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A CANCER STEM CELL:
Might explain why patients relapse // Might hold the key to new therapies // Might yield a unifying theory of the diseases // Or might not exist.

Cancer Stem Cells: The Missing Piece

By Cathryn Delude // Photographs by Jamie Chung // Spring 2011
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Jamie Chung for Proto

During cancer—not just bumping up survival rates or making incremental progress on a few kinds of malignancies, but wrestling the thing itself to the ground and driving a stake through its heart—has proved maddeningly quixotic. At one time or another, surgery, radiation and chemotherapy each seemed to do the trick. Yet even in combination, those often can’t eliminate stray cancer cells that appear endlessly able to seed new tumors, so researchers have come up with ever more ingenious approaches. With immunotherapy the goal is to stimulate the body’s immune response to recognize cancer cells as dangerously foreign. Antiangiogenesis uses drugs to try to shut off a tumor’s blood supply. In targeted therapies, so-called smart drugs are designed to block specific pathways of cancer growth.

All of these approaches have had their successes. Yet patients continue to relapse and die, and now another potentially game-changing—but controversial—cancer theory could explain why. This latest idea runs counter to the prevailing view that any cancer cell in a tumor is as likely as any other to propagate a new tumor. In this alternative model, only a select few cells—cancer stem cells—are able to sustain the disease, and they’re the ones anticancer strategies should target.

But cancer stem cells are a tough lot, says Max Wicha, a cancer biologist at the University of Michigan. They can expel therapeutic agents sent to kill them, and they can repair damage to their DNA caused by drugs, radiation or surgery. Normal adult stem cells rest quietly until they receive signals from wounded, infected or dying cells that rouse them to differentiate into whatever type of tissue cell is needed, and stem cells often migrate to remote locations that need repair. So it’s conceivable that anticancer therapies could inadvertently awaken similar survival and repair mechanisms in cancer stem cells, stimulating them to metastasize.

“If the cancer-stem-cell hypothesis is true, treating the majority of dividing cancer cells will shrink a tumor but won’t cure the cancer unless we can target the cancer stem cells themselves,” says Daniel Haber, who directs the Massachusetts General Hospital Cancer Center. That could explain why tumor shrinkage—the gold standard for measuring a drug’s effectiveness—doesn’t always translate into longer survival for patients.

Scientists spotted the first cancer stem cell in 1994, in a form of leukemia, and during the past decade, reports of cancer stem cells in diverse solid tumors have proliferated, although much of the latest research has yet to be replicated and confirmed. What’s more, the cancer-stem-cell hypothesis—even the idea that such cells exist in most cancers—is far from universally accepted. “There are lots of ideas about which cancers follow the model and which don’t,” says Sean Morrison, a colleague of Wicha’s at the University of Michigan. “Dogmas are being created at a furious rate, with ideas that people find intuitively attractive getting repeated to the point that nobody remembers that they’ve never actually been tested.”

But discovering the truth about cancer stem cells is crucial, Haber says, “because either our current strategy of developing therapies aimed at rapidly shrinking a tumor is wrong or insufficient, or we’ve been on the right path and shouldn’t be distracted. So we’d better know, one, whether cancer stem cells exist, two, how to find them, and three, what their defenses are.”

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1. “Cancer Stem Cells: An Old Idea—a Paradigm Shift,” by Max S. Wicha, Suling Liu and Gabriela Dontu, Cancer Research, Feb. 15, 2006. A clear overview of the mounting evidence that suggests a special subset of resilient cancer cells exists in many tumors.

2. “Phenotypic Heterogeneity Among Tumorigenic Melanoma Cells From Patients That Is Reversible and Not Hierarchically Organized,” by Elsa Quintana et al., Cancer Cell, Nov. 16, 2010. From the research group that in 2008 threw cold water on the cancer-stem-cell model, this study provides more evidence that reputed melanoma stem cells break many of the rules of the model as it was originally understood.

3. “Looking Ahead in Cancer Stem Cell Research,” by John E. Dick, Nature Biotechnology, January 2009. The researcher who provided the first evidence of cancer stem cells in leukemia joins the call for more rigorous experimental methods to better discriminate among cancer cells with varying degrees of self-renewal capabilities.

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