Stem Cells: The Real Culprits in Cancer? [Preview]

A dark side of stem cells--their potential to turn malignant--is at the root of a handful of cancers and may be the cause of many more. Eliminating the disease could depend on tracking down and destroying these elusive killer cells
Closing In

THE IMPLICATIONS of a stem cell model of cancer for the way we understand as well as treat malignancies are clear and dramatic. Current therapies take aim against all tumor cells, but our studies and others have shown that only a minor fraction of cancer cells have the ability to reconstitute and perpetuate the malignancy. If traditional therapies shrink a tumor but miss these cells, the cancer is likely to return. Shideng Bao, Jeremy N. Rich and their colleagues at Duke University showed that this was indeed the case for glioblastoma, where the stem cells were resistant to radiation. Treatments that specifically target the cancer stem cells could destroy the engine driving the disease, leaving any remaining nontumorigenic cells to eventually die off on their own.

Circumstantial evidence supporting this approach already exists in medical practice. Following chemotherapy for testicular cancer, for example, a patient's tumor is examined to assess the effects of treatment. If the tumor contains only mature cells, the cancer usually does not recur and no further treatment is necessary. But if a large number of immature-looking—that is, not fully differentiated—cells are present in the tumor sample, the cancer is likely to return, and standard protocol calls for further chemotherapy. Whether those immature cells are recent offspring that indicate the presence of cancer stem cells remains to be proved, but their association with the disease prognosis is compelling.

Stem cells cannot be identified based solely on their appearance, however, so developing a better understanding of the unique properties of cancer stem cells will first require improved techniques for isolating and studying these rare cells. Once we learn their distinguishing characteristics, we can use that information to target cancer stem cells with tailored treatments. If scientists were to discover the mutation or environmental cue responsible for conferring the ability to self-renew on a particular type of cancer stem cell, for instance, that would be an obvious target for disabling those tumorigenic cells.

Encouraging examples of this strategy's promise have been demonstrated by Craig T. Jordan and Monica L. Guzman of the University of Rochester. In 2002 they identified unique molecular features of malignant stem cells believed to cause acute myeloid leukemia (AML) and showed that the cancer stem cells could be preferentially targeted by specific drugs. In 2005 they reported their discovery that a compound derived from the feverfew plant induces AML stem cells to commit suicide while leaving normal stem cells unaffected.

Some research groups are hoping to train immune cells or antibodies to recognize and go after cancer stem cells. Tobias Schatton, Markus H. Frank and their co-workers at Children's Hospital Boston showed that an antibody could inhibit the growth of melanoma stem cells. Yet another idea under investigation is that drugs could be developed to force cancer stem cells to differentiate, which should take away their ability to self-renew.

Most important is that cancer investigators are now on the suspects' trail. With a combination of approaches, aimed at both targeting genetic pathways unique to the maintenance of cancer stem cells and disrupting the cross talk between tumor cells and their environment, we hope to be able soon to find and arrest the real culprits in cancer.

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