What makes melanoma cells, which cause the most dangerous type of skin cancer, spread to other organs in the body? What causes these cells to change form, suddenly making them aggressive and violent?
Scientists have long wondered, but now, Tel Aviv University (TAU) researchers have the answer. Fat cells allow melanoma cells to penetrate the dermis – the thick layer of living tissue below the epidermis that forms the true skin and contains capillaries, nerve endings, sweat glands, hair follicles, and other structures – from which they spread, causing fatal metastases in vital organs.
Prof. Carmit Levy and Dr. Tamar Golan of the department of human genetics and biochemistry at TAU’s Sackler Medical School headed the team that just published the important findings in the latest issue of the Journal Science Signaling, which featured the discovery on its cover.
Fat cells, they found, are involved in the transformation that melanoma cells undergo from cancer cells of limited growth in the epidermis to lethal metastatic cells attacking patients’ internal organs.
“We have answered a major question that has preoccupied scientists for years,” explained Levy. “Locked in the skin’s outer layer, the epidermis, melanoma is very treatable; it is still at Stage 1, has not penetrated the dermis to spread through blood vessels to other parts of the body and can simply be removed without further damage.”
Melanoma turns fatal when it “wakes up,” dispatching cancer cells to the dermis and metastasizing in vital organs. “Blocking the transformation of melanoma is one of the primary targets of cancer research today, and we now know fat cells are involved in this change,” she continued.
In the study, the researchers examined dozens of biopsy samples taken from melanoma patients at Wolfson Medical Center in Holon and Tel Aviv Sourasky Medical Center and observed a suspicious phenomenon – fat cells near the tumor sites.
“We asked ourselves what fat cells were doing there and began to investigate,” added. Levy. “We placed the fat cells in a petri dish near melanoma cells and followed the interactions between them.” The researchers watched fat cells as they transferred proteins called cytokines, which affect gene expression, to the melanoma cells.
“Our experiments have shown that the main effect of cytokines is to reduce the expression of a gene called miRNA211, which inhibits the expression of a melanoma receptor of TGF beta, a protein that is always present in the skin,” Levy explained. “The tumor absorbs a high concentration of TGF beta, which stimulates melanoma cells and renders them aggressive.”
The researchers also made the important discovery of a way to block this transformation. “It is important to note that we found the process is reversible in the lab; when we removed the fat cells from the melanoma, the cancer cells calmed down and stopped migrating,” she added.
A trial of mouse models of melanoma yielded similar results – when miRNA211 was repressed, metastases were found in other organs while re-expressing the gene blocked metastases formation.
In the search for a potential drug based on the new discovery, the researchers experimented with therapies that are known to inhibit cytokines and TGF beta but that have never before been used to treat melanoma.
“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,” Golan said. “We saw that they restrained the metastatic process and that the melanoma returned to its relatively ‘calm’ and dormant state.”
“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,” concluded Levy. “In the future, we are seeking to collaborate with drug companies to enhance the development of the metastatic melanoma prevention approach.”
The research was conducted in collaboration with several senior pathologists, Dr. Hanan Vaknin of Wolfson and Dr. Dov Hershkowitz and Dr. Valentina Zemer of Sourasky.