New research argues that melanoma can start not only in the skin, but also inside hair follicles. When they become cancerous, the cells then leave the follicles and move into the skin’s outermost layer, or epidermis.
The scientists demonstrated this effect in a new mouse model of human melanoma and confirmed it in samples of human tissue.
In a recent Nature Communications study paper, the team describes melanoma starting in immature, pigment producing cells in hair follicles, then moving into the epidermis.
Melanoma is an aggressive skin cancer that is very difficult to treat in its advanced stages.
For this reason, while only 1% of people who develop skin cancer have invasive melanoma, it is responsible for most deaths due to skin cancer.
The cancer begins in melanocytes, which are the cells that make the pigment that gives color to the hair, skin, and eyes. This pigment is called melanin.
The new study focuses on melanocyte stem cells, which are cells that have not yet fully differentiated into their final mature state.
New mouse model
The strain of mice that the team genetically engineered for the study addresses a need for better animal models of how human melanoma begins and progresses.
Researchers who have used previous models of the disease have maintained that exposure to sunlight is a major risk factor for melanoma.
However, the new mouse model reveals that the cell environment inside hair follicles can also trigger cancer in melanocyte stem cells.
“Our mouse model,” says first study author Qi Sun, Ph.D., a researcher in dermatology and cell biology at The New York University School of Medicine, “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.”
Using the new model, the team demonstrates three stages of melanoma arising in hair follicles then entering the skin.
In the first stage, melanocyte stem cells undergo genetic changes that make them cancerous. The second stage spurs the cancer further by exposing the cancerous cells to growth signals — the same signals that promote hair growth.
In the third stage, the newly cancerous melanocytes move upward in the hair follicle, leave it, and enter the surrounding epidermis to establish tumors that then spread deeper.
The team believes that the findings offer a better understanding of melanoma’s biology and could lead to new ideas about how to stop it.
From stem cell to descendants in tumors
From a single stem cell, an embryo grows into a fetus with multiple and various organs and tissues comprising hundreds of different cell types. All this is thanks to the ability of stem cells to divide, multiply, and differentiate into a plethora of specialized cells.
Stem cells can also switch cell type. While this flexibility is an asset during development, it can be hazardous in adulthood, when there is a risk that it might help drive cancer.
Scientists believe that this flexibility makes it difficult to pin down the stem cell of origin in melanoma.
Knowing the stem cell of origin could make it easier to track the progress of the cancer, rendering the disease less difficult to treat.
Because melanocytes are cells that make the pigment that colors the skin and eyes, as well as the hair, the researchers needed a way to manipulate only melanocyte stem cells in hair follicles.
They achieved this by genetically engineering a breed of mice that they called the c-Kit-CreER mouse. With this mouse model, they could alter the genes of melanocyte stem cells in hair follicles without impacting those in other parts of the body.
In addition, by altering the genes in the new mouse model, the researchers could make the follicular melanocyte stem cells glow and trace their glowing descendant cancer cells, regardless of where they ended up.
This feature allowed the team to track the full journey of the melanocyte stem cells, from hair follicle to epidermis, then deeper into the dermis — or inner layer of skin — as the melanoma tumor formed.
Follicular signals can trigger melanoma
In another set of experiments, the researchers tested what happened when they silenced cell environment signals in the hair follicle one by one.
These showed that, even when melanocyte stem cells had taken on cancerous properties, they did not travel and divide to form melanomas unless they received two particular signals from their environment.
These signals are called Wnt and endothelin, and they normally promote proliferation of pigment cells and growth of the hair shaft in the follicles.
“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.”
Qi Sun, Ph.D.
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