Mole And Melanoma
Given the same genetic mutation, what causes melanocytes to develop into harmless moles or deadly melanoma?
Melanoma is a cancer that develops from pigment-producing cells in the skin called melanocytes. Moles, or nevi, and melanoma often result from the same genetic mutation, but the difference between the two on the molecular level has been a mystery. Researchers at the Howard Hughes Medical Institute (HHMI) have identified a protein that stops the growth of the skin tumour cells by making them enter a state of programmed hibernation or cell death.
Melanocytes contain the pigment melanin, which protects the skin against the sun’s UV light. Both melanoma and nevi result from abnormal growth and proliferation of melanocytes. Although nevi are non-cancerous, more than half of the time, the same amino acid change in a protein called BRAF is responsible for the development of nevi and skin cancer cells. BRAF is involved in a signaling pathway that is important for cell growth and proliferation. The mutation increase BRAF activity, causing the cells to multiply abnormally.
In some melanocytes, this process can not be stopped, leading to cancer. On the other hand, some melanocytes expressing the mutated BRAF enter a state of permanent hibernation through senescence, leading to nevi. This shows that the cells “sense” the presence of the oncogenic protein and activate their anti-cancer mechanism to throw themselves into the dormant state. Sometimes they even commit suicide via apoptosis rather than entering this frozen state. In melanoma, this defense mechanism is faulty, resulting in cancer.
The scientists at HHMI seek to identify the components involved in this mechanism. They use retrovirus to insert short fragments of RNA to turn off different genes in a series of melanocytes. Some progressed to cancer cells, some enter senescence. After screening the entire genome, they found 17 genes required to activate BRAF-induced senescence or apoptosis. 3 of these are responsible for both pathways.
One protein encoded by these genes that surprised the scientists was insulin-like growth factor binding protein 7 (IGFBP7). Nothing much is know about the protein, other than that it is secreted. This suggests that the process is not entirely intracellular. This may be useful because melanocytes expressing this protein can release it into the surrounding, telling the neibouring cells to “switch off.”
In the Cell article (doi:10.1016/j.cell.2007.12.032) published by the research team, culturing tumour cells in IGFBP7 and injecting the protein into mice grafted with skin cancer caused the cells to commit suicide and stopped the growth of melanoma. This result is very encouraging, and has a significant implication. Many believe that moles could be the precursor of skin tumour cells. While the cells in nevi are expressing IGFBP7, even when one of the cells stop producing the protein and threatens to become a cancer cell, IGFBP7 excreted by the surrounding cells can kill it.
IGFBP7 is also important clinically. It can be used to target melanoma throughout the body and treat a condition called metastatic melanoma, which is basically untreatable today. It can also be used to treat other types of cancer caused by mutations in the BRAF oncogene.
Howard Hughes Medical Institute (2008, February 8). Natural Secretion Marks Difference Between Mole And Melanoma. ScienceDaily. Retrieved April 12, 2008, from http://www.sciencedaily.com/releases/2008/02/080207124631.htm
Wajapeyee, N., Serra, R.W., Zhu, X., Mahalingam, M., and Green, M.R. (2008) Oncogenic BRAF Induces Senescence and Apoptosis through Pathways Mediated by the Secreted Protein IGFBP7. Cell. 132(3):363-374.