New research at Tel Aviv University has unlocked the secret of how melanoma spreads and points the way to techniques that will prevent the disease from turning into a killer.
“Maybe in the future, people will be able to rub some substance on their skin as a prevention measure,” said TAU’s Dr. Carmit Levy.
Melanoma accounts for just 2% of skin cancer – which is the most common of all cancers overall – but is responsible for nearly all skin cancer deaths. Melanoma death rates have been rising in recent decades, with overexposure to ultraviolet (UVB) light in the form of sunshine pegged as a major cause. As a result, doctors have long urged sun-worshipers to use copious amounts of sunscreen, which numerous studies have shown can help limit UV exposure.
Melanoma is unlike other cancers in that it doesn’t start out as the result of mutated, invasive cells that form within the body, but rather is caused by external factors that cause changes in skin cells and only later turns into a killer cancer. That change generally takes place when mutated melanoma cells remain untreated on the skin surface (the epidermis) and later sink down to the dermis, from where melanoma-affected cells can spread to the rest of the body, turning from benign growths on the skin to aggressive, metastasizing invasive cancer cells.
How this transformation takes place has long been a mystery to researchers, but in a new study published this month in the journal Molecular Cell, Levy and her team at the Department of Human Genetics and Biochemistry at TAU’s Sackler School of Medicine, along with researchers from the Technion, Sheba Medical Center, the Institut Gustave Roussy, and Hebrew University pinpointed the precise place in the process where “traveling” melanoma-affected cells turns lethal.
Now that the transformation pivot has been identified, she said, researchers will be able to develop interventions that stop melanoma in its tracks before it gets to the dermis and the adjacent subcutaneous tissues.
“To understand melanoma, I had to obtain a deep understanding about the structure and function of normal skin,” said Levy. “Before invading the dermis, melanoma cells surprisingly extend upward, then switch directions to invade.
“It occurred to me that there had to be a trigger in the microenvironment of the skin that made the melanoma cells ‘invasive,’” Levy continued. “Using the evolutionary logic of the tumor, why spend the energy going up when you can just use your energy to go down and become malignant?”
Ironically, the researchers discovered, it is the body itself that gives melanoma cells the idea to turn into malignant cancer cells. After collecting samples of normal skin cells and cancerous melanoma cells from patients at hospitals around Israel, the researchers mixed the cells and performed gene analysis expression to study the traveling cancer’s behavior. They found that, completely independent of any mutation acquisition, it was an element in cells themselves – a spike on the surface of a cell, called a ligand – that converted a melanoma-affected cell into an aggressive, “traveling” cell that sought to invade the area below the epidermis.
“Normal skin cells are not supposed to ‘travel,'” said Levy. “We found that when melanoma is situated at the top layer, a trigger sends it down to the dermis and then further down to invade blood vessels. If we could stop it at the top layer, block it from invading the bloodstream, we could stop the progression of the cancer.”
That trigger, the ligand, “convinces” the melanoma cells that they should move vertically downward, into the body, instead of horizontally on the epidermis. The process by which the transformation is made within the melanoma cell is called notch signaling, a well-known process in which the ligands are used to communicate between cells. In healthy individuals, notch signaling promotes cell growth, fat gain and loss, and other activities. Apparently, it can also encourage melanoma cells to become aggressive cancers that invade any part of the body they can reach, the research shows.
“When I saw the results, I jumped out of the room and shouted, ‘We got it!’” Dr. Levy said. “Now that we know the triggers of melanoma transformation and the kind of signaling that leads to that transformation, we know what to block. The trick was to solve the mystery, and we did. There are many drugs in existence that can block the notch signaling responsible for that transformation,” she said, and now all that is needed is the commercial development of a treatment to do just that.
Levy and her team are continuing to explore the research with the end goal of providing medical professionals with another tool of analysis of different stages of melanoma, she said. “Melanoma is a cancer with a very long gestation period. If you can provide a simple kit with precise answers, you can catch it at the beginning stage and hopefully save lives.”
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