When a tumor disappears during treatment and later recurs, the question is always: Why? One theory to be tested in the coming years blames such recurrences on a small but hardy population of cells inside tumors that can withstand an attack by drugs and then reconstitute a tumor. These cells, known as cancer stem cells, resemble traditional stem cells in their ability to perpetuate themselves while giving rise to different types of cells.

Stem cells in tumors are not the same cells that, early in human development, give rise to all the tissues of the body. But tumors are like other tissues in that they develop according to certain rules. Research on cancer stem cells aims to understand how this process unfolds and the roles of stem cells in that process. At the moment, cancer stem cells appear to be the driving force behind the development of some tumors, but beyond that there are more questions than answers.

"This field is in its infancy right now, and the cells themselves have only recently been described," said Dr. Michael Clarke of the University of Michigan Medical School in Ann Arbor, who led a team that identified cancer stem cells in breast tumors. His laboratory is trying to refine the techniques for isolating stem cells in human tumors so that researchers might one day routinely detect the rare cells in any tumor, if they are present.

The potency of cancer stem cells was illustrated recently in a study led by Dr. Peter Dirks of the University of Toronto. After isolating stem cells in human brain tumors, his team showed that these cells alone were able to initiate new brain tumors when transplanted into mice. The vast majority of brain tumor cells could not "seed" new growth, the researchers reported in the Nov. 18, 2004, issue of Nature.

If current notions about cancer stem cells are correct, then some chemotherapy and cancer drugs may be missing their most important targets, nearly wiping out whole tumors but leaving stem cells intact. Leading stem cell researchers, including Dr. Clarke and Dr. Irving Weissman of the Stanford University School of Medicine in California, believe that in order to cure cancer it is necessary to locate and kill tumor stem cells.

The hypothesis that stem cells may play a role in cancer is an old one, going back decades. But no one had been able to isolate the cells from tumors until 1994, when they were found in patients with acute myeloid leukemia. In recent years, cancer stem cells have been isolated in tumors of the breast and the brain and found in cancer cell lines, sparking new interest among researchers.

"The evidence that there are now identifiable cancer stem cells in solid tumors is, to my mind, revolutionary," commented Dr. Michael Dean of the Laboratory of Genomic Diversity, NCI-Frederick. "The concept of cancer as a stem cell disease could dramatically change our understanding of the disease and lead to new targeted approaches for treatment."

Dr. Dean and his collaborators have begun to investigate the mechanisms of drug resistance in cancer stem cells. The goal is to identify agents, such as the drug cyclopamine, that might prevent cancer stem cells from replicating.

Drs. Clarke and Weismann expect eventually to find cancer stem cells in most of the tumors they examine. The cells isolated to date have certain proteins on their surfaces that can serve as "markers" for tracking the involvement of cancer stem cells throughout a disease.

"Many people years ago thought that stem cells and cancer cells were similar because they self-renewed, but no one could test the role of stem cells in cancer because they had not been isolated," explained Dr. Weissman. "When you finally get to the point of isolating stem cells then you can begin to use markers to look at the stages of disease to see where stem cells are involved."

The origins of cancer stem cells are not clear. One theory holds that cancer stem cells were originally normal stem cells that acquired genetic mutations over time, predisposing themselves to becoming cancerous under certain conditions. Normal stem cells that maintain adult tissues such as bone marrow and skin have long life spans; they could accumulate the necessary mutations over decades.

Another theory says that cancer stem cells are actually adult cells that acquired the ability to self-renew through genetic changes. "There may be evidence for both theories," said Dr. Clarke.

By Edward R. Winstead