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May 2005 -- Stem cells are the body's paramedics, materializing at sites of injury to repair damaged tissue. But the very qualities that make the cells potent sources of healing can also create chaos; their plasticity, for example, makes them the perfect cancer precursor cell.
Frequent division of stem cells—as with any cell—ups the risk that their regulatory paths will go haywire. Because of that, says molecular biologist Phil Beachy, tissues and organs in a perpetual repair mode are particularly vulnerable.
“For a long time we've known that chronic injury is associated with cancer,” Beachy says. “But we really didn't know why.”
Now a decade of research in Beachy's lab on the hedgehog pathway has begun to illuminate molecular mechanisms that could enable active stem cells to go bad. The work defines the role played by hedgehog—a cell-to-cell signaling protein critical for normal development—in the etiology of cancer of the lung, prostate and pancreas. This understanding has revolutionary implications for cancer treatment.
“If it's true that the important cancer cells are activated stem cells and that part of the activated stem cell phenotype is a requirement that certain pathways are constantly active, then it may be possible to impose a blockade,” says pathologist David Berman.
In other words, target only the population of cells in which hedgehog, or some other pathway, is fueling the out-of-control cell growth, using a chemical compound that blocks pathway traffic like an overturned truck at rush hour.
In hedgehog, that blocker is cyclopamine.
Cyclopamine is a natural plant compound; since the 1960s scientists have known that the offspring of pregnant sheep who ingest it at a critical period of development are born with cyclopia—one eye. However, the mechanism by which cyclopamine produces this birth defect was not known until 1996, when Beachy's lab produced a mouse with a hedgehog gene knockout. Their first paper—which described the isolation and characterization of the hedgehog gene in fruit flies—had come out four years earlier.
Beachy's hedgehog work grew out of basic research on the molecular biology of development in Drosophila.
“We had no way of knowing in advance that hedgehog signaling would turn out to be central not only to the development of flies, but also to that of vertebrates and mammals,” says Beachy. “And certainly no way of knowing it would be relevant to cancer.”
But when Beachy's hedgehog knockout mice were born with an extreme form of holopresencephaly—a malformation in which the brain fails to divide—and have resulting cyclopia—he knew he was on to something medically relevant.
“We already knew that cyclopamine causes cyclopia in the offspring of pregnant ewes,” he says. “When we realized that cyclopamine's effect was very similar to the hedgehog knockout—a good phenocopy—that led us to suppose it acted on the hedgehog pathway. And that, in turn, led us to use it as a tool to investigate various normal and abnormal processes, including cancer.”
Assistant Professor David Berman joined Beachy's lab in 1999, “just as hedgehog was becoming implicated in disease, specifically, in a limited set of rare brain tumors and skin cancers,” he says. Like most fellows, he “started a bunch of projects,” but the first to succeed was an investigation of whether blocking the hedgehog pathway in vivo would have any effect. Berman did that—in spontaneous tumors transplanted into mice—and showed that hedgehog pathway activation was not only required for maintenance and growth of tumors, but that the pathway itself seemed to promote a stem cell-like phenotype.
Since then, other researchers have used topical cyclopamine as a pathway antagonist in trials of patients with basal cell carcinoma—with good results. Phase I trials of cyclopamine or related compounds taken systemically to treat small cell lung cancer, prostate cancer and other epithelial cancers are several years away, Beachy says.
Fortunately, recent experiments in his lab do not support the legitimate concern that the drug might permanently suppress stem cell regeneration. Animals treated with pathway blockers for one month—long enough to cause complete regression of their tumors—are subsequently able to continue producing the new cells required to maintain their tissues.
“This suggests that cancer is locked out by pathway blockade,” he says, “but that stem cells may survive and continue to renew themselves after the blockade is lifted.”
– Deborah Rudacille
New View of Cancer: "Epigenetic" Changes Come Before Mutations