Michigan Team Singles Out Cancer Stem Cells For Attack

The progression of some cancers, including leukemia, appears to be driven by cancer stem cells - rare cancer cells that have a greater ability to proliferate than other cancer cells and which are therefore the most malignant. To have any hope of curing cancer it is necessary to develop therapies that kill these cancer stem cells. Yet these cells frequently have properties that are similar to normal stem cells in the same tissue, making it difficult to kill cancer stem cells without damaging the normal stem cells.

"This study proves that it is possible to identify differences in the mechanisms that maintain normal stem cells and cancer stem cells, and to therapeutically exploit these differences to kill the cancer stem cells without harming normal stem cells in the same tissue," said Sean J. Morrison PhD, lead author on the study and the Director of U-M's Center for Stem Cell Biology, LSI research associate professor and associate professor of internal medicine in the Medical School. Morrison is also a Howard Hughes Medical Institute investigator.

Three years ago, Morrison was part of a U-M team that made the breakthrough discovery that breast cancer has its own stem cells. These cells appear to be the primary drivers in tumor growth and possibly metastasis and the discovery pointed to a new direction in cancer therapy: Rather than trying to eliminate every last tumor cell, cancer therapies might be more specifically targeted at just the stem cells in cancer.

But telling the bad guys from the good guys - normal adult stem cells that the body relies on to replace cells damaged by injury, disease and old age - is a big problem, because they have so many features in common, Morrison explained.

In a new paper appearing as the advance online publication in Nature for April 5, 2006 (to be published in print in the near future), Morrison's team has found a way to tell stem cell friends from foes, as well as a drug that can make them behave differently.

"In many types of tumors, the gene Pten is missing or turned off," Morrison said. "Because Pten regulates cell proliferation and survival, we studied its role in the maintenance of normal blood-forming stem cells."

Omer Yilmaz, a graduate student in the Morrison laboratory, deleted the Pten gene from adult blood-forming stem cells in mice and found that the loss of Pten led to leukemia, marked by the generation of leukemic stem cells. Transplantation of even a single leukemic stem cell from these Pten -deficient mice into a second mouse caused leukemia, demonstrating the powerful cancer-causing ability of these cells.

In addition to pumping up leukemic stem cell numbers, Pten deletion also caused normal blood-forming stem cells to start dividing, but over time the normal stem cells became depleted in the absence of Pten. Additional experiments by the team established that every blood-forming stem cell needs Pten to maintain itself, in contrast to leukemic stem cells that thrive without Pten.

This finding of a key difference between normal stem cells and cancer stem cells suggested that drugs that target the metabolic pathway in which Pten acts should have opposite effects on normal blood-forming stem cells and leukemic stem cells. To test this, the team treated the mice with rapamycin, a drug that reduces the activity of this metabolic pathway. The drug is used to prevent tissue rejection in transplant patients, and is currently being tested in clinical trials for activity against a variety of cancers.

They found that rapamycin inhibited the creation and maintenance of leukemic stem cells. And even better, it "rescued" the function of normal blood-forming stem cells in these mice, that otherwise crashed without Pten.

Mice that were put on rapamycin immediately after Pten deletion failed to develop leukemia. Mice that already had leukemia were kept alive longer by the drug.

These results suggest that by better understanding the mechanisms that regulate the maintenance of normal stem cells it will be possible to develop new anti-cancer therapies that are more effective and less toxic. This is particularly important issue for leukemia patients that often cannot be cured with current therapies, and for whom existing therapies sometimes have fatal side-effects.

"The ability to strategically target and kill leukemia-initiating stem cells will undoubtedly have a significant impact on our capacity to treat these often fatal diseases more effectively," said Riccardo Valdez, M.D. an assistant professor of pathology at U-M who participated in the study. "At the same time, it would minimize potentially life-threatening side effects caused by conventional drugs."

Morrison is quick to point out that these findings are limited to mice so far, and cannot be immediately extrapolated to human patients. However, the study raises the possibility that rapamycin could be effective in depleting leukemic stem cells for at least certain patients. Clinical trials will be required to test this in human patients.