Stem cells are often touted for their therapeutic promise. Because they can give rise to any of the body's cell types, they offer the potential for developing cells to replace those lost to degenerative disorders such as Parkinson's disease. Much less attention has been paid to what happens when stem cells turn bad. This has been the focus of Joerg Huelsken at the Swiss Federal Institute of Technology (EPFL) in Lausanne and his colleagues. On page 650 of this issue, they describe how stem cells can give rise to a type of skin cancer in mice.

In 2004, Huelsken and his collaborators were studying β-catenin, a protein whose activity is essential for the formation of skin tumours in mice. When the team blocked the action of β-catenin in skin, tumours began to regress. This is because the cancer cells progressively became more specialized, and finally stopped dividing. “We realized that this is the result you would expect if you were to eliminate a tissue's stem-cell population,” says Huelsken.

This realization was the beginning of a four-year project to determine whether stem cells might have a role in skin cancer. Some researchers believe that there is a distinct population of cancer cells within tumours that have similar properties to normal stem cells and maintain the malignant tissue. The idea, if correct, could explain both why tumours often regenerate even after being almost completely destroyed by chemotherapy, and how metastases form. The development of therapies targeted specifically at cancer stem cells could greatly improve patients' survival.

An initial set of experiments provided clues that the skin tumours in Huelsken's mice did contain stem-like cells. Huelsken knew that one population of normal skin stem cells is located in the 'bulge' region of mouse hair follicles and is marked by a protein known as CD34. He found some CD34-marked cells in skin tumours. When his group transplanted these or CD34-negative cells into normal mice, only the CD34-marked cells gave rise to cancers, and these were indistinguishable from the tumour from which the cells had originally been taken.

When Huelsken and his colleagues discovered that these CD34-containing cancer stem cells had enhanced β-catenin activity, they knew they were on the right track. And it turned out that blocking β-catenin was sufficient to deplete the population of CD34 cancer cells.

To make the connection between the stem cells found in the bulge region and the CD34 cells of the tumour, Huelsken's team genetically labelled the bulge stem cells and tracked them as they gave rise to specialized cells. When the researchers induced tumours chemically, they found cells in the tumours that carried the stem-cell label. This showed that the normal stem cells and the tumour stem cells were linked.

Through a series of experiments knocking down various proteins, Huelsken and his team finally identified the tumour-causing gene H-Ras as responsible for activating β-catenin in the cancer stem cells. Huelsken is still looking for the underlying molecular mechanism, but predicts that turning on β-catenin keeps the cancer stem cells behaving like stem cells. “Because factors that sustain the undifferentiated state of stem cells are not well characterized, we don't yet know which targets of β-catenin signalling are essential,” Huelsken admits.

Getting to this point was time-consuming because of the sheer number of in vivo experiments required — all of which involved tracking many biomarkers. “We had to try a lot of things,” Huelsken says of the project. “But there was not much that did not work out in the end.”