Why, despite the best possible care, does cancer often return – sometimes months or years after it was thought cured?
For a survivor eager to get on with life, a recurrence is devastating. For the field of cancer medicine, it is a frustrating conundrum that costs millions of lives.
Until recently, the prevailing view was that cancers return because they contain billions of dangerous malignant cells, and it's very difficult to wipe them out completely. And, to complicate matters, because they are "genetically unstable," some of the tumor cells rapidly evolve into highly resistant strains or "clones" that survive treatment.
But now a different hypothesis is roiling the cancer field – especially because it implies new directions in cancer treatment. According to the "cancer stem cell" concept, tumors are fueled by a tiny, elite population of cells with powerful survival skills that most cells in the tumor lack. These cells defend themselves with molecular "pumps" that expel toxic chemotherapy, and they can activate self-repair mechanisms that enable them to survive DNA-damaging treatments.
These hardened evildoers are termed "stem cells" because, like normal, healthy stem cells that generate specialized tissues in the body, they can reproduce endlessly, while turning out new malignant progeny.
Cancer stem cells in a tumor are believed to be rare – one in 10,000 or 100,000, or even one million cells. According to the hypothesis, these healthy stem cells are the cause of recurrences because conventional therapy isn't designed to knock them out. Advocates argue that if efforts were focused on identifying and destroying these cancer stem cells, millions of lives might be saved.
According to the hotly debated "cancer stem cell" concept, tumors are fueled by a tiny population of cells with powerful survival skills.
As alluring as this proposal may be, some leading scientists at Dana-Farber and elsewhere remain decidedly skeptical. Nor do they think a major shift of research based on the notion is justified at this point.
Cancer stem cells are "a very attractive idea" because it suggests "this is how you cure cancer," says Kornelia Polyak, MD, PhD, a Dana-Farber researcher who studies the origin and progression of breast cancer. However, she and several colleagues say the model provides a simplistic – and probably erroneous – explanation for cancer recurrences and offers false hope of a "silver bullet" for many types of cancer.
"The major problem with the cancer stem cell idea is that it is not supported by data – neither clinical observations nor basic science," says Polyak. She has been investigating differences among cancer cells within the same tumor and found that some have stem cell-like features. But her studies suggest that the traits of the cancer cells are determined by their genes, along with environmental effects like treatment. These traits, moreover, change over time, she says, arguing against the existence of a fixed, single type of cancer stem cell.
"One of the most upsetting aspects is that the supporters have been popularizing this theory without enough sound evidence to back it up," she says.
William Kaelin, MD, a Dana-Farber oncologist, is also a skeptic, and he shares Polyak's concern with the "spin" of stem cell advocates. "They are saying we've been studying and treating the wrong cells and that if only we'd been focusing on these rare cells, we would have done much better," says Kaelin, who disputes any assertion that mainstream research has been running on the wrong track.
Kaelin is particularly critical of laboratory tests through which scientists claim to have identified cancer stem cells in a variety of tumor types. In these tests, researchers implanted millions of cancer cells into mice with weakened immune systems and observed that only a tiny fraction of them could spawn new tumors. Those must be the rare cancer stem cells, they reported.
However, Kaelin says it's equally plausible that a large number of the implanted tumor cells could have fueled new tumors – but most were killed off by the animals' remaining immune defenses.
He adds that the idea that tumors contain different types of cells, some of them more capable than others of forming a new cancer, is not new – and doesn't mean that an extremely rare and all-powerful cancer stem cell exists.
Yet some Dana-Farber scientists find the theory plausible and well worth continued exploration. "People are very interested because there are some important clinical observations that could be potentially explained by the cancer stem cell theory," says oncologist Ian Krop, MD, PhD, "I think it's a valid idea, and there are enough data to say that it's worth testing." Which, in fact, he and collaborators are doing as part of a clinical trial of an experimental compound designed to strip breast cancer stem cells of their powers of drug resistance and self-renewal, then hit the weakened cells with standard chemotherapy.
"What's nice about the cancer stem cell hypothesis is it explains a lot of things – especially in the area of brain cancer, where I work – such as how you get brain cancer in the first place," says Charles Stiles, PhD, co-chair of Dana-Farber's Department of Cancer Biology.
He notes that "a highly malignant cell with stem-like properties could account for the bizarre collection of different cell types found within the most deadly brain cancer, glioblastoma multiforme."
By definition, a stem cell is any primitive, "blank-slate" cell that spawns more-specialized cells to form tissues and organs, and is also self-renewing.
The most primitive stem cells of all are found in the early embryo formed by the fusion of sperm and egg at conception. These "embryonic stem cells," which are at the center of controversy over potential medical uses, generate ever-more-specialized generations of cells to create the body's entire array of tissues and organs. They have very limited relevance to treating cancer.
The body also maintains "pools" of "adult stem cells" that are slightly less versatile than those in the embryo, but which can manufacture replacement cells for specific organs when needed.
The concept that cancer could originate in a stem cell goes back more than 100 years, and attracted increased interest in the 1950s and 1960s, when some scientists suggested that a normal adult stem cell might be turned to the "dark side" because of a chance mutation. This random change could make the stem cell tumorigenic – capable by itself of forming a new tumor – as well as gaining self-renewal and treatment-resistant traits. Such cells might be at the root of all tumors and the cause of cancer recurrences.
