Zebrafish provide clues to new treatment approaches in cancer

20 Dec 2010

Taking advantage of the translucency of zebrafish larvae has allowed scientists to image the earliest interactions involved between oncogene transformed cells and their host environment in the initiation of cancer, reports the journal PLOS Biology.

The joint collaboration between UK and Italian researchers reveals how newly formed cancer cells have the capacity to co-opt the immune system into helping spread disease.

Using different coloured fluorescent tags collaborators from the University of Bristol, University of Manchester and Institute of Molecular oncology, Milan, labelled immune cells and tumour forming cells in order to track their behaviour and interactions by live cell imaging. When the team switched on the human oncogene HRAS in melanocytes in the skin of the early stage zebrafish embryos they found that the transformed cells actively attracted immune cells.

Furthermore they found that tumour cells produce hydrogen peroxide and that immune cells are drawn up the hydrogen peroxide gradient towards the cancer.

To test whether tumour cells co-opt the immune cells in their earliest stages of development, the investigators blocked the immune response in three different ways – they prevented the development of immune cells for the first three days after fertilisation and used two different strategies to limit hydrogen peroxide production.

In each case, the immune cells failed to migrate to the cancer site and researchers found when the immune response was blocked fewer cancer cells went on to be formed. To the investigators this suggested that immune cells have the ability to promote disease through some kind of growth signal.

The researchers went on to achieve the same results after inserting the HRAS oncogene into a different cell population of mucous secreting cells, and again when experimenting with a different oncogene, SRC.

To investigate the analogy that tumours resemble wounds, the team made a laser cut in the same region of the zebrafish larvae where tumours had been observed and imaged the immune response. Early immune cells responded to the cut in a similar manner, with both wounds and tumour cells producing hydrogen peroxide, with immune cells travelling up the gradient towards the cut or cancer.

"This gives us the first insight into how immune cells sense and then attempt to deal with the earliest stages of cancer. Now we can look closer to figure out why it is that immune cells seem to aid growth of these young cancer cells and figure out ways for guiding immune cells how better to search and destroy," said investigator Paul Martin from the University of Bristol.

Investigator Adam Hurlstone, from the University of Manchester, added, "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."


Y Feng, C Santoriello, M Mione et al. Cells in Zebrafish Larvae: Parallels between Tumour Initiation and Wound Inflammation PLoS Doi:10.1371/journals.pbio.1000562