At least four decades of research support the idea that cancer stem cells play a major role in the origin of the so-called liquid tumors of the blood and lymphatic systems. But scientists have only recently begun exploring the possibility that cancer stem cells may be responsible for the development of solid tumors—such as cancers of the lung, breast and liver—as well. The presence of cancer stem cells might also clarify why imatinib does not cure CML. If stem cells uniquely did not need the Bcr-Abl enzyme to survive, no amount of the enzyme-blocking drug would eliminate them. “Those cells can be swimming in a sea of imatinib, but they’re not being killed,” says John E. Dick of the University of Toronto, a pioneer in cancer stem cell research. Investigators also suspect that cancer stem cells may be the reason relapses can occur years after an apparently successful treatment. Some cancer stem cells seemingly enter a dormant state, allowing them to survive the initial treatment relatively unscathed.
The first strong evidence that cancer stem cells might play a role in solid as well as liquid tumors came in 2003 from the study of malignant breast tissue. The study kicked off an era of what Dick calls “breathless excitement.” The cancer stem cell idea appealed to many researchers because it seemed to explain so much, not only the variety of cells within tumors but also why traditional cancer therapies often fail. A second study, also of breast tumors, by Jenny C. Chang, who is now an oncologist at Methodist Hospital in Houston, provided compelling evidence that cancer stem cells might be unusually resistant to standard treament.
At the time, Chang was working with patients at Ben Taub General Hospital in Houston, which serves the region’s 1.5 million uninsured residents. Because so many Ben Taub patients have limited access to health care, they tend to delay going to the doctor, so their cancers are more advanced when they receive a diagnosis. In fact, the tumors are often so big that they require a dose of chemotherapy to shrink the growths before surgery can even be attempted. These circumstances afforded Chang a unique opportunity to look at drug resistance.
Chang began taking biopsies of the tumors before and after chemotherapy. When she, along with Jeffrey M. Rosen of Baylor College of Medicine, and colleagues compared these biopsies, they found that the samples taken after treatment contained a greater proportion of what appeared to be cancer stem cells, as determined by the presence of certain proteins on their surface. Before the treatment, the putative cancer stem cells accounted for about 4.7 percent of the tumor, on average. After 12 weeks of chemotherapy, the ratio had risen to 13.6 percent, suggesting that the cancer stem cells were better able to survive chemotherapy than other cells in the tumor. In addition, when the cells from the postchemotherapy biopsies were grown in suspension, they formed more multicellular balls than the prechemotherapy ones, something only stem cells typically do.
To date, researchers have reported finding evidence of cancer stem cells in tumors of the breast, brain, skin, colon, prostate, pancreas and liver, among others. But as more and more scientists have joined the field—and tried to replicate one another’s work—the picture has gotten a lot more complicated. In 2008, for example, Sean J. Morrison, director of the University of Michigan Center for Stem Cell Biology, found that if he tweaked a test, or assay, in mice that is used to detect cancer stem cells, he could dramatically change the results. A previous study had suggested that only one cell out of every million was a melanoma stem cell. Morrison found one in four cells could form a tumor. “If you make changes in the assay and you get huge changes in the spectrum of human cancer cells that can form a tumor, then that makes you really worry about drawing conclusions,” he says.