A new study has suggested melanoma, the deadliest form of skin cancer, has multiple origins and can originate in the hair follicles, not just in the layers of the skin.
The research suggests that while exposure to sunlight is a risk factor for melanoma, the triggers are already present in hair follicles. Melanocyte stem cells (MSCs) give rise to the pigment making cells that give hair and skin its color. These MSCs can give rise to cancers through a two-step process. As immature pigment-making cells start to mature, they then develop cancer-causing genetic changes and then are exposed to normal hair growth signals. and
The research showed that cancerous pigment stem cells in the hair follicles then migrate out of the follicles and establish melanomas in the surface layer of the skin close to the hair follicle, before moving into deeper skin layers.
In order to study the migration of these stem cells the researchers had to develop a new mouse model – c-Kit-CreER. This mouse model allowed the researchers to edit genes in follicular melanocyte stem cells, which made the cells, and their descendants glow as they travelled outside the hair follicles. This is the first time that it has been possible to accurately track a specific stem cell type as it migrated.
The researchers were able to track the abnormal migration of the stem cells from the hair follicle to the epidermis. The cells then multiplied and moved deeper into the dermis. The pigment and the markers were then shed in the dermis, which the researchers hypothesized was in response to local signals. The cells then obtained molecular characteristics almost identical to those in melanomas.
Having confirmed that oncogenic pigment cells in the hair follicles can certainly give rise to melanomas in mice, the researchers showed that this was also possible in human tissue samples. Since the researchers knew exactly where to look, they then attempted to find signaling proteins that triggered the migration and proliferation of the cells to form melanomas. After systematically eliminating each of the signals in the hair follicles one by one, they were able to show which were responsible for triggering the formation of melanomas.
Through that process of elimination, they found that even though cancer-causing genetic mutations were present, the cells did not migrate or multiply to form melanomas unless they were exposed to endothelin (EDN) and WNT. These proteins cause pigment cells to multiply in hair follicles and cause hairs to become longer under normal circumstances. The findings could prove useful for identifying new diagnostics and treatments or melanoma.
“While our findings will require confirmation in further human testing, they argue that melanoma can arise in pigment stem cells originating both in follicles and in skin layers, such that some melanomas have multiple stem cells of origin,” explained the researchers.
The study is detailed in the paper – A novel mouse model demonstrates that oncogenic melanocyte stem cells engender melanoma resembling human disease – which was recently published in Nature Communications. DOI: 10.1038/s41467-019-12733-1