Tumors can come equipped with time-bombs—cells that migrate through the bloodstream, lodge in a distant organ, and then enter a dormant state. A new study of such cells in the lungs of mice examines how they wake up from dormancy and unleash their power, proliferating to form deadly metastatic tumors. It seems that a cellular program—called the epithelial-mesenchymal transition, known to occur in metastasis—can nudge the cells awake in response to inflammation.
Dormant tumor cells may underlie many cancer deaths that occur years after the initial diagnosis and treatment. “It’s an understudied area,” says Julio Aguirre-Ghiso, a professor of hematology and oncology at Mt. Sinai School of Medicine in New York City who was not involved in the study. He points out that the most common type of breast cancer has a relapse rate of 1 to 2 percent per year over decades. “Patients can be free of disease sometimes for 5-20 years before they develop metastasis, and those are the patients that we think are carrying dormant cells.”
Despite being key in tumor formation, little is known about how dormant cells wake up and begin proliferating, “This is one of the burning questions,” says Filippo G. Giancotti, scientific director of the David H. Koch Center for Applied Research of GU Cancers at U.T. M.D. Anderson Cancer Center in Houston, Texas.
To examine this question, senior author and cancer biologist Robert Weinberg and colleagues injected mice with mouse mammary cancer cells that migrate to the lung and focused on those that later turned out to be dormant. The researchers enriched for the dormant cells by repeatedly isolating them from the lung, growing them in a petri dish, and reinjecting them into mice. With this enriched population of cells—which proliferated in a petri dish but entered dormancy in the lungs—the researchers asked what wakes them up.
Earlier studies by Weinberg and his colleagues had previously implicated the epithelial-mesenchymal transition—which can prompt increased cell migration, invasion and survival—in metastatic processes such as migration from primary tumors. The researchers found that this cellular program also seems to awaken dormant cells. For instance, they activated the program by turning on a cellular regulator that drives it, Zeb-1. Turning on Zeb-1 in the dormant cells in the lung prompted them to proliferate and form metastases.
The researchers also found that an inflammatory trigger—a bacterial molecule—could induce Zeb-1 and activate dormant cells. This response seemed to be mediated by a specific cell type, neutrophils. “These are the first responders of the immune system,” explains the study’s first author, Jasmine De Cock, now technology specialist at the law firm Fish & Richardson in Boston.
The study strengthens arguments that the epithelial-mesenchymal transition can prompt metastatic processes, a paradigm with some conflicting data, says Giancotti. Adds Aguirre-Ghiso, “This is an interesting finding, that inflammation can tap into these programs driven by [Zeb-1].” The findings also jibe with a December 2015 study, by Tina El Rayes et al. that Aguirre-Ghiso says also implicate activated neutrophils—and a molecule they release—in waking up dormant tumor cells.
But Aguirre-Ghiso also cautions against drawing broad conclusions about inflammation—the human clinical data are much less clear, he says. Why, he asks, don’t tumors activate in response to inflammatory conditions such as the flu? “Where is the data that there is an association of inflammation and relapse? … There is no clear signal in the literature that there is an association.“
Meanwhile, ongoing studies in the Weinberg lab should uncover additional molecular mediators involved in activating dormant tumor cells. Identifying such mediators could result in new drug targets and suggest ways to defuse dormant cells by keeping them dormant or preventing them from appearing in the first place.