There is a growing consensus amongst cancer biologists that not all cancer cells are equal. There is a hierarchy of cells inside a tumor, and only a few cells, called cancer stem cells, are capable of generating new tumors. Such tumor-initiating cells have been identified in many cancers, including those of the colon, brain, and breast. These cells are also thought to play an important role in chemotherapy resistance and cancer recurrence.
Previously, researchers had connected the presence of cancer stem cells with breast-cancer patient outcomes. Now the Harvard team has demonstrated a second important connection between cancer stem cells and clinical impacts, linking the presence of such cells with the speed at which the disease progresses in humans.
"We've defined for the first time a direct link between cancer stem cells and cancer progression," says Markus Frank (pictured), an assistant professor at Harvard Medical School, who led the melanoma research.
This research grew out of Frank's study of a protein made by some melanomas that confers resistance to chemotherapy. Frank and his colleagues at Harvard Medical School and Brigham and Women's Hospital in Boston report that human melanoma cells that make this protein can be characterized as cancer stem cells because they generate tumors when implanted in mice. Examining melanoma biopsies, they found that tumors expressing this protein were more aggressive.
Frank's group also demonstrated that an antibody specifically targeting the melanoma stem-cell protein slowed tumor growth in mice. Many other researchers are working on therapies that attack cancer stem cells, but Frank believes that his group is the first to develop such an antibody.
"Most current therapies target the bulk cells of the tumor," he says. "Resistant stem cells are left behind," allowing the tumor to come back after therapy seems to be progressing. Frank and other researchers hope that therapies that specifically target cancer stem cells can completely eradicate tumors.
Robert Weinberg, a founding member of the Whitehead Institute for Biomedical Research, in Cambridge, MA, and director of the Ludwig Center for Molecular Oncology at MIT, agrees that the Harvard work adds to the growing evidence of cancer stem cells' importance. "We don't really understand how tumors renew themselves, or how to treat many tumors," he says. Some researchers remain unconvinced, Weinberg says, but he and many others think that cancer stem cells may hold the answers to these questions. Cancer stem cells are "going to be very important," he predicts. Slowly but surely, he believes, the evidence is building.
Frank says that much remains to be learned about the newly identified melanoma stem cells. It's not clear, for example, whether the protein that the Harvard researchers have been focusing on causes the cells to act as cancer stem cells, or whether this protein is simply a marker for these cells. Further studies of their gene-expression patterns will tell the researchers more about what makes them different from normal melanoma cells. In the meantime, the Harvard researchers will continue to develop their antibody in hopes of taking it to human trials.
Illustration: Dana-Farber/Harvard Cancer Center.
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Abstract (Nature 451, 345-349, 17 January 2008)