A new study published online in Nature Communications on November 4, 2019, reports that some melanomas, which are among the deadliest skin cancers, originate in melanocyte stem cells that are located within the hair follicles.
Dermatologist examining potential melanomas - Image Credit: Africa Studio / Shutterstock
The study adds significantly to the current understanding of melanoma by showing that potential melanoma precursors lurk in the hair follicles themselves, in the form of cancerous melanocytes, and visualizing their transformation into melanoma tumors. Melanomas cause most skin cancer-related deaths despite making up only 1% of all skin cancers.
Within the hair follicles, some of the immature cells that have not yet developed features of differentiation into mature melanocytes – pigment-generating cells – turn cancerous due to mutational changes. These cells are still subject to the normal growth-promoting influence of molecules produced by the cells of the hair follicle, called growth factors, which causes the development of a cancer.
Anatomy of the hair follicle. Distribution of differentiated and immature melanocytes is shown. - Illustration Credit: Designua / Shutterstock
In other words, even apart from external influences such as ultraviolet radiation from sunlight or tanning lamps, the hair follicles present an intrinsic risk factor for melanoma, among the most deadly types of skin cancer. The stem cells, which have acquired malignant characteristics, move up the hair follicle shaft and outwards on to the surrounding skin, to form melanoma tumors there, and then invade the deeper tissues to move downwards as well. The current study in bioengineered mice saw this process in action, and it was validated in studies of human samples subsequently.
Melanocytes and hair follicles
Hair follicles are actually separate organs, and are merely related to the skin spatially. They give rise to hair shafts. Melanocytes produce the pigment called melanin which is responsible for absorbing some of the ultraviolet radiation that falls on the skin every day. Since ultraviolet rays are known to produce DNA damage, the presence of melanin is a protective factor. The color of hair and skin is because the pigment reflects some of the colors in visible light spectrum but absorbs others. The reflected colors are responsible for the hair, eye and skin colors we see. Depending on the amount of melanin present, a deeper color is perceived. In people with low levels of melanin, the skin is pale or white, the hair typically blonde or auburn, and the eyes blue or green. With high melanin levels, the skin is dark and so are the hair and the eyes.
Following the union of a sperm and an ovum, which is called fertilization, a single cell is produced, called a zygote. This then divides successively to form an early embryo, made up of a few hundred stem cells. These then differentiate in various directions to form mature cell types which are then locked into developing in only a single direction, for instance, a skin cell, a nerve cell, or a retinal cell. Hundreds of cell types are present in a single human organism.
However, stem cells are capable of forming different types of cells, and in the early stages of development, a single stem cell can shift between more than one type of cell. This is very useful during the formation of the early organism, when a host of tissues and organs are being formed through the interaction of dozens of different cell types. However, in the mature state, this variability, if present increases the risk of cancerous change.
This is primarily because cancer cells seem to lose some of their fixed characteristics, and to return to those of early embryonic cells that proliferate rapidly, can shift in a variety of directions, and express multiple proteins.
The current study
Because of this chameleon-like behavior, some scientists feel that melanomas could arise from more than one type of stem cell. This means that tracing their origin becomes correspondingly difficult, and they do not respond to the same type of treatment in all cases.
In the current study, the researchers did some carefully focused engineering of the mouse genes, producing an experimental species called the c-Kit-CreER mouse. The advantage of this model is that gene editing can be restricted to the melanocyte stem cells within the hair follicles alone. This helped them to track the effects of mutations, or introduced gene changes, that made these cells glow. They could thus detect the course of the edited cells in the body.
Further observation showed that some melanocyte stem cells transform into melanoma cells, and then travel up and out of the follicle of origin to lodge in the epidermis, or outer skin layer. These cells then proliferated to form a small local tumor, before burrowing deeper into the dermal layer underneath.
In the dermis, the cells underwent some remarkable changes in response to local cellular signals. They were stripped of all identifying labels such as the proteins and pigment markers that show their follicular origin. They disguised themselves by adopting new protein patterns characteristic of nerve cells and skin cells, which originate from neuronal and mesenchymal tissue respectively. These have been repeatedly identified in almost identical form in human melanoma tissue samples.
Now that the researchers had confirmed the origin of the melanoma in the follicle, they went ahead and removed signals from the follicular microenvironment, singly, to try and determine which of these was important in preventing cancerous change in the melanocyte stem cell. Their efforts showed that even oncogenic melanocyte stem cells, or in other words, those which had mutations that could change the parent cells into cancer, failed to migrate up and out of the follicle or to develop into local tumors in the absence of two local factors called endothelin and WNT. The physiological or normal function of these signaling factors is to promote hair growth and increased pigment cell number by follicle melanocyte proliferation.
Researcher Qi Sun says, “Our mouse model is the first to demonstrate that follicular oncogenic melanocyte stem cells can establish melanomas, which promises to make it useful in identifying new diagnostics and treatments for 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.”
Sun, Q., Lee, W., Mohri, Y. et al. A novel mouse model demonstrates that oncogenic melanocyte stem cells engender melanoma resembling human disease. Nat Commun 10, 5023 (2019) doi:10.1038/s41467-019-12733-1, https://www.nature.com/articles/s41467-019-12733-1