Science, Technology and Engineering

Hulett Laboratory

Department of Biochemistry

Research - Cancer Metastasis, Angiogenesis and Inflammation

The ability of malignant tumour cells to escape from primary tumour sites and spread through the circulation to other sites in the body (metastasis) is what makes cancer such a deadly disease (Figure 1). The essential processes in metastasis are cell invasion - where tumour cells move into and out of the vasculature, and angiogenesis - where new blood/lymph vessels are formed in and around the tumour that provide an escape route and also supply nutrients for tumour growth. Cell invasion is also a critical event in the migration of white blood cells of the immune system (leukocytes) to sites of inflammation to combat infections. Understanding the molecular basis of cell invasion and angiogenesis is vital to develop strategies to combat cancer spread and inflammatory disease.

The major barrier for invading tumour cells, migrating leukocytes, and growing blood vessels (endothelial cells) is the basement membrane (BM), which surrounds the vessels, and the extracellular matrix (ECM) which forms a scaffold in tissues to hold cells together. The BM and ECM are composed of an interlocking network of proteins and complex carbohydrates, and for cells to breach this barrier, they deploy a battery of enzymes that break down these proteins and carbohydrate components. A major carbohydrate is heparan sulphate (HS), which acts as the glue to maintain the integrity of the BM and ECM. The enzyme responsible for cleaving HS, heparanase, has been shown to play a key roll in the degradation of the BM and ECM, and its activity strongly correlates with the metastatic capacity of tumour cells and the migratory capacity of leukocytes and endothelial cells.

In contrast to many of the proteases involved in degrading the protein component of the BM and ECM, until recently knowledge of the exact structure of heparanase remained elusive. In collaboration with Professor Chris Parish at the John Curtin School of Medical Research, we were the first to clone the first mammalian (human, mouse, rat) heparanase genes (Hulett et al., 1999. Nature Medicine 5:803-809). This opened the door to develop the tools to enable the direct study of the role of the enzyme in cell invasion and angiogenesis, which is the main focus of our research.

We have since shown that (i) the cloned heparanase enzyme is the dominant heparanase in mammalian tissues, making it an extremely attractive drug target, (ii) the enzyme is synthesised as an inactive pro form that requires proteolytic processing for activity, and (iii) identified the active site of the enzyme and proposed a model structure of the enzyme (Figure 2), (iv) defined key transcription factors that regulate heparanase gene expression in disease, and (v) generated heparanase conditional knockout mice. We are currently working towards (i) further understanding the molecular basis of heparanase function at the structural level, (ii) defining the dysregulation of heparanase gene expression in cancer and inflammatory disease, and (iii) using heparanase conditional knockout mice to define the precise role and contribution of heparanase in tumour progression, inflammation, and vascular injury. Our overall goal is to better understand both the biology and structure of heparanase to enable the development of specific inhibitors of the enzyme, which will hopefully lead to new drugs for the treatment of tumour metastasis, angiogenesis, and inflammatory diseases.