Thousands of brain tumour stem cells, that form a neurosphere, were generated in cell culture from a small number of cells that has been surgically removed from an adult human glioblastoma multiformae.
Not all cancer cells are created equal, and a growing number of Canada's top cancer scientists are wondering if they've made a deadly mistake by targeting the wrong ones.
The buzz these days is all about cancer stem cells – cells that have the ability to renew themselves as well as generate other types of cells in a tumour, just as true stem cells spawn tissue of various types.
Researchers once believed that all cancer cells could make a tumour grow. But mounting evidence suggests that this rare, aggressive sub-type may be the engine driving cancer growth, as well as the majority of recurrences, which up until now have been difficult to explain.
Much of the interest springs from the fact that these cells are highly resistant to most common chemotherapy and radiation therapies. The proportion of stem cells in a tumour spikes over the course of treatment as non-stem cells perish and resilient stem cells stand their ground.
But in a groundbreaking study published this month in the journal Cell, researchers at the MIT and Harvard joint venture, The Broad Institute, identified for the first time a chemical, salinomycin, shown to selectively kill stem cells that common chemotherapies leave behind, opening the door to new, two-pronged, attack strategies that target both non-stem and stem cells.
But the debate over cancer stem cells is far from settled. Skeptics dismiss the excitement as yet another false promise in a field that, despite billions in funding, has accomplished only modest results.
In the United States, the death rate for cancer dropped less than 6 per cent from 1950 to 2005, the National Cancer Institute reports. In Canada, the five-year survival rate increased 4.5 per cent from 1992-94 to 2002-04.
Ontario Cancer Institute researcher John Dick, arguably the world's leading authority in the field, first identified stem cells in leukemia in the 1990s. Today, few doubt they play a key role in blood cancers.
But scientists who support the cancer stem-cell hypothesis say that stem cells are also critical for solid tumours, like those of the breast, colon and brain.
Samuel Weiss, director of the Hotchkiss Brain Institute at the University of Calgary, has spent the past two decades establishing himself as one of the country's leading stem-cell experts. He began his career studying the brain and, in 1992, made one of the field's most startling discoveries, disproving the long-held notion that neural development is fixed by proving the existence of stem cells in adult brains.
Dr. Weiss now dedicates two-thirds of his lab's resources to the study of cancer stem cells, which he believes offer "tremendous potential" for new treatments that "could benefit humanity in ways that very few efforts have."
The wake-up call, Dr. Weiss said, came two years ago when his team implanted 10 brain-tumour stem cells into a mouse's brain. It typically takes up to a million generalized cancer cells to reliably make cancers grow. But just eight weeks later, the little mouse was on the edge of death. An MRI revealed its entire brain had been riddled by the disease.
"If that doesn't convince you … well then you're not drinking strong enough coffee," Dr. Weiss said. "That was the point at which I knew my research program was never going to be the same."
But Dr. Weiss and other proponents of the cancer stem-cell theory have been met with deep suspicion by critics who fear the hypothesis is not just overblown, but drawing limited resources away from more promising areas of study.
Scott Kern, a cancer researcher at the John Hopkins University School of Medicine, is one of the hypothesis's greatest critics. He has publicly questioned the very existence of stem cells in solid tumours and thinks that focusing on destroying one subset of cells, instead of all cancer cells, is misguided.
"The idea that the large majority of cancer cells in a typical colon, breast, or lung cancer are involved in a vast conspiracy to behave like nice Boy Scouts, leaving all the badness of the cancer to a few rare hoodlum cells, strikes my funny bone more than my intellectual curiosity," Dr. Kern explained.
At the heart of the debate are unanswered questions about exactly what cancer stem cells are and how they function.
Researchers still don't know exactly how the cells form or whether non-stem cells can mutate into stem cells, or at what point. Perhaps all cancer cells are capable of infinite proliferation when exposed to certain triggers, Dr. Kern said.
The hypothesis also hinges on the assumption that these cells are rare. Otherwise, traditional cancer therapies that shrink tumours would be killing them, too, and there would be no need to develop specialized treatments, said P. Richard Hill, a senior scientist at the Ontario Cancer Institute.
But what if they're not?
The majority of experiments in the field rely on isolating cancer stem cells and implanting them into genetically engineered, immune-deficient mice.
But in a game-changing paper published in Nature last year, a team led by Sean Morrison, director of the University of Michigan Center for Stem Cell Biology, found that it could drastically decrease the number of implanted melanoma cells it takes to spawn cancer in mice from one million to just four cells.
What was responsible for this stunning change? The experimenters tried the experiment on a new breed of mice.
While it's possible that melanomas really do have a huge number of stem cells, the paper has raised profound concerns that the methods being used to test the theory are biasing results.
The moral, Dr. Morrison argued, is that it's too early to tell how relevant the cancer stem-cell model will be for different forms of the disease.
As the dust settles, much of the initial frenzy over the potential of cancer stem cells will be proven premature, Dr. Dick said. Now, researchers are taking a more cautious approach, recognizing that stem cells may be key for some kinds of cancers and not for others.
The hope now is that, as scientists learn more, new drug combinations that target all cell types will add to the growing arsenal of weapons that might, one day, conquer the country's leading cause of death.
"Whether the hypothesis is correct or incorrect in its full-blown beauty is really not important in the end," said Harvard Medical School cancer researcher William Hahn.