Researchers decipher cancer cells’ passage through the body’s “net”

Researchers decipher cancer cells’ passage through the body’s “net”

An international research team under Danish leadership describes a biological mechanism that enables cancer cells to spread.

Nine out of ten cancer deaths are due to metastasis – the spread of cancer cells to other tissue. In other words, cancer cells that originally developed in one location in the patient’s body spread to other areas and organs and develop there into secondary cancer tumours.

If we can stop this spread, the patient will have a significantly improved chance of overcoming the disease. Cancer researchers the world over are therefore working tirelessly to understand the biological mechanisms underlying cancer cells’ ability to spread.

An international research team, under Danish leadership, has now succeeded in identifying such a mechanism.

The researchers have found that properties linked to the so-called basement membrane have implications for metastases formation.
It seems that these properties determine the ease with which cancer cells are able to spread in a patient’s body – as well as which organs and areas they will attack.

The research project was headed by Professor Janine Erler and postdoc Raphael Reuten, both from the Biotech Research & Innovation Centre (BRIC) at the University of Copenhagen. And this finding, which was funded by the Lundbeck Foundation, was recently published in the prestigious scientific journal Nature Materials.

Professor Janine Erler – BRIC
Photo: © clausboesen.dk

A kind of net

In humans and other mammals, the basement membrane surrounds the body’s blood vessels and cells like a supportive net. Professor Erler explains that the new discovery involves the stiffness of this membrane:

‘Our research project shows that the softer the basement membrane, the more difficult it is for cancer cells to slip through it and spread to other organs and parts of the patient’s body.’

The researchers also demonstrated in animal trials that the stiffness of the basement membrane is closely linked to levels of the netrin-4 protein. ‘We were able to prove that the greater the prevalence of netrin-4 molecules, the softer the basement membrane,’ says Professor Erler.

In the trials, the researchers were able to demonstrate a significant spread of cancer cells in mice whose ability to produce the netrin-4 protein had been removed by genetic engineering. By contrast, injections of netrin-4 led to a significant decline in the spread of cancer in these mice.

In order to evaluate the significance of the netrin-4 link to metastasis in humans, the researchers examined biological samples taken from a large number of cancer patients.
The samples originated from a broad geographical area, not merely northern Europe, and were taken from patients in treatment for breast cancer, kidney cancer, skin cancer or ovarian cancer.

‘We could see that the survival rate for all four cancer types was best in patients with a high level of netrin-4 – so, the same as our findings from the mouse trials. And we also got the same results from our mathematical models,’ says Professor Erler.


On the path to new treatments

But if it seems like the netrin-4 level plays a significant role in the ability of cancer cells to spread, would it not be logical to give cancer patients with low netrin-4 levels a supplement in the form of an injection?

The researchers are considering this option, but it’s not imminent. Before this can happen, there are numerous issues to be addressed.

One of these is that we cannot simply assume that the inhibiting effect of the netrin-4 injections on the cancer cells’ ability to spread in laboratory mice will be the same in humans. There are therefore more tests to be done before netrin-4 can be used to treat cancer patients.

Professor Erler explains that it seems as though this discovery of netrin-4’s effect on the basement membrane may also have potential for assessing the risk of metastasis in cancer patients:

‘Our results are extremely exciting because they indicate that it may be possible to predict which of a person’s organs cancer cells may spread to if they were to contract cancer. So, we could perform an assessment that identifies particularly vulnerable locations in a person’s organism before they even develop cancer. And information of this kind will unquestionably be useful for improving cancer therapies in the future.’

The researchers have not yet developed an actual method for performing this kind of risk assessment, but we already have the ability to determine netrin-4 levels in a person’s kidneys from a cell sample taken from this organ.

Researchers from Denmark, Sweden, Germany, the UK and Belgium were involved in the scientific study published in Nature Materials.


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