Zebrafish may help researchers identify targets for treating cutaneous melanoma

Scientists in the UK and Switzerland have identified a signalling pathway, PI3K (phosphoinositide 3-kinase) that shows promise as a target for treating aggressive skin cancer. Their results, based on a study of the see-through zebrafish, are published in the Journal Disease Models and Mechanisms.

Cutaneous melanoma is an aggressive skin cancer that is occurring more and more often in northern Europe, North America and Australia; indeed, its incidence is increasing more than any other type of cancer. Usually the cancer is 'cured' by being surgically removed. But when it spreads to other organs, as it does in around 20% of cases, the life expectancy of its victims is around 6 months. According to the researchers, "there is an urgent need to understand the molecular basis of this disease in order to develop better treatments."
Cells are directed to divide, migrate or die depending on a complex set of signals delivered along a number of pathways. When the molecules that relay these signals mutate and cease to function normally, cancer often results.

The team of scientists from the University of Manchester in the UK and University Hospital Zürich in Switzerland examined two signalling molecules in the zebrafish: Raf, which is almost always activated in both malignant and benign cancers involving melanocytes (pigment-producing cells); and PI3K, which is activated mostly in malignant skin cancers. Both of these molecules are involved in the Ras signalling pathway. The goal of the research was to define the roles of Raf and PI3K in two 'deregulated' Ras signalling pathways that are involved in neoplasia (pre-tumour) development.

According to the researchers, melanocytes in fish are similar to those seen in humans, and changes that occur in the melanoma cells of Xiphophorus (a genus of tropical freshwater fish) are strikingly similar to those seen in human melanoma. Importantly, past experiments using zebrafish (a different type of freshwater fish) have shown that one type of signalling involving Raf is enough to initiate melanocyte neoplasia formation.

To gain insight into the two signalling pathways, the researchers created several zebrafish models for studying melanoma in which the Ras signalling pathways were disrupted in different ways. They targeted a cancer-causing Ras (HRAS G12V) to the fishes' melanocytes, and found that this alone was enough to cause malignancy. They then looked at which Ras pathways were responsible for starting the tumour-forming process and which were responsible for its progress to malignancy, and found that the Raf-Mek-Erk pathway can initiate melanocyte neoplasia, while PI3K is necessary for promoting malignant progression in the melanocytes.

The zebrafish used in the experiments responded to signalling changes in much the same way as humans. Interestingly, the offspring of the mutant fish displayed abnormal growth of their melanocytes, which is reminiscent of the human FAMM (familial atypical mole and melanoma) syndrome. By producing other signalling molecules in the mutant fish, the researchers were also able to identify a pathway that reduced the effects of Ras mutations on cancer progression.

The new zebrafish model provides a highly expedient way of studying tumourigenesis in living creatures. Together with other distinctive advantages offered by zebrafish (they are small, practically transparent and easy to propagate and maintain), the model could prove a valuable tool for gaining new insights into the mechanisms of cutaneous melanoma, and hopefully for developing new treatments.

Journal source: Christina Michailidou, Mary Jones, Paul Walker, Jivko Kamarashev, Amanda Kelly, Adam F. L. Hurlstone. Dissecting the roles of Raf- and PI3K-signalling pathways in melanoma formation and progression in a zebrafish model. Disease Models & Mechanisms, 2009; DOI: 10.1242/dmm.001149