|Source:||Stanford University Medical Center|
Leukemia Stem Cells Identified By Stanford Researchers
STANFORD, Calif. â?? 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.
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.
Editor’s Note: The original news release can be found here.
This story has been adapted from a news release issued by Stanford University Medical Center.
Reported August 12, 2004
Whoâ??s the Boss? Researchers ID Cancer Stem Cells
(Ivanhoe Newswire) — Stanford University in California researchers have identified a key type of cancer cell that appears to lead the way when it comes to the disease.
These â??cancer stem cellsâ? are considered the source of cancerous tumors because they divide and create more cancer cells — both the normal variety and additional cancer stem cells just like themselves.
The finding could help explain why cancer drugs often fail to cure cancer, even though they destroy cancer cells. Study author Catriona Jamieson, M.D., Ph.D., says, â??We were missing the boat because we were targeting the wrong cell.â? She and her colleagues believe treatments that target cancer stem cells could eliminate cancer more effectively than those that only attempt to kill cancer cells across the board.
The discovery was made as researchers searched for key cancer cells in patients with myelogenous leukemia. The laboratory work involved separation of cancer cells into different groups depending on the pattern of proteins found on their surface. Once the cells were differentiated, investigators placed them in lab dishes to see which ones would be capable of reproducing. Only one group of cells fit the bill, and these were dubbed cancer stem cells.
An interesting aspect of the findings is that the cells that turned out to be the leaders — in other words, the cancer stem cells — did not appear to arise from normal stem cells found in the bone marrow as researchers had suspected, but instead from normal blood cells.
The researchers now plan to look for cancer stem cells in different types of cancer and study how they become so deadly. Irving Weissman, M.D., co-author of the study, notes, â??When drugs that inhibit those targets become available, combination therapy might have a chance of really working.â?
This article was reported by Ivanhoe.com, who offers Medical Alerts by e-mail every day of the week. To subscribe, go to: http://www.ivanhoe.com/newsalert/.
SOURCE: The New England Journal of Medicine, 2004;351:657-667
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Cancer Stem Cells Hint at Cure
By Kristen Philipkoski | Also by this reporter Page 1 of 1
02:00 PM Aug. 11, 2004 PT
Researchers have discovered cells that continually replenish leukemia tumors. Killing these infinitely renewing cells could be key to halting the disease.
A genetic mutation causes the leukemia cells to divide out of control and allows tumors to grow, according to research published in the Aug. 12 issue of the New England Journal of Medicine. Previously, no one knew the exact identity of these cells.
Isolating these so-called cancer stem cells paves the way for creation of drugs to target them. Specifically destroying leukemia’s stem cells — the source of the cancer — could eliminate the disease better than treatments that randomly kill cancer cells.
The work provides opportunities for pharmaceutical companies to investigate drugs that could inhibit the development of cancer stem cells, said Irving Weissman, a stem-cell researcher at Stanford who contributed to the study.
The study focused on the stem cells that lead to chronic myelogenous leukemia. In recent years, researchers have discovered several similar stem cells, including those behind acute myeloma leukemia, two brain cancers and breast cancer. Finding cancers’ stem cells is a rapidly growing area of research, Weissman said, and it will be a main focus of the Institute of Cancer and Stem Cell Biology, which he heads at Stanford. The institute was established in December 2002 through an anonymous $12 million donation.
Cancer stem cells make up only a tiny number of the total cancer cells in a leukemia patient, which makes the cells next to impossible to find. In order to grow a larger number of them, the researchers took samples from healthy patients and from patients with chronic myelogenous leukemia. They separated the various types of leukemia cancer cells into separate dishes to find which ones could replenish themselves — an indication that they are likely cancer stem cells. Further tests confirmed they had found the cells they were looking for.
The promise of this line of research can only be realized, Weissman said, by studying adult stem cells as well as embryonic stem cells, which are controversial because an early embryo is destroyed when researchers remove stem cells from it. While in this study volunteers could provide samples, that won’t be the case for all types of disease. An alternative is to take the stem cells from embryos that carry a genetic defect for specific diseases.
“There are whole areas of tissues you can’t get at, but which human embryonic stem cells almost certainly will develop daily,” Weissman said.
Scientists at the Reproductive Genetics Institute, a private clinic in Chicago, are also studying stem cells to discover the origins of disease. They have isolated 12 new stem-cell lines from genetically flawed human embryos, providing stem cells that will specifically develop seven diseases, including two forms of muscular dystrophy, thalassemia, Fanconi anemia, fragile X syndrome, Marfan syndrome and a type of neurofibromatosis. Couples undergoing in vitro fertilization donated the embryos after the clinic performed prenatal genetic screening.
The Chicago clinic funded the research privately. President Bush declared on Aug. 9, 2001, that only research on existing stem-cell lines would qualify for federal funding. He said at the time that 64 stem-cell lines were available. Today, the National Institutes of Health lists 21 lines that are available for federal funding.
Catriona H.M. Jamieson, M.D., Ph.D., Laurie E. Ailles, Ph.D., Scott J. Dylla, Ph.D., Manja Muijtjens, M.S., Carol Jones, B.A., James L. Zehnder, M.D., Jason Gotlib, M.D., Kevin Li, Ph.D., Markus G. Manz, M.D., Armand Keating, M.D., Charles L. Sawyers, M.D., and Irving L. Weissman, M.D.
WEDNESDAY, Aug. 11 (HealthDayNews) — A new discovery on cancer stem cells could eventually lead to better treatment options for people with an often-fatal type of leukemