Cancer's culprit

The findings imply that cancer cells are moving targets, Polyak argues, which is more in line with the "clonal evolution" model of tumor generation—the long-standing idea that normal cells mutate to become cancerous, and abnormal descendants transform again, creating a mass of competing, genetically-varied cancer cells. Thus, eliminating the so-called CSCs might not be sufficient to halt cancer dead in its tracks, because the remaining cells might be able to fuel tumor growth and develop drug resistance, too.

From stem to stern

Despite the popularity of Polyak's paper, most researchers continue to believe the CSC hypothesis, though they acknowledge it may need some fine-tuning. "This so-called distinction between the two models of carcinogenesis is really a false dichotomy," says Wicha. "It's not all or none—there are parts of both [models] that are really correct."

"There's nothing about the cancer stem cell hypothesis that would preclude cells changing over time within the tumor," says Michael Lewis, a developmental biologist at Baylor College of Medicine in Houston, Texas. Indeed, Dick showed that CSCs in leukemia also mutate during disease progression,3 which can potentially give rise to more aggressive tumorigenic cells. "Cancer stem cells themselves aren't a homogeneous entity and they can evolve," Dick says.

The hierarchical CSC model also generally assumes that the ruling CSCs are vanishingly rare. Yet a recent study casts doubt on this prediction, as well. Last December, Morrison found that the number of tumor-initiating cells in human melanoma was about one in four in severely immune-compromised mice, compared to about one in a million as previously observed in standard assays.4 "Melanoma is not following a cancer stem-cell model, at least not in the way the model has been formulated so far," says Morrison.

Rarity, however, is beside the point, notes Lewis. "The relative frequency of [CSCs] can't be one of the criteria by which you assess if cells are cancer stem cells or not," he says. Instead, one needs to test for a subpopulation—no matter how frequent—that can reform tumors and is resistant to standard cancer treatments, he argues.

Notably, Baylor oncologist Jenny Chang, together with her colleague Jeffrey Rosen, compared breast tumors in patients before and after chemotherapy, and found a three-fold enrichment in cells resembling CSCs following treatment, signifying that tumorigenic cells are, indeed, more resilient.5 "There are different subpopulations of [cancer] cells that we need to target separately," says Chang. These results lend credibility to the CSC hypothesis where it really counts, adds Wicha. "It's a valid model because it actually predicts behavior in the clinic," he says.

Fashioning a model

The root cause of cancer remains fuzzy in part because the methods used to find the cells capable of regenerating tumors are flawed, says William Kaelin, a cancer geneticist at the Dana-Farber Cancer Institute. "I'm definitely worried about the bioassays that we're using," because they involve injecting human cells into immune-compromised mice. In response, several researchers, including Jane Visvader of the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia, are now turning to syngeneic mouse models of human breast and other cancers. "There is no doubt that the xenotransplantation system is far from perfect," Visvader says.

Last year, Visvader, Clarke, and Rosen all independently found evidence of CSCs in various mouse models of breast cancer. These studies "argue pretty strongly that it's a subset of the cells that are responsible for initiating tumor growth," says Lewis. Visvader, however, only found CSC markers in two of the three mouse models she tested.6  "Some, but not all, models of mammary tumorigenesis seem to be driven by cancer stem cell propagation," she notes.

Michail Shipitsin, the Hot Paper's first author, agrees. "Every cancer case is somewhat unique," he says. The CSC hypothesis may be relevant for some tumors, but "at this point it's unclear" if it applies to breast cancer. "There's a lack of data to support one opinion or the other," he says.

"Like all good things in science, I suspect that the rigid version of the cancer stem cell model is going to need some tweaking," says Dick. "It'll be interesting times to see what the data holds."

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