Leukemia stem cells identified by Stanford researchers

August 11, 2004

STANFORD, Calif. -- A handful of leukemia cells constantly replenish the supply of cancerous cells, according to new work by Stanford University School of Medicine researchers. These self-renewing cells, called cancer stem cells, are the ones chemotherapy must wipe out in order to eliminate the disease. Treatments that destroy these cells could more effectively eliminate cancer.

Current treatments destroy cancer cells indiscriminately, draining the reservoir of cancer cells without specifically eliminating the cancer's source. "We were missing the boat because we were targeting the wrong cell," said Catriona Jamieson, MD, PhD, instructor in hematology and first author of the paper.

Other researchers have found cancer stem cells in acute myelogenous leukemia, breast cancer and two types of brain cancer. The current work, published in the Aug. 12 New England Journal of Medicine, is the first to describe these cells in chronic myelogenous leukemia. This is also the first time researchers have identified which cell becomes cancerous, transforming from a normal healthy cell to a cancer stem cell.

Jamieson and her team working with Irving Weissman, MD, the Karel H. and Avice N. Beekjuis Professor in Cancer Biology, and hematology colleagues at Stanford, the University of Toronto and UCLA, found the cells through careful detective work. She separated the cancerous cells into subgroups, each with a characteristic pattern of proteins on their cell surface. She then put each of these populations on a separate lab dish to see which could renew their population. In the end, only one group of cells had the ability to self-renew, constantly dividing to produce both new stem cells and cells that matured.

Jamieson examined these cancer stem cells and found they resembled normal cells in the blood called granulocyte/macrophage progenitor cells. This finding came as a surprise. Researchers had thought that the cancer stem cells came from normal stem cells - such as the blood-forming stem cells in the bone marrow that produce both red blood cells and immune cells. Instead, Jamieson found that the cancer started when a normal adult cell mutated and gained the ability to self-renew.

Another surprise has to do with how chronic myelogenous leukemia develops. Most people with the disease have a mutation in which chromosomes 9 and 22 swap ends. This trade fuses genes coding for two different proteins into a single unit that makes a cancer-causing protein called BCR-ABL. All blood cells in these people carry the swapped chromosome, but only macrophage/granulocyte progenitor cells become cancerous.

Although the cancer stem cells still bore some resemblance to macrophage/granulocyte progenitor cells, they also stood apart. One difference was a protein called beta-catenin, found in abundance in the nucleus of the cancer stem cells. This protein is commonly found in embryonic cells where it keeps them in a dividing state. "What's novel is that you have this gene turned on in a mature cell," Jamieson said. The protein was particularly abundant in people whose cancers were resistant to the chemotherapy drug Gleevec.

Beta-catenin is part of a pathway kicked off by a protein called Wnt (pronounced "wint"), which has only recently been found to play a role in helping stem cells continue dividing. Wnt is normally only active in cells that must continually divide, such as stem cells and embryonic cells. Most adult cells don't make Wnt and can only divide a limited number of times. In collaboration with Roeland Nusse, PhD, professor of developmental biology, and Laurie Ailles, PhD, a postdoctoral scholar in Weissman's lab, the group found that blocking beta-catenin's Wnt-activating role in the cancer stem cells also blocked their ability to self-renew.

Weissman said that proteins activating the Wnt pathway are commonly mutated in several types of cancer. What's more, a strain of mice in which Wnt is inappropriately activated is also susceptible to breast cancer. He said that many proteins in addition to beta-catenin are involved in the Wnt pathway, any one of which might activate the pathway and trigger self-renewal.

One goal of Weissman's lab is to identify cancer stem cells in a broad range of cancer types to learn more about which proteins go awry in these cells. Eventually, he said this work could lead to new drugs that shut down these inappropriately active proteins. "When drugs that inhibit those targets become available, combination therapy might have a chance of really working," Weissman said.
-end-
The project to identify cancer stem cells in solid tumors is partly funded through Stanford's Institute for Cancer/Stem Cell Biology and Medicine, which Weissman directs.

Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at http://mednews.stanford.edu.

Stanford University Medical Center

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