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Dr Hulett, right, and Dr Lock are fighting to
find cancer's "Achilles' heel".

It’s known as metastasis, and it’s often the beginning of the end. It’s that crisis point in the progression of cancer when what was a localised disease suddenly appears in different places all over the body.

The spread of cancer cells is no random act. It’s a highly organised process, and researchers in La Trobe University’s Department of Biochemistry led by Dr Mark Hulett are hot on its trail. They have recently bred a new line of mice that lack the enzyme heparanase – long suspected to be a critical agent in facilitating metastasis.

The new mice should assist them in unravelling the molecular details of how cancer cells can spread, and maybe finding ways of putting a stop to it.

In the meantime, another group in the Biochemistry Department, led by Dr Peter Lock is investigating regulation of the genetic, biochemical and physical changes which take place in tumour cells as they prepare to migrate throughout the body. The more we know about the control of these changes, he says, the better the chances of being able to infl uence the growth and spread of tumours.

Both groups are to be housed in the new La Trobe Institute of Molecular Science. There, they will work alongside groups working on other topics to do with cancer, such as programmed cell death and the molecular mechanism of anti-cancer drugs, as well as on many other aspects of molecular science.

In order for cancer cells to spread, they must move into the body’s transport system, the bloodstream. That’s not so easy, says Dr Hulett, as access to blood vessels is restricted by a dense layer of protein and carbohydrate known as the extracellular matrix and bounded by the basement membrane.

A principal component of the glue that holds this physical barrier together is heparan sulphate. Heparanase is the enzyme that catalyses its breakdown, says Dr Hulett, and thus plays a significant part in any breach.

With the advent of the new mice, Dr Hulett’s team will have access to animal models which help define the precise contribution of heparanase to several critical biological processes – the growth and spread of tumours, the formation of new blood vessels or angiogenesis, vascular disease, and the immune response.

The researchers should be able to discover whether heparanase is required for the spread of solid tumours, and if it also plays a critical role in infl ammatory and vascular diseases. In short, they hope to establish whether the enzyme could be the ‘Achilles’ heel’ of cancer –if drugs that inhibit its action also block metastasis and angiogenesis, thereby halting the growth and spread of tumours.

Key process in tumours

‘Angiogenesis is a natural process that happens every day in menstruation and wound healing, where the blood vessels need to re-form. But it is also a key process in the development of tumours,’ Dr Hulett says.

‘A tumour requires blood vessels to grow. It won’t grow any bigger than the size of a pea unless it has a new blood vessel network supplying nutrients and oxygen. Not only is this critical for tumour growth, but it also provides an escape route for tumours to get into the bloodstream and move throughout the body. It’s this process of metastasis that really makes cancer such a deadly disease.’

Heparanase, normally made by immune cells, is hijacked by tumour cells. They both use it to break down the membrane and scaffolding constituting the principal barrier surrounding blood vessels.

‘Immune cells make and secrete heparanase as a normal, physiological process for good – so they can get out of your bloodstream to infection sites to combat infection,’ says Dr Hulett. ‘Tumour cells exploit it to survive, multiply and promote themselves; they exploit it for bad. And in heart disease immune cells also move in and out of the vasculature, which can promote infl ammation, atherosclerosis and occluded arteries, leading to heart attacks.

‘This enzyme has been implicated in all these processes, but not proven. We are one of many groups around the world studying heparanase. A lot of pharmaceutical companies are extremely interested in the enzyme as a drug target – because if we can inhibit it, we will hopefully have a strategy to treat cancer, infl ammatory disease and heart disease,’ Dr Hulett says.

‘We’ve bred the mice so we can specifically eliminate heparanase in individual tissues,’ Dr Hulett says. ‘We can eliminate it from immune cells and nothing else – or from tumour cells or the endothelial cells that line the blood vessels. This should allow us to understand the role of heparanase in specific types of cells, and how it contributes to various disease processes.’

Dr Hulett’s research team also has particular expertise in understanding how the gene for heparanase is regulated.

‘We’ve done a lot of work to understand the control mechanisms and the molecular structure of the enzyme, so we can design ways to inhibit it. We have already shown using various molecular techniques that when you reduce expression of heparanase in cancer cells they no longer spread or promote angiogenesis. Now we’ll be able to test this in vivo.’

Serial breakthroughs

Australian research on the role of heparanase in disease began ten years ago at the ANU’s John Curtin Medical Research School in Canberra in twin laboratories intent on developing a new approach to cancer immunotherapy. While scientists in Mark Hulett’s Molecular Immunology Lab targeted the mechanisms of cell invasion in inflammation, tumour metastasis and angiogenesis, their Canberra colleagues in Professor Chris Parish’s Cellular Lab aimed to develop inhibitor drugs to target heparanase and angiogenesis.

That collaboration has yielded serial breakthroughs – most significantly the cloning of the human heparanase gene and progressively stronger data implicating heparanase as a principal biological agent behind the spread of cancer.

While Mark Hulett is exploring the molecular tool tumour cells use to facilitate migration, Peter Lock and his group are documenting the changes the cells undergo to kit them out for the journey.

Metastasising tumour cells begin to break down the extracellular matrix from physical protrusions they form called invadopodia. In order to do this, Dr Lock says, they need to coordinate activities to reorganise their internal skeleton, and gear up to produce and secrete destructive enzymes. That involves regulating the activity of a whole array of proteins.

Dr Lock, who recently moved to La Trobe from the University of Melbourne, has had a long term interest in a gene known as Src which plays a fundamental role in bone remodelling as well as cell movement and migration. In addition, it has a well known involvement in cancer.

Initially Lock and his colleagues looked for the molecules with which the protein product of Src interacted. An important one was Tks5, an adaptor protein which appears to act as a scaffold on which several proteins involved in the development of invadopodia can assemble. Significantly, work by others has shown that when the gene responsible for Tks5 is silenced, the formation of invadopodia is suppressed. And this appears to affect metastases in animals.

Lock now has evidence that the levels of Tks5 vary during the cell cycle. If further work at La Trobe confirms this, he will try to find out why it occurs – whether Tks5 is regulated by or controls the cell cycle.

‘If it turns out that the growth and spread of tumours is regulated by Tks5 levels,’ Lock says, ‘then we may have a means of controlling tumours.’