March 8, 2011

New Clue to Controlling Skin Cancer

(Ivanhoe Newswire) "“ When do organs know to stop growing? The answer could be useful in regenerative medicine, and also in cancer- where there "stop growing" signals either aren't issued or aren't listened to. Researchers have found a regulator of gene activity that tells epidermal stem cells when it's time to grow more skin, as well as a "crowd control" molecule that senses stem cell crowding and turns the growth off.

The work, in mice and in human cancer cells, provides clues to new therapeutic strategies for cancer, particularly squamous cell carcinoma, the second most common skin cancer, in which epidermal cells don't stop growing. It could also aid efforts to grow skin grafts and treat burn patients.

"We have found a molecular switch that tells your skin to keep growing or stop growing," Fernando Camargo, PhD, the study's senior investigator and a principal investigator in Children's Stem Cell Program, was quoted as saying.

Camargo and colleagues manipulated a molecule previously known to cause massive tumor growth, and saw that in mice their epidermal skin stem cells failed to expand and had thin, fragile skin.

The opposite was also true. "The more Yap1 you have in your stem cells, the thicker your skin grows," says Camargo, who is also a member of the Harvard Stem Cell Institute.

However, activation of the molecule also caused the mice to develop squamous-cell carcinoma-like tumors, the researchers found. The molecule is inactivated by alpha-catenin, a tumor suppressor.

"Alpha catenin is silenced in many types of epithelial cancer "“ skin cancer, colon cancer and other squamous cell cancers," says Camargo. "When alpha catenin is absent or mutated, you get an overgrowth of cells, but until now it was unclear why. Our work suggests that over-activation of Yap 1 is likely what drives these cancers."

When cells are packed too tightly, alpha-catenin inhibits the molecule "“ the first demonstration of a direct link between an environmental cue (cell density) and a molecular regulator of organ size. Until now, little has been known about what maintains organs at a specific size.

"Through Yap1, alpha-catenin tells epidermal stem cells to either proliferate or not proliferate, depending on the needs of the tissue," Camargo explains.

Now that the "switch" for skin growth is known, manipulating it could provide ways to grow skin cells when they're needed or, conversely, to stop cancerous growth. Camargo's group is conducting screening tests to find small molecules that mimic Yap1, to induce skin regeneration at the site of a wound, or that inhibit the molecule to treat skin tumors. The team is also looking for other molecules that may also interact with the current molecule.

SOURCE: Cell, published online March 4, 2011