Goal is to block cancers before they start

Researchers led by Zigang Dong, director of the U’s Hormel Institute, have found what may be the first step in the development of skin cancer.
By Deane Morrison
May 20, 2008

University researchers have pinpointed what may be the earliest event in the development of sun-induced skin cancer. Their work, published May 15 in the journal Cancer Research, could lead to the equivalent of a “morning-after pill” to stop skin cancer in its tracks.

“The idea is to find an agent that can prevent skin cancers after exposure to the sun,” says lead researcher Zigang Dong, professor of cellular and molecular biology and director of the University’s Hormel Institute in Austin, Minn., where the research team performed the study.

Ultraviolet light from the sun is a key cause of several types of skin cancer, which are the most common cancers in humans. A million people in the United States are expected to develop nonmelanoma skin cancer in 2008, and several hundred will die of it, according to the National Cancer Institute. Melanoma is estimated to strike 62,000 people and account for upwards of 8,000 deaths.

“We asked, ‘Why does ultraviolet light induce skin cancer?'” says Dong, who, with his colleagues, studies the molecular mechanisms that lead to the development of cancer.

In order to do its deadly work, UV light must start by interacting with cells in some way. Therefore, the researchers looked for the first point of contact between UV light rays and cells in the epidermis, the thin outer layer of skin.

They began their search with plant cells because plants must interact with UV light in order to harness its energy for photosynthesis. The interaction begins when UV light is captured by tiny protein structures known as receptor molecules.

“The idea is to find an agent that can prevent skin cancers after exposure to the sun.”

But light isn’t the only thing captured by receptors. The outer surfaces, or membranes, of animal cells are dotted with receptors for numerous chemical signals. Like tiny receiving docks, receptors snag specific compounds from the blood, enabling the cells to engulf or otherwise interact with the compounds. Receptors have been identified for many substances, including hormones and and other chemical signals that regulate what cells do.

Too transient for tumors

The epidermis is composed of cells called keratinocytes, which originate in the deep layers and migrate up to the surface of the skin. As they get near the top, they flatten out and keratin, the tough protein within them, forms a protective barrier to water, microbes, etc.

Because these cells eventually get sloughed off at the skin surface, they don’t live long enough to produce tumors. But in the deep layers of the epidermis are stem cells that stay in the epidermis and divide to replenish the supply of keratinocytes. Damage to them is believed to be the source of many skin cancers, says Dong.

Melanoma, the deadliest skin cancer, arises from damage to melanocytes, the cells that produce granules of dark pigments and distribute them to keratinocytes. In a keratinocyte, the granules tend to spread out over the cell nucleus as if to shield its DNA from incoming solar UV rays.

“We wanted to find the UV receptor in skin cells, and we looked for many years,” Dong says. The researchers reasoned that the UV receptors in plants ought to resemble those of humans or mice, and, therefore, the plant and animal genes for UV receptors must also be similar.

When they compared genes for plant UV receptors to human genetic material, they had a surprise. The human genes that matched were for receptors, all right–receptors designed to snag components of marijuana smoke called cannabinoids and pull them out of the bloodstream.

Why should evolution have produced receptors that respond to both UV light and cannabinoids?

“That we don’t know,” says Dong. If cannabinoid receptors are important in the initiation of skin cancer by UV light, then animals that lack the receptors should be relatively protected from the ravages of the light. Working with mouse embryos, the researchers removed the genes for the cannabinoid receptors. They found that the skin of the resulting adult mice, which lacked the receptors, was resistant to the development of UV-induced inflammation and skin tumors called papillomas.

Also, when they exposed cannabinoid receptors to UV light, the receptors changed from an inactive to an active state, indicating they had absorbed and responded to the light.

It is possible, says Dong, that other receptors, still to be identified, also absorb and respond to UV light and play a role in cancer. And plenty remains to be learned about the process of cancer development. But identifying the first step is crucial to understanding the onset of cancer, and thus finding ways to thwart it.