Cancer flip-flop: gene acts in both proliferation and control of growth.

Decades ago, cancer geneticists latched on to an attractively simple model in which only two types of genes control the disease's spread: Oncogenes trigger cancers and their growth, but tumor-suppressor genes keep cancer cells in check.

Now, Patrick Mehlen of the University of Lyon in Villeurbanne, France, and his colleagues describe, in the Sept. 2 Nature, what may be a third class of cancer-controlling genes. Dubbed "conditional suppressors," these genes switch between halting and promoting cancer, depending on the presence or absence of a particular protein.

"What [these genes do] is put the brakes on cancer under one set of circumstances and [step] on the accelerator under another set of circumstances,' says study coauthor Dale Bredesen of the Buck Institute for Age Research in Novato, Calif.

The researchers focused on a possible conditional-suppressor gene called DCC, which stands for "deleted in colorectal cancer," and a protein called netrin-1. Previous research suggested that DCC acts as a tumor-suppressor gene because, as its name implies, it's frequently missing in people with colorectal cancer. However, some researchers doubted that DCC played a role in cancer because mice engineered to lack the gene do not show an increased incidence of colorectal cancer compared with normal mice.

DCC codes for a cell-surface receptor that binds to netrin-1, which scientists had previously linked to nervous system development. In 1998, Mehlen, Bredesen, and their colleagues showed in lab-cultured human cells that the DCC receptor belongs to a class of receptors that makes a cell's survival dependent on an outside protein. If the protein is missing, cells bearing the receptors die, but if it's present, they survive indefinitely, a trait shared by cancer cells.

To find out how DCC operates in animals, Mehlen's team engineered mice that made extra netrin-1. The scientists found that these mice had an abnormal buildup of intestinal cells, which normally have short lives and get sloughed off the gut's lining. Although sections of the test animals' intestines formed precancerous lesions and buckled like "a rug that's too big [for the room]" few cells were truly cancerous, says Bredesen.

However, when these mice were crossed with animals carrying a mutation that frequently leads to benign tumors, many of their offspring developed aggressive colorectal cancers. Bredesen credits this result to some animals inheriting the tendency for developing benign tumors as well as the gene for extra netrin-1. Higher numbers of DCC-carrying intestinal cells, kept alive by netrin-1, increased the likelihood that any one cell would become malignant, he explains.

Eric Fearon, a geneticist at the University of Michigan in Ann Arbor who has studied DCC, rates the finding as "very intriguing." However, he says, "the story is perhaps best seen as an evolving one, rather than a completed work." Many more conditional suppressor genes are probably waiting to be discovered, Fearon notes. Moreover, no one yet knows how, and to what extent, receptors such as the one in this study might be involved in controlling cancer.