Skin Duel

Rapidly dividing and migrating cells are the body's bandages for healing wonds-and the most recognizable and lethal hallmark of cancer.

by Lori Oliwenstein

Every time a paring knife accidentally slices into your finger, every time those new shoes rub a blister onto your heel, every time you stumble and scrape your knee, your body kicks into wound-healing mode. Heeding an unknown signal, cells called keratinocytes stop differentiating into the outermost layers of skin—their normal job—and instead begin rapidly dividing and mobilizing to cover the gap.

This is a critical job since the skin is the body’s first and most vigilant line of defense against the outside world. It is also an unusual—and somewhat disturbing—departure from the cells’ normal role. After all, notes David Woodley, M.D., professor and chief of dermatology at the Keck School of Medicine, rapid division and migration are among the most recognizable—and lethal—hallmarks of cancer.

Woodley points out that chronic wound healing can and does lead to cancer: In a number of dermatology’s most serious ailments, the constant destruction and healing of the skin results in lethal forms of squamous cell carcinoma, the second most common type of skin cancer.

Understanding the connection between wound healing and cancer is just one of the investigations going on in Woodley’s laboratory in the USC/Norris Comprehensive Cancer Center. Along with Wei Li, Ph.D., associate professor of medicine, and Mei Chen, Ph.D., professor of medicine, Woodley is currently involved in five major National Institutes of Health research grants totaling almost $7 million.

And, most recently, their research has been getting a good deal of attention from the scientific community at large, especially after two major publications carried their research results.

The first was in the December 2002 issue of Nature Genetics, where Chen and Woodley reported the successful engineering of mouse cells capable of producing a type of human collagen—type VII—that is missing in a family of inherited skin diseases called dystrophic epidermolysis bullosa. Chen, Woodley and their colleagues also prompted the mouse cells to create the structural fibers that normally arise from type VII collagen.

“This is the first demonstration of in vivo gene therapy where the genes have made a large extracellular molecular structure that you can actually see with a microscope,” says Woodley, who collaborated with scientists from Shriners Hospital for Children in Portland, Ore., Northwestern University in Chicago, and Xgene Corporation in San Carlos, Calif.

The scientists in the Woodley lab were able to get to this place by building on their previous efforts in the field: In 1992, Woodley and some of his colleagues became the first team to clone the human gene for type VII collagen. Collagen makes up the tendrils and fibrils that provide a cushion for the skin’s cells to rest upon; type VII collagen, in particular, is critical to the creation of the skin’s so-called anchoring fibrils.

“Anchoring fibrils,” Woodley explains, “are like connective tissue staples—they staple the epidermal layer of the skin to the dermis.” Without these fibrils, the layers of the skin can separate like layers of pastry, blistering and sloughing off at the slightest insult or injury—as they do in epidermolysis bullosa.

“By the time people with epidermolysis bullosa are 20,” says Woodley, “they often have developed aggressive squamous cell carcinomas.”

Woodley, Chen and Li, along with former USC gene therapist Nori Kasahara, M.D., Ph.D., were able to get two different skin cells in a living mouse model to produce type VII collagen and then construct anchoring fibrils. And they have preliminary evidence that the cells in laboratory dishes can continue to pump out type VII collagen for at least six months.

The Woodley team produced its second major finding in February 2003. The Lancet published their study showing that keratinocytes get their marching orders from the liquid portion of the blood—but only after the blood has released its platelets to form a clot.

“Dr. Wei Li is trying to understand the signal transduction pathways involved in skin re-epithelialization,” Woodley says. “We want to know just what signals the keratinocytes to become a completely different kind of cell—a cell that stops differentiating and begins proliferating and migrating. If we can answer that, it should give us some insight into what’s happening to cause these aggressive squamous cell carcinomas and possibly other forms of skin cancer as well.”

What Li, Ginard Henry, a surgical research associate, and Woodley found, and reported in The Lancet, is that these signals seem to come from the environment in which the cells find themselves—from the fluids in which the cells are bathed. In their recent paper, Li, Henry and Woodley, along with Warren Garner, M.D., director of the LAC+USC Burn Center, showed that human serum—the liquid-only portion of the blood—is at least one of the things that prompt keratinocytes to change into migrating cells. At the same time, they showed that plasma, which is essentially serum with clotting proteins mixed in, does nothing of the sort.

What is interesting, notes Woodley, is that “keratinocytes are normally bathed in plasma. In fact, when there’s a wound, that’s the first time they see pure serum.”
In other words, it is only when there has been some sort of injury to the skin, and the plasma is converted to serum—or, as Woodley puts it, “has spewed out its platelet guts”—to create a clot, that the keratinocytes get the word that they need to become migratory.

“So what we’ve found is that the serum is somehow signaling the keratinocytes, telling them that they need to move and proliferate,” Woodley says. “We now hope to figure out what the signal is in human serum that turns on the switch for cells to migrate. And once we’ve done that, we can begin to learn how to turn it off when we need to, like in aggressive squamous cell carcinomas that result from chronic skin wounds.”

It is this sort of translational outlook—taking scientific findings to a patient’s bedside—that fuels Woodley’s research. “I see patients who would definitely benefit from our better understanding of the basic mechanisms of skin biology,” he says.

“That’s the goal: to help the patients who need it. Hopefully, that’s what we’re doing.”