Cells meant to fix injuries can trigger tumours in cancer-prone mice.
Wounds could allow certain types of mutated cell to migrate to the surface of the skin, triggering tumours in people predisposed to cancer, according to a study.
A variety of cancers have been associated with wounds — for instance, battlefield injuries can lead to a type of tumour called Marjolin’s ulcer, and ‘kangri cancer’ afflicts some people from Kashmir at the site of burns caused by personal heaters carried under the clothes. But until now, no one has shown how skin tumours could arise when the skin is damaged by a physical injury.
A study published today in Proceedings of the National Academy of Sciences1 by Sunny Wong and Jeremy Reiter, biochemists at the University of California, San Francisco, suggests that the mechanism could involve the migration of mutated stem cells.
“We know that chronic wounding can contribute to cancer development,” said Anthony Oro, a dermatologist at Stanford University School of Medicine in California. “This work says that if you have a predisposition to getting cancer, wounding might enhance the chance it will develop.”
Wong and Reiter looked at a mouse model for basal cell carcinoma — the most common type of skin cancer. The tumours are thought to be caused by sun damage to the epidermis, the outer layer of skin. But some features of basal cell carcinomas mimic those of the stem cells that mend damage to the skin; for example, the cancers grow slowly and can sometimes differentiate into other types of cells. That has led researchers to speculate that stem cells might contribute to the formation of such cancers.
“This work says that if you have a predisposition to getting cancer, wounding might enhance the chance it will develop.”
To test this, the researchers investigated an oncogene — a gene that, when mutated, can cause cancer — called Smoothened — which is sometimes mutated in people with basal cell carcinomas. They activated a mutated version of the gene in the skin stem cells near hair follicles in mice, but this alone did not cause the rate of cancers to increase. So the team conducted a second experiment, activating the gene and then wounding the mice by punching out a small disc of skin from their backs. This time, the mice developed tumours resembling basal cell carcinomas at the wound sites.
Wong and Reiter found that the stem cells with mutated genes stayed near the follicles, in the lower layers of skin — until the mice were wounded. Once the animals had been cut, the cells migrated to the upper layers of skin to fix the damage, but while there, they disrupted a biochemical signalling pathway that has been linked to basal cell carcinoma development — and thus seeded cancer growth.
What’s more, the cells were able to seed cancers for up to five weeks after the oncogene was activated, and even when the wounds were no more severe than a paper cut.
In fact, Reiter says that when he first found that injuries could trigger cancer, he “started to get worried about shaving”.
The study suggests that, after DNA in the skin’s stem cells is damaged to create a mutation in an oncogene, the mutated cells might rest for years without causing cancer, and might cause problems only when a wound prompts them to act.
But other researchers say that most basal cell carcinomas do not develop at the sites of injury, so the finding is of limited significance. “This is certainly not a major mechanism underlying basal cell carcinoma formation in humans,” says Sabine Werner, a cell biologist at the Swiss Federal Institute of Technology in Zurich.
But Werner acknowledges that the study does demonstrate a note-worthy principle. “It may well be that mobilization of cells with oncogenic mutations to other sites — in particular to sites with a pro-tumorigenic micro-environment, such as wounds — could trigger tumorigenesis. This is the most interesting finding of this manuscript,” she says.
Reiter says that his paper holds a hopeful message: that the niches in which stem cells are normally found — such as the area surrounding hair follicles in mice — are good at suppressing cancers.
“It’s surprising that activating oncogenes in a stem-cell population doesn’t cause tumours,” he says. “This gives us a glimpse of a way in which our bodies protect us.”