Like a seed, a tumor can remain dormant for years. But what's the trigger that causes a tumor to switch from dormancy to aggressive growth? (OpenCage/Flickr)
Believe it or not, you—and I, and everyone around us—quite likely has cancer right now.
While just a third of us will be diagnosed with cancer in our lifetimes, more than 90 percent of us harbor dormant, microscopically small tumors—maybe just a few cells in size—that will never be cause for alarm.
“Most people will live their lives without these tumors growing any larger,” says Randy Watnick, PhD, a researcher in the Vascular Biology Program at Boston Children’s Hospital. “But why? What is the difference between tumors that remain dormant and those destined to grow?”
It’s no small question: As screening and diagnostic technologies improve (allowing us to detect tumors smaller and earlier), the risks of overtreatment rise. That’s fueling a need for better ways to sift potentially dangerous tumors out from ones that will stay quiet.
It’s also a question that Judah Folkman, MD, the late founder of Boston Children’s Vascular Biology Program (VBP), was deeply interested in answering. Many years ago, Folkman started collecting lines of tumor cells that tended to remain dormant.
“When he studied them in mice, he found that the cell growth and death rates in these dormant lines balanced out,” says Watnick. “And when he looked more closely, he found that these cells couldn’t activate angiogenesis.” This process of blood vessel growth, first discovered by Folkman 40 years ago, is exploited by tumors to get the oxygen and nutrient supply they need to become active and grow.
What Folkman unfortunately did not live long enough to discover, though, was the role of an unexpected protein in the switch that turns angiogenesis on, allowing a dormant tumor to awaken.
Watnick and former VBP researcher George Naumov, PhD, took the first steps toward that answer. Extending Folkman’s work, they tested how dormant tumor cells behaved in a mouse model over a long time—100 days or more. From those experiments, they identified a list of genes that appeared to play a role in maintaining dormancy.
One of these was the gene that encodes a protein called HSP27. Part of a family of proteins called heat shock proteins, HSP27 is produced by cells under stress—from heat, starvation, lack of oxygen or other causes. When healthy cells get stressed, HSP27 helps them survive by making sure proteins get folded, packaged and delivered properly. But what was it doing in tumor cells?
To find out, Naumov, Watnick and collaborators compared HSP27 production in angiogenic and dormant breast cancer cell lines. Sure enough, angiogenic cells produced large amounts of HSP27 compared to the dormant ones. By tinkering with HSP27 production, they could force dormant cells to become aggressively growing angiogenic tumors and angiogenic cells to become dormant.
“If you think of cancer as a chronic disease to be managed, rather than an acute one to be cured, then discoveries like this could lead us down a path where tumor dormancy becomes a desired outcome of cancer treatment.”
Most strikingly, when they shut HSP27 production off, then implanted once-angiogenic cells in mice, “not only did the tumors become dormant, but in addition they couldn’t stimulate blood vessel growth,” Watnick says.
Armed with this knowledge, Watnick and Naumov—in collaboration with a group of researchers in Bergen, Norway, led by Lars A. Akslen, MD, and Oddbjorn Straume, MD, both former VBP visiting scientists—compared HSP27 production with the survival of patients with breast or skin cancer. “What we found is that tumors with low HSP27 production were not as aggressive, and that their survival rates were better,” Watnick says. “The opposite was also true: higher HSP27 production meant lower survival.”
Taken together, the team’s experiments—as reported in a recent issue of the Proceedings of the National Academy of Sciences—establish HSP27′s role as a molecular switch, waking up small, dormant tumors and turning them into aggressive, growing killers.
“This is a very new finding,” Watnick says. “No one had ever thought of HSP27 as being an angiogenic factor, and there’s still a lot of controversy around the idea. But there are a lot of gene and signaling pathways that converge to turn angiogenesis on, and we think HSP27 could be helping those pathways along.”
Watnick thinks that, apart from its potential as a therapeutic target, HSP27 could help doctors decide which tumors need to be treated aggressively and which can be just kept under close watch.
“If you think of cancer as a chronic disease to be managed, rather than an acute one to be cured,” says Watnick, “then discoveries like this could lead us down a path where tumor dormancy becomes a desired outcome of cancer treatment.”
