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Dr Mark Hulett
Division of Immunology and Genetics, John Curtin School of Medical Research
Australian National University
Canberra, ACT 0200
Email: Mark.Hulett@anu.edu.au
Tel: + 61-(0)2-6125 4480
Fax: +61-(0)2-6125 2595
Homepage: http://jcsmr.anu.edu.au/dicb/parish/m_hulett.htm
| Research |
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. The essential processes in metastasis are cell invasion - where tumour cells move into and out of blood vessels, and angiogenesis - where new blood vessels are formed in and around the tumour that provide an escape route and also supply nutrients for tumour growth.
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. The major carbohydrate (heparan sulphate) is cleaved by heparanase, whose activity strongly correlates with the metastatic capacity of tumour cells and the migratory capacity of leukocytes and endothelial cells.
We were the first to clone the human and mouse heparanase genes, and have since gone on to show (i) the cloned heparanase enzyme is the dominant heparanase in mammalian tissues, making it an extremely attractive drug target, (ii) shown that 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 of how heparanase cleaves HS. We are currently working towards (i) further understanding the molecular basis of heparanase function at the structural level, (ii) defining the regulation of gene expression, (iii) identifying the protease(s) responsible for processing the enzyme to its active form, and (iv) generating gene targeted mice that lack heparanase in specific cells and tissues to further define its role in cell invasion and angiogenesis.
Our overall goal is to better understand both the biology and structure of heparanase to enable the development of inhibitors of the enzyme, which will hopefully lead to new drugs to prevent cancer spread, angiogenesis, and inflammation.
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| Collaborations |
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| Publications |
Hulett MD, Freeman C, Hamdorf BJ, Baker RT, Harris MJ and Parish CR (1999) Cloning of mammalian heparanase A key enzyme in tumour invasion and metastasis. Nature Medicine 5, 803-809.
Hulett MD, Hornby JR, Ohms J, Zeugg J, Freeman C, Gready JE and Parish CR (2000) Identification of active site residues of the pro-metastatic endoglycosidase heparanase. Biochemistry 39, 15659-15667
Parish CR, Freeman C and Hulett MD (2001) Heparanase: a key enzyme involved in cell invasion. Biochimica et Biophysica Acta 1471, M99-M108.
deMestre AM, Khachigian LM, Santiago FS, Staykoba A and Hulett MD (2003) Regulation of inducible heparanase gene transcription in activated T cells by early growth response 1. J Biol Chem. (In press).
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