Zebrafish ’window on cancer’ shows birth of tumour - and body’s response

Scientists using translucent zebrafish as a “window on cancer” have been able to see in real time how tumour cells are born – and immediately attract cells from the immune system.

This inflammatory response seems to both attack and aid the cancer cells and the balance between the two provides a new therapeutic target for cancer researchers. It also links cancer to the wound healing process, which may even lead to anti-inflammatory drugs being used to treat cancer patients.

Dr Adam Hurlstone, of the University of Manchester’s Faculty of Life Sciences, explained: “This is a very exciting finding. It was a huge surprise to us to see the tumour cells detected by the immune system so quickly: a cancer cell appears, gives a signal and the body’s immune system is immediately alerted.

“The speed of the response and being able to see it so clearly in the zebrafish was very exciting.

“In addition we have established other novel aspects: that hydrogen peroxide is the signal molecule given by both wounded and transformed pre-cancerous cells to the immune system and that the carefully choreographed response can both attack and aid cancer cells at their very birth.

“This link between wound healing and cancer gives us new therapeutic targets and potential therapies such as anti-inflammatory drugs that have already undergone clinical trial.”

The study, published in PLoS Biology today (Tuesday 14 December 2010) and funded at the Manchester end by Cancer Research UK, was a collaboration between Dr Hurlstone, and the team of Professor Paul Martin, the University of Bristol, and of Dr Marina Mione, FIRC Institute of Molecular Oncology in Milan.

The team studied the onset of different cancer types, including melanoma, an extremely aggressive form of skin cancer, in zebrafish larvae. Zebrafish have been used to study embryonic development for years but it is only recently that they have become a popular species for modelling disease, and notably cancer. Mutations in their genes result in the same diseases as humans, while their transparency is extremely useful for seeing the disease’s progress.

The team found that the immune system’s leucocytes (white blood cells) home-in on sites containing only very few cancer cells. They also found that they had been attracted to the site by hydrogen peroxide produced by cancer cells and their neighbours, a molecule also used to trigger the immune system when the body is wounded. The leucocytes immediately began to work at the sites – some attacking the cancer cells, others providing stimulants to them.

Dr Hurlstone said: “We have returned to a classical concept that cancer is a wound that will not heal. We are asking, what is the significance of that? Inflammation is supposed to be a good thing – it is painful but specialist cells zoom in and eat the debris and secrete factors to heal a wound. So with inflammation in cancer, is it fighting or helping the disease? The answer is both.

“That has been addressed before but this is the first time it has been seen at the birth of cancer.

“We have now shown how quickly the immune system responds to cancer, what its role is in the progression of the disease and also made clear the parallels between cancer and wound healing (for instance, the common signal molecule hydrogen peroxide).

“This throws up some exciting leads in terms of clinical applications. We should look at inflammation again from a therapeutic perspective. Now we know the role of hydrogen peroxide in recruiting leucocytes to the area, producers and receptors of that molecule could become therapeutic targets. We could even see anti-inflammatory drugs being used for cancer. Another route is to target the immune system’s response in order to tip the balance from the leucocytes that heal to those that attack in cases of cancer.”

He added: “This study and its novel, significant findings was only possible because we used live cell imaging in the almost transparent zebrafish embryos.”