Hunting for clues to the causes of cancer

	What makes radiation exposure risky? When a person is exposed to radiation, the incoming photons interact with macromolecules like DNA or protein, or with the water molecules that make up most tissue -- the human body is about 80 percent water. The interaction with water molecules creates electrically charged atoms or “ions” that are also highly energized and harmful to living cells. The ionizing radiation of biggest concern is that from alpha and beta particles (helium ions and electrons), gamma rays, and x-rays. For a typical person living in the United States, most of the exposure to ionizing radiation other than medical x-rays comes from natural sources, primarily from radioactive decay products such as radon, and from radioactive elements found in the earth's crust, such as uranium and thorium. While exposure to sufficiently large doses of ionizing radiation can result in immediate death, exposure to smaller doses generally sets off a defense response in tissue that can itself become a problem. For example, exposure to just the right dose of ultraviolet radiation will cause skin tissue to respond by producing melanin, a protective skin-darkening pigment. This is the goal of tanning salons. Too much exposure at once, however, leads to sunburn, and repeated exposures over time will damage the tissue, causing wrinkles and possibly skin cancer. Everyone is exposed on a daily basis to background levels of radiation present in the environment. The type, total amount, and duration of radiation exposure determines whether an individual’s risk of developing cancer is increased. At very low doses, the estimated risk is extremely small. This is why the benefits of diagnostic radiation, like mammograms, outweigh the risk, especially for women who are at high risk for getting breast cancer.

Experimental findings by Berkley Lab cell biologist Mary Helen Barcellos-Hoff and her research group showed that exposure to ionizing radiation creates a microenvironment in the tissue that surrounds breast cells, which can cause even nonirradiated cells and their progeny to become cancerous. The discovery that it is the tissue surrounding breast cells that may be the primary target of ionizing radiation damage rather than the DNA within the cells suggests new and possibly more effective means of treating breast cancer.

“Repairing damaged tissue would be a much less cumbersome strategy for interrupting the cancer process than trying to repair individual damaged cells,” says Barcellos-Hoff. “We find that radiation elicits rapid and persistent global alterations in the mammary gland microenvironment. These radiation-induced microenvironments might lead to changes in the phenotypes (physical characteristics) of cells and their progeny that promote carcinogenesis.”

In one study, a special line of nonirradiated, nonmalignant breast cells were transplanted into mammary glands that had been exposed to low dosages (less than 5 grays or 500 rads) of ionizing radiation. Nearly 75 percent of these transplanted cells developed tumors and the effect persisted up to 14 days after the radiation exposure. Tumors did not develop when the same type of cells were transplanted into nonirradiated portions of the mammary glands.

Barcellos-Hoff and her research team established that damage to the irradiated tissue was generating signals that altered how the genomes of the transplanted cells were being expressed. This resulted in the creation of a new cell phenotype with physical characteristics that were cued by the extracellular signals to act cancerous. Breast cells acquiring the new phenotypes passed these characteristics on to their daughter cells.

“Genomes are like the keys on a piano, in that the same keys can be used to play a wide variety of music,” says Barcellos-Hoff.

“In our studies, the ionizing radiation elicited changes in how the genomes of the transplanted cells were being expressed by changing the extracellular signals they were receiving.”

Additional information

More about Mary Helen Barcellos-Hoff and the Bay Area Breast Cancer Center