Melanoma spread found to be triggered by fat cells
A team of scientists from Israel report compelling new insights into how the metastatic spread of melanoma is assisted by nearby fat cells. The research does not suggest obesity enhances the metastatic potential of skin cancers but it does point to new drugs that can stop the spread of melanoma.
For many people melanoma is a ticking time bomb. Although melanoma is the most dangerous type of skin cancer, it is extraordinarily treatable if caught before it spreads. If removed before it metastasizes, 99 percent of people are essentially cured, but as few as 25 percent of people survive the disease once it spreads to other parts of the body.
"We have answered a major question that has preoccupied scientists for years," says Tel Aviv University's Carmit Levy, one of the lead researchers on the new study. "What makes melanoma change form, turning aggressive and violent? 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."
After studying a large number of melanoma biopsy samples the researchers found fat cells unexpectedly collecting near the tumor sites. What was strange was that these subcutaneous fat cells had seemed to move to an upper dermal skin layer, from their regular location deeper in the hypodermis.
"We asked ourselves what fat cells were doing there and began to investigate," says Levy. "We placed the fat cells on a Petri dish near melanoma cells and followed the interactions between them."
It was discovered that these fat cells secreted signaling proteins called cytokines, which decreased the expression of a certain gene that suppresses a tumor's ability to switch into an aggressive metastatic mode.
"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," says Levy. "The tumor absorbs a high concentration of TGF beta, which stimulates melanoma cells and renders them aggressive."
Confirming this newly revealed metastatic mechanism, the researchers tested the effects of both blocking and enhancing the miRNA211 gene on melanoma spread. When the expression of miRNA211 was reduced in mice a melanoma quickly metastasized to other organs, and when the gene was re-expressed, that metastatic activity ceased.
What is not clear at this stage is whether this fat-cell-triggered metastatic action is enhanced by obesity, or whether this mechanism is more deeply systemic. The researchers do point to a few studies that have suggested obesity can enhance the risk of developing melanoma but it isn't known at this point if there is a direct association between an increased volume of fat cells and heightened metastatic activity.
The more immediate outcome from the research is the promise of drug therapies that can disrupt this metastatic mechanism. Tamar Golan, who also worked on this new research, suggests there are already new cancer drugs in development targeting cytokines and TGF beta, so it is entirely possible these experimental therapies could be adapted into novel melanoma treatments.
"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," adds Golan. "We saw that they restrained the metastatic process, and that the melanoma returned to its relatively 'calm' and dormant state."
Switching off a melanoma's ability to metastasize would undeniably be a groundbreaking step forward for cancer clinicians, saving the lives of thousands every year. It is still early days for this research but Levy and her team are enthusiastically collaborating with drug companies to investigate future clinical outcomes.
The new research was published in the journal Science Signaling.
Source: Tel Aviv University