Staying alive: cell protein guards cancers.

In a move that can protect the organism, individual cells that have somehow gone awry often commit suicide. Indeed, this self-sacrifice may eliminate most mutated cells before they become fully cancerous.

Yet tumors sometimes arise, and researchers are now finding evidence that the cells of those cancers have found ways to inhibit apoptosis, the process by which cells kill themselves (SN: 7/27/96, p. 55).

One such survival tactic may employ a gene used primarily during fetal development, report Grazia Ambrosini of Yale University School of Medicine and her colleagues in the August Nature Medicine.

This newly discovered human gene encodes a protein, called survivin, that seems to delay or prevent cell suicide.

"The cancer cells turn this gene on so that apoptosis is inhibited and the cells keep growing," explains Ambrosini.

Because it appears that most tumor cells, but very few normal adult tissues, produce survivin, the protein offers an appealing target for cancer drugs. Compounds that block its function may thwart tumor growth while producing few side effects, says Ambrosini.

The discovery of survivin is "very exciting," agrees John C. Reed of the Burnham Institute in La Jolla, Calif., who studies the role of other apoptosis inhibitors in cancer. "Having read the paper, we'll start working on it immediately," he adds.

Ambrosini and her colleagues chanced upon survivin's gene while looking for another gene. When they searched databases for proteins similar to the amino, acid sequence predicted by the gene, they discovered that survivin belongs to a small family of proteins known to stymie cell suicide.

Over the last few years, genes encoding these apoptosis-inhibiting proteins have been found in viruses, insects, and most recently, mammals, including people.

The Yale investigators created antibodies that bind to survivin and used them to show that cancer cells grown in the laboratory invariably contain the protein. Many fetal tissues, including kidney, lung, and liver, also have lots of survivin.

Yet when the researchers examined many adult tissues, including lung, liver, brain, blood, and heart, they found no evidence of survivin. Only in the adult thymus and the placenta did they detect even small amounts of it.

Ambrosini and her colleagues also studied tissue from some of the most common human cancers: lung, colon, pancreas, prostate, and breast. They found survivin in every tumor sample but not in nearby normal tissue. In addition, they observed that the protein is rarely present in the less aggressive forms of non-Hodgkin's lymphoma but is abundant in the most dangerous ones.

Finally, the investigators added the gene for survivin to laboratory-grown cells whose lives normally depend upon a chemical called interleukin-3 (IL-3). After IL-3 was withdrawn, the cells making survivin died significantly more slowly than unaltered, IL,3-dependent cells.

The scientists have begun to examine whether survivin helps cancer cells to resist the drugs traditionally used in chemotherapy.

Reed notes that cancer cells may also employ other proteins in survivin's family, but that notion has been difficult to assess. Unlike survivin, those apoptosis-inhibiting proteins are normally made by most adult cells. Consequently, investigators face the subtle task of determining whether cancer cells make even greater amounts of the proteins.

With survivin, he says, "it's such a night-and-day comparison between normal tissues and tumors."

In the July 17 Nature, Reed and his colleagues provide data to explain how such survivinlike proteins halt cell suicide. They bind and apparently inhibit apoptosis-induced proteases, enzymes that chop up other proteins.