Tumor Biology Research Unit
Our team
Israel Vlodavsky, Ph.D. -Professor, Head of Unit
Ruth Atzmon, M.Sc. - Lab. Technician
Raanan Bulvik, M.Sc. Student
Michael Elkin Ph.D.-Senior Lecturer
Rachel Goldberg, Ph.D. Candidate
Esther Hermano, Ph.D. Candidate
Rivka Ishai-Michaeli, M.Sc. - Lab. Technician
Emmanuel Lerner, -Ph.D. Candidate
Ariel M. Rubinstein, Ph.D. - Postdoctoral fellow
Eyal Zcharia, Ph.D. – Research Associate
Heparanase enzyme: a critical determinant of extracellular matrix remodeling in cancer, angiogenesis, inflammation 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 (metastases), as well as to recruit continuously new blood vessels in order to sustain themselves and grow (angiogenesis). 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 extracellular matrix barriers. Extracellular 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 extracellular matrix. Prof. Israel Vlodavsky, who established the Tumor Biology Research Unit in the Sharett Oncology Institute, initiated in 1979 studies on the control of cell growth and differentiation by the extracellular 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 extracellular 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 led to cloning and extensive characterization of human heparanase and elucidation of its 3D structure, significance and mode of action in cancer progression. These achievements 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 extracellular matrix by heparanase emerges as a fundamental mechanism of tumor progression. 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 growth factors stored in extracellular matrix depots. Heparanase-targeting approaches (i.e., gene silencing, inhibition of enzymatic activity) have been 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, embryonic implantation, bone turnover, hair growth as well as kidney dysfunction, autoimmune and autoinflammatory diseases (i.e., diabetic nephropathy, inflammatory bowel disease, psoriasis).
Regulation of the heparanase gene and protein.
Given heparanase involvement in diverse biological processes, 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 molecular/cellular elements responsible for transcriptional control of the heparanase gene and post-translational regulation of the pro-enzyme.
The research effort focusing on heparanase regulation and pivotal role in malignancy is now reaching its culmination point as the lead heparanase-inhibiting compound has entered a phase I clinical trial in cancer patients.