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Research
Cell invasion in cancer 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. 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. 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. Clearly, 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. The 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.
However, despite having been first described over 20 years ago, and 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. Two years ago, in collaboration with Professor
Chris Parish and Craig Freeman here at the John Curtin School of Medical
Research, we were the first to clone the human and mouse heparanase genes.
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 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
cleves 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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