Fluorescent zebrafish shed light on the onset of cancer

Researchers have visualised the onset of skin cancer at its earliest, single-cell stage for the first time.

In humans, only a very small percentage of moles will become cancerous. But almost every mole contains mutations known to cause melanoma, the most fatal form of the disease.

'An important mystery has been why some cells in the body already have mutations seen in cancer, but do not yet fully behave like the cancer,' said Dr Charles Kaufman of the Boston Children's Hospital, first author of the study, which was published in Science.

His team's research revealed that skin cells that already harboured cancer-causing mutations could revert to a stem cell-like state, after a gene usually active only in the embryo was switched back on – and it was these cells that went on to form tumours.

The researchers tracked the onset of melanoma in the translucent zebrafish, which they engineered to carry BRAF and p53 mutations – two important mutations found in human skin cancer. In addition, the fish contained a fluorescent marker for a gene called crestin, which would cause a cell to light up bright green when crestin was turned on.

They found that every cell that lit up went on to divide and form a tumour. Cells that did not light up never progressed to cancer, even though they had the melanoma-causing mutations.

In zebrafish, crestin is normally only switched on during early embryonic development, in a group of stem cells called neural crest progenitors. These cells go on to form many different cell types, including the melanocyte pigment cells in the skin, after which crestin is switched off.

'What's cool about this group of genes is that they also get turned on in human melanoma,' said Dr Leonard Zon, head of the laboratory which carried out the research. 'It's a change in cell fate, back to neural crest status.'

The researchers suggest that in future genetic tests that identify this status in skin cells could be used to diagnose melanomas. They were also able to identify other genes in the cancerous cells involved in switching crestin back on, hinting at potential therapeutic targets.

However, the question remains as to what causes certain cells to revert back to this stem-cell status.

Dr Kornelia Polyak, a breast cancer researcher at the Dana-Farber Cancer Institute who was not involved in the study, spoke to the New York Times. 'What is the stimulus that allows a single cell out of millions to become cancerous?' she asked. 'Why does it turn on, this particular genetic program? What is the trigger and why does it happen so rarely?'

The researchers say that the fluorescent zebrafish model may help to answer these questions about melanoma, and possibly about other types of cancer too.