New research may have found the answer to a question that has preoccupied scientists for years: What makes melanoma become 'aggressive and violent'? The answer brings with it some important therapeutic implications.
According to American Cancer Society estimates, in 2019 and in the United States, doctors will diagnose 96,480 new cases of melanoma, and 7,230 people will die from the disease.
But what causes melanoma to become aggressive? A new study, appearing in the journal Science Signaling, has found an intriguing answer.
Professor Carmit Levy and Dr. Tamar Golan, of the Department of Human Genetics and Biochemistry at Tel Aviv University's Sackler School of Medicine, in Israel, led the new research.
How fat cells help melanoma advance
Prof. Levy and colleagues collected dozens of tissue samples from people who had been diagnosed with melanoma at the Wolfson Medical Center and Tel Aviv Medical Center, both in the Tel Aviv metropolitan area.
Examining the biopsy samples revealed that, at first, tumors grow in a "lateral" phase in the upper epidermal layer of the skin. Although this stage is proliferative, it is highly treatable.
However, at a certain point, tumors enter a "vertical," more aggressive, stage, wherein they start to invade the deeper layers of skin that contain fat. So, the researchers asked, what causes this "metastatic switch"?
Clinical analyses of in situ melanoma cells — from melanoma in its highly treatable stage — showed that adipocytes, or fat cells, which usually reside in the deeper layers of the skin, had risen to the upper dermis layer, close to melanoma cells. This event correlated with the aggressiveness of the disease.
Furthermore, co-culture experiments of fat cells and melanoma cells revealed that fat cells secrete two cytokines that triggered the metastatic switch.
Namely, they secreted interleukin-6 and tumor necrosis factor-alpha, which are cytokines, or proteins, that have the ability to alter gene expression.
"We asked ourselves what fat cells were doing [near melanoma cells] and began to investigate," explains Prof. Levy.
"We placed the fat cells on a petri dish near melanoma cells and followed the interactions between them."
"Our experiments have shown that the main effect of cytokines is to reduce the expression of a gene called miRNA 211, which inhibits the expression of a melanoma receptor of [transforming growth factor-beta (TGF-beta)], a protein that is always present in the skin," reports Prof. Levy.
"The tumor absorbs a high concentration of TGF-beta, which stimulates melanoma cells and renders them aggressive."
Returning melanoma to its 'calm' state
"It is important to note that we found the process reversible in the laboratory: When we removed the fat cells from melanoma, the cancer cells calmed down and stopped migrating," explains Prof. Levy.
So, the researchers also used a mouse model of melanoma to see if they could block this metastatic process. Repressing miRNA 211 causes melanoma to metastasize to distant organs in the body, while expressing the gene stopped the metastasis.
Prof. Levy and the team went on to experiment with drugs, which, although never used to treat melanoma specifically, had the potential to inhibit cytokines and TGF-beta.
"We are talking about substances that are currently being studied as possible treatments for pancreatic cancer and are also in clinical trials for prostate, breast, ovarian, and bladder cancers," notes Dr. Golan.
"We saw that they restrained the metastatic process and that the melanoma returned to its relatively 'calm' and dormant state."
"We have answered a major question that has preoccupied scientists for years: What makes melanoma change form, turning aggressive and violent?"
Prof. Carmit Levy
"Locked in the skin's outer layer, the epidermis, melanoma is very treatable; it is still stage 1, it has not penetrated the dermis to spread through blood vessels to other parts of the body, and it can simply be removed without further damage," continues Prof. Levy.
"Melanoma turns fatal when it 'wakes up,' sending cancer cells to the dermis layer of skin below the epidermis and metastasizing in vital organs."
"Blocking the transformation of melanoma is one of the primary targets of cancer research today, and we now know that fat cells are involved in this change."
"Our findings can serve as a basis for the development of new drugs to halt the spread of melanoma — therapies that already exist, but were never used for this purpose," Prof. Levy concludes, adding that in the future, the researchers plan to collaborate with pharmaceutical companies in order to develop such treatments.