Researchers tease out one critical role of tumor-suppressor gene

Scientists are taking the first steps to find out how a gene that is mutated in many cancer cells functions in healthy cells.

The researchers hope that learning how this gene, called Rb, operates in health cells will give them a better idea of how cancer develops and progresses. While mutations in Rb, are linked to several types of cancer including the childhood disease retinoblastoma, Rb normally keeps cell division in check. That means Rb is a tumor suppressor gene, which keeps cells from growing out of control. Scientists believe that Rb is linked to two key processes that frequently malfunction when cancer begins – proliferation (cell growth), and apoptosis (cell death). But they don’t know how Rb, which is found in every cell of the body, does this. New findings reported in the December 23 issue of Nature begin to shed light on the gene’s role in cells.

The researchers found that in mice, a lack of Rb during embryonic development kept red blood cells from fully maturing. “While we don’t think this finding has a specific link to cancer development, it is a first step to getting at the basic mechanism of how Rb works,” said Gustavo Leone, a study co-author and an assistant professor with the Human Cancer Genetics Program at Ohio State University. “Knowing how Rb works in normal cells could help us to someday understand how tumor-suppressor genes function in tumor development and growth.”

Leone was part of a team of researchers led by Antonio Iavarone, a professor with the Institute for Cancer Genetics at Columbia University.

The researchers studied red blood cells and macrophages taken from the liver tissue of mouse embryos bred to lack Rb. Macrophages are scavenger cells — they eat up foreign material such as bacteria and viruses. In the developing embryo, macrophages bind to red blood cells, and this binding forces red blood cells to lose their nuclei. A mature red blood cell lacks a nucleus.

Leone and his colleagues surmised that the reason why the red blood cells from the embryos without Rb never lost their nuclei was due to a reduction in the number of macrophages in these fetal mouse livers. “Without Rb, the number of mature macrophages in the fetal liver was markedly reduced,” said Leone, who is also a geneticist with Ohio State’s Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.

The researchers identified part of the molecular pathway that may help explain this reduction in mature macrophages: Cells carry a gene called Id2, an inhibitor protein that, in this case, probably kept macrophages from maturing. In a normal cell, it’s thought that Rb counterbalances Id2’s inhibitory effects. Since Id2 went unchecked, macrophages did not fully develop and therefore couldn’t bind to immature red blood cells.

In order to test this idea, the researchers created a mix of embryonic liver cells – some had the Rb gene, while others did not. Interestingly, the red blood cells from the embryos that lacked Rb immediately bound themselves to the Rb-containing macrophages. “This binding restored the red blood cells’ ability to give up their nuclei and, therefore, mature,” Leone said.

Knowing how Rb functions in normal cells could clue scientists in to the gene’s behavior as a tumor suppressor and why it mutates. It could also ultimately help scientists understand how other types of cancer progress. “Cancer cells are altered in so many different ways that it’s hard to conduct controlled experiments with them,” Leone said. “That’s why we need to figure out what Rb normally does, as opposed to studying a mutated version of the gene in a cancer cell. This may also help us uncover the mechanisms that cause mutations in other tumor-suppressing genes.”

Leone and Iavarone conducted the study with Emerson King and Anna Lasorella, both with Columbia University, and Xu-Ming Dai and E. Richard Stanley, both with the Albert Einstein College of Medicine in New York.

This work was supported by the National Institutes of Health.