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Melanoma is the most dangerous form of skin cancer, affecting over 135,000 individuals in the United States and killing an estimated 10,130 of those individuals annually. Melanoma is most commonly found in the form of skin growths, which originate from the pigment-producing melanocytes in the basal layer of the epidermis. These cancerous growths develop due to excess exposure to sunlight or ultraviolet radiation, causing DNA damage to skin cells and triggering mutations the multiply rapidly and form malignant tumors.

 Microscopic view of malignant melanoma.

Image Source: Michael J. Klein, MD

It is well established that some cells in the body already have mutations similar to cancer but do not behave like the cancer. They are instead displayed as benign skin growths. A fundamental question regarding melanoma formation is, ‘what exactly initiates the change in these “mutated cells” from benign to cancerous?’. A recent study at the Boston Children’s Hospital has investigated this mechanism. A research team under Dr. Charles Kaufman found that the beginning of cancer occurs after activation of an oncogene or the loss of a tumor suppressor, and it involves a change that takes a single cell back to a stem cell state.

The study utilized zebrafish, which all had a cancer cell mutation and had lost a tumor suppressor gene. The zebrafish involved in the study were engineered to fluorescently light the cells up that expressed a gene called crestin. Crestin is responsible for activating a transition in cell-fate from a differentiated state to a stem cell de-differentiated state. The stem cells are then capable of multiplying rapidly and forming malignant tumors. The tracking of the illuminated cells in the engineered zebrafish indicated that they initially underwent de-differentiation back to a stem cell state, within the neural crest. Further tracking of the cells indicated that every single one of them became tumors. It is estimated that only one in tens or hundreds of millions of cells in a mole express this crestin gene, eventually becoming a melanoma cancer cell. 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 discoveries made by Kaufman’s team could lead to a new genetic test for suspicious moles to see whether the cells are behaving like neural crest stem cells. If melanoma is recognized and treated early, it is almost always curable, but if it is not, the cancer can advance and spread to other parts of the body, where it becomes hard to treat and can be fatal. The results from this study may forever change the way scientists understand melanoma and could lead to new, early treatments before the cancer has fully established itself, reducing the likelihood of cancer metastasis.

Feature Image Source: Zebrafish by Connie Ma

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