Researchers have identified a key protein that keeps moles from turning cancerous, a finding that may lead to new treatments for melanoma.
Moles are benign tumours found on the skin of almost every adult. Scientists have known that a mutation in the BRAF gene makes them start growing, but it was not known why they stop.
Now, researchers from the Perelman School of Medicine at the University of Pennsylvania have identified a major genetic factor that keeps moles in their usual non-cancerous, no-growth state.
"The BRAF mutation that stimulates the initial growth of moles also stimulates the production of a tumour suppressor protein, p15, which ultimately acts as a powerful brake on further cell division," said senior author Todd W Ridky, an assistant professor of Dermatology at Penn.
"It's this cell division that ultimately allows the transition from a normal mole into melanoma. When mole cells lose the p15 brake, cells can start dividing again and can progress into cancer," said Ridky.
For their study, Ridky and his colleagues developed a new model of human melanoma, using tissue engineering to make skin grafts containing human mole cells in which p15 was removed.
When combined with other mutations known to be important for the development of melanoma, and transplanted into mice, the p15 depleted cells progressed into melanoma.
Ridky and colleagues also compared cells from patient melanomas that had originated from previously benign moles, and found high p15 levels in the mole tissue, and very low or undetectable p15 in the melanomas.
This suggested that p15 is important for holding regular moles in a benign state.
Researchers also found that the BRAF over-activation that drives the mole growth also causes the mole cells to secrete a signalling molecule called TGF-beta, which in turn, signals back to the mole cells to make p15.
These findings hinted at a possible explanation for the fact that most moles have to reach a diameter of at least a few millimeters before they stop growing - TGF-beta has to build up to a sufficient level first, and small collections of mole cells don't lead to enough local TGF-beta production in the mole to stop cell division.
Many researchers have assumed that a different, but related, tumour suppressor protein, p16, does the main work of growth-inhibition in moles, Ridky said.
While the two tumour suppressors normally work together to keep the brakes on cell proliferation in moles, researchers found evidence suggesting that p15 has unique functions.
For example, inserting p15 into normal cells was enough to halt proliferation completely, whereas inserting p16 only slowed proliferation, researchers said.
The study was published in the journal Cancer Discovery.
