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Michael Green is using senescence-inducing proteins to stop cancer cells from dividing.
But starting in the mid 1990s, researchers discovered ways to track senescent cells in living tissues, not just in cell culture. For instance, senescent cells produce an enzyme called beta galactosidase. When bathed in a particular sugar compound, cells with this enzyme turn blue, providing a way to spot senescent cells. Since then, researchers have used this method to show that tissues from people, as well as from animals such as rodents and monkeys, carried blue cells. And, “the older you got the more blue cells you had,” says Lowe. Other markers exist, and although none of the markers is exclusive to senescent cells—they tag other things too—these studies have provided robust evidence that senescence is important beyond the culture dish.
Recent research supports the notion that senescence helps divert cells when they start down the path toward cancer. Four studies in 2005 revealed that senescent cells accumulate in precancerous growths such as moles, and quieting senescence pathways suffices to trigger melanoma and prostate cancer. “Premalignant tumors are chock full of senescent cells,” says Lowe. The studies' findings settled the controversy about whether senescence works to prevent cancer in people, he adds.
Senescent cells might seem to be introverted wallflowers, but new work suggests that they are rather social, communicating and influencing their neighbors. HHMI investigator Michael Green, of the University of Massachusetts Medical School in Worcester, made the discovery after looking deeper into how senescence prevents melanoma from taking hold. A cancer-causing mutation in a gene called BRAF occurs frequently in melanoma; most benign mole cells also carry the mutation. Like other oncogenes, BRAF spurs cells in culture to senesce. Green wondered what spurred cells carrying BRAF to senesce rather than grow into tumors.
He and his colleagues identified a set of genes that appear to hold mole cells in senescence; when they shut down any of these genes, the cells grew like crazy. Green was surprised to discover that one of the genes makes a protein called IGFBP7 that gets discharged out of the cell. “We were expecting it to be a purely intracellular event,” he says. The team reported its findings in the journal Cell in February 2008. Mole cells didn't need to make this protein themselves to stay quiet. Applying IGFBP7 to the outside of mole cells was enough to keep cells in senescence. The findings suggest that, by spewing IGFBP7, one cell could help its neighbors from turning cancerous.
At about that time, other groups also showed that other types of senescent cells discharge proteins that stall cell division. The results of all the studies are striking, says Lowe. “Senescent cells aren't just sitting there.”
Melanoma cells don't make IGFBP7, says Green, but his studies suggest that they still respond to the molecule. Bathing cancer cells in IGFBP7 prodded them to die. Green is exploring the idea of using IGFBP7 as an anti-cancer drug. He will collaborate with scientists at the National Cancer Institute to conduct preclinical studies that will lay the foundation for clinical trials.