Gap in the Defense: Brain cancer patients short on valuable protein

Brain-tumor cells have a dearth of an obscure protein whose sister compounds have shown anticancer effects, scientists report in the March 18 Nature.

The protein is called p29 or ING4, shorthand for inhibitor of growth. After earlier research had indicated that a related protein, ING1, has antitumor properties, scientists became interested in other members of the ING family. By scanning various tumor cells taken from patients, Igor Garkavtsev of Harvard Medical School and Massachusetts General Hospital in Boston noticed that brain cancer and kidney cancer cells seemed deficient in ING4. His team has initially focused on the brain cells.

Garkavtsev and his colleagues closely examined 50 brain tumors called gliomas, the most common brain cancer. They concluded that cells from slow-growing cancers had only one-half to one-third as much ING4 protein as did healthy brain cells. Cells from aggressive tumors, called glioblastomas, had only one-sixth as much.

Next, the researchers implanted human glioblastoma tumors into mice, some of which had functional genes that encode ING4 protein and others that had defective genes and little ING4 protein.

Tumors in mice deficient in ING4 grew faster and larger than did tumors in mice with a full complement of the protein.

Also, a shortage of ING4 permitted more new blood vessels to form around the mouse tumors, a process called angiogenesis. An enhanced blood supply enables cancer to flourish. The researchers found that ING4 binds to and inhibits a compound called nuclear transcription factor kappa B.

Other studies have linked this compound to vessel growth.

The ING proteins operate inside cells, switching genes on and off in response to stresses confronting the cell, says Karl T. Riabowol, a molecular biologist at the University of Calgary in Canada. Since he teamed with Garkavtsev and others to discover the first ING protein and its gene in 1996, they and other researchers have found evidence that ING proteins play several roles. They can activate the tumor-suppressor protein p53, regulate growth of a cell, and influence cell replication, Riabowol says.

The finding that ING4 might inhibit angiogenesis “opens a new avenue of investigation in the ING family of proteins,” says Curtis C. Harris, chief of the Human Carcinogenesis Laboratory at the National Cancer Institute in Bethesda, Md. “I’m enthusiastic about this study but cautious,” he says, noting that it remains unclear why people with brain cancer seem to have less ING4 than healthy individuals do.

Nobody knows how the new findings might translate into benefits for cancer patients, Riabowol says. But he adds that “any research that allows us to better understand how cancer cells emerge” is progress.