enzyme and proper heterodimerisation of two functional subunits forming the active heparanase.

A close collaboration between leading clinicians and basic researchers in the Sharett Institute, inspired initially by Profs. Zvi Fuks, Shoshana Biran and even more so by Prof. Tamar Peretz, yielded more than 250 scientific articles and presentations in top conferences on cancer metastasis and vascularization over the last 25 years.