An important mystery has been why some cells in the body already have mutations seen in cancer, yet do not fully behave like the cancer.  Now, researchers led by the Boston Children’s Hospital have, for the first time, visualized the origins of cancer from the first affected cell and watched its spread in a live animal. The team state that their work could change the way researchers understand melanoma and other cancers and could lead to new treatments before the cancer has taken hold.  The study is published in the journal Science.

Previous studies show that the ‘cancerized field’ concept posits that cells in a given tissue sharing an oncogenic mutation are cancer-prone, yet only discreet clones within the field initiate tumours. Studying the process of cancer initiation has remained challenging because of the rarity of these events, the difficulty of visualizing initiating clones in living organisms, and the transient nature of a newly transformed clone emerging before it expands to form an early tumour. Therefore, a more complete understanding of the molecular processes that regulate cancer initiation is needed to provide important information about which precancerous lesions are most prone to becoming cancer.  The current study shows that the beginning of cancer occurs after activation of an oncogene or loss of a tumour suppressor, and involves a change that takes a single cell back to a stem cell state

The current study imaged live zebrafish over time to track the development of melanoma.  All the fish had the human cancer mutation BRAFV600E, found in most benign moles, and had also lost the tumour suppressor gene p53.  The group engineered the fish so that individual cells would light up in fluorescent green if a gene called crestin was turned on, the beacon indicated activation of a genetic program characteristic of stem cells. The lab explain that this program normally shuts off after embryonic development, however, occasionally crestin and other genes in the program turn back on in certain cells.  Results show that when a green spot was observed on a fish, they became tumors 100% of the time.

Data findings show that with these early cancer cells crestin and the other activated genes are also turned on during zebrafish embryonic development, specifically, in the stem cells that give rise to the pigment cells known as melanocytes, within a structure called the neural crest.  The team note that this group of genes are also turned on in human melanoma.

The group state that it’s estimated that only one in tens or hundreds of millions of cells in a mole eventually become a melanoma, however, as they can also efficiently breed many fish, they can look for these very rare events. They go on to conclude that the rarity is very similar in both humans and fish, which suggests that the underlying process of melanoma formation is probably much the same in humans.

The team surmise that their findings show that normal tissue becomes primed for cancer when oncogenes are activated and tumour suppressor genes are silenced or lost, however, cancer only develops when a cell in the tissue reverts to a more primitive, embryonic state and starts dividing. They go on to hypothesize that their model may apply to most if not all cancers, not just melanoma.  For the future, the researchers state that their findings could lead to a new genetic test for suspicious moles to see whether the cells are behaving like neural crest cells, indicating that the stem-cell program has been turned on. They go on to add that they are also investigating the regulatory elements of the genetic program which have epigenetic functions that are similar in zebrafish and human melanoma.

Source: The Boston Children’s Hospital