The first cancer stem cell was reported about 10 years ago, making up about one in 10,000 cells of a form of leukemia. Yet even today, "the extent to which these cells are responsible for the majority of clinical relapses is still being investigated," according to Scott Armstrong, MD, PhD, a specialist in blood cancers at Dana-Farber and Boston Children's Hospital.
Cancer stem cells were reported in breast cancers in 2003, in brain tumors in 2004, and in several more types since then.
The first cancer stem cell was reported about 10 years ago, in a form of leukemia. They have been reported in several more types of cancer since then.
Despite the continuing debate over the definition of cancer stem cells, how common they are, and whether they even exist, the National Cancer Institute is funding the field and some scientists are moving ahead with early efforts to target them. The goal is to pinpoint molecular signaling pathways believed to give the cells their "stem-ness" – their treatment-resistant, self-renewing powers – and then use designer drugs to block those pathways. That might kill the stem cells or at least make them more vulnerable to chemotherapy and radiation.
Krop is directing Dana-Farber's participation in a small multi-center Phase 1 clinical trial testing a drug aimed at targeting stem cells in women with advanced breast cancer. Previous reports indicate that conventional chemotherapy actually boosts the proportion of cancer stem cells in a tumor even as the tumor shrinks; this is because the hardy stem cells survive while the drug kills off more susceptible cells.
Krop is testing the experimental drug, which is designed to block a molecular mechanism within breast cancer cells, called the NOTCH pathway, that has been found to be overactive in some very aggressive breast cancers. It's known that NOTCH is active in embryonic cells and may, when switched on in an adult, give cancer cells their powerful survival tools.
One hypothesis is that the NOTCH blocker will strip the cancer stem cells of these tools so that they will be more easily killed by a potent chemotherapy drug, taxotere. In addition to determining the drug's safety and any possible clinical benefit, the researchers will count breast cancer stem cells and see if they are decreased following treatment.
Kaelin says that using drugs to block the NOTCH pathway "is a good idea whether the current cancer stem cell model is correct or not," because it is widely accepted that cancer cells can turn on embryonic stem cell pathways in adults.
Max Wicha, MD, head of the Comprehensive Cancer Center at the University of Michigan, and a leading advocate of the cancer stem cell theory, was involved in the development of the three-center trial. Krop says that he, Wicha, Anne Schott, MD, a colleague of Wicha's at Michigan, and Jenny Chang, MD at Baylor College of Medicine, designed the study "to begin to actually put the stem cell hypothesis to the test."
Meanwhile, the debate continues. Last December, Sean Morrison, PhD, a stem-cell scientist at the University of Michigan, reported in the journal Nature that when deadly malignant melanoma cells were transplanted into mice, not just a handful but as many as one-quarter of the cells could trigger new tumors. If these were cancer stem cells, they were too abundant to fit with the theory. If they weren't, the results meant that a large population of regular melanoma cells was tumorigenic – also not a good fit with the theory.
"Our data suggest that it's not going to be possible to cure melanoma by targeting a small sub-population of cells," Morrison said.
Morrison's results are a "shot across the bow" of cancer stem cell theory, "or maybe even a direct hit," says Kaelin at Dana-Farber. "It means that cancer stem cell researchers better go back and see what they have been measuring."
Morrison, in fact, echoed Kaelin's criticism, saying that current tests for identifying cancer stem cells are badly flawed and seriously underestimate the proportion of tumor-generating cells. "I think the cancer stem cell model will, in the end, hold up for some cancers," Morrison wrote. "But other cancers, like melanoma, probably won't follow a cancer stem cell model at all. The field will have to be reassessed after more time is spent to optimize the methods used to detect cancer stem cells."
Findings like these complicate the simple stem cell model, and are more in line with the view of researchers like Polyak, who emphasize how many different populations of cancer cells with distinct traits are in a tumor. "As soon as tumors grow, the heterogeneity increases," she says, "especially in solid tumors, where different compartments within the same tumor have different environments and selection pressures."
Even enthusiasts like Wicha admit that hopes are dimming for any single weapon that could cure a cancer by knocking out its stem cells. "As [Polyak] says, there may be different clones of stem cells, and you'll have to use combination therapies to hit different molecular pathways," Wicha reflects.
"The question is whether these cells are rare or not so rare, but it stands to reason that the creation of a self-renewing state is part of what cancer is," says Ronald DePinho, MD, head of Dana-Farber's Center for Advanced Cancer Science.
Stiles agrees. "What we're going to see is that cancer is pretty clever and there is more than one way to create a malignant cell," he concludes. "For example, one tumor could be the result of mutation that gives a normal stem cell cancer-causing powers, while the cause of another tumor might be a cancer cell that has mutated so that it has stem cell-like capabilities."
These uncertainties may seem daunting, but "I think it's better to understand the complexity than to ignore it," says Polyak. "Our approach is to determine how we can better understand the diversity within tumors – and how we can use this knowledge to develop better treatments."
Spring/Summer 2009 Table of Contents
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