Moles are more than a sometimes unsightly skin growth. Most harbor mutations that can trigger deadly skin cancer--melanoma--and most fair-skinned humans have at least 10 such moles. Yet, only one in 65 of such people will develop melanoma in their lifetimes. And research has now pinpointed how a series of mechanisms prevents the cells that produce pigment--known as melanocytes--from fulfilling any cancerous destiny.
Daniel Peeper of the National Cancer Institute and his team discovered in previous research that when cells in a mole (or nevus, in scientific terms) begin to show signs of mutation, a genetic program kicks in that prevents them from continuing to divide. Known as premature senescence--shutting down the melanocyte before the end of its natural life span--this mechanism keeps a specific tumor-promoting protein from completing its work. But there are at least 20 different types of moles, along with several oncogenes, which create tumor-promoting proteins that might also be at work.
Dermatologist Maria Soengas of the University of Michigan and her team explored a specific type of mole--known as Spitz nevi--because they never become cancerous, despite harboring various mutations and oncogenes. The scientists found that the endoplasmic reticulum (ER)--an organelle within melanocytes and other cells that folds amino acids into proteins--played a key role. Specifically, it induced cancerous cells to prematurely shut down in such moles by sensing the presence of oncogenes and stopping its protein folding.
On supporting science journalism
If you're enjoying this article, consider supporting our award-winning journalism by subscribing. By purchasing a subscription you are helping to ensure the future of impactful stories about the discoveries and ideas shaping our world today.
This capacity is actually built into one of the ER's normal abilities. If it falls behind in its protein-folding work, the organelle triggers what researchers have named the unfolded protein response. This slows the overall process and stems the flow of amino acids, allowing the ER time to catch up. In extreme cases of failure it can even trigger apoptosis, or cellular suicide. In the case of malignant melanocytes, their own endoplasmic reticulum puts them into stasis--not dead but no longer dividing. Thus moles--and the cells that make them--can remain in this senescent, non-cancerous state for decades. "We found that the ER can also induce senescence, and this induction of senescence depends on the type of oncogene being activated," Soengas explains. "Some oncogenes do not affect the ER and thus are less efficiently blocked and may favor subsequent tumor development."
This mechanism works independently of apoptosis and is yet another way that cells protect against tumor growth, the researchers write in the paper presenting their work in the October issue of Nature Cell Biology. Of course, melanoma does happen. "Our data supports the notion that cancer happens when the endoplasmic reticulum is not altered or affected by mutations," Soengas notes. "In addition, it is possible that tumor cells take advantage of the [unfolded protein response] to favor survival and resistance to drugs." In other words, the internal mechanisms of melanocytes can both help guard against cancer as well as help promote its growth. All the more reason to keep a close eye on moles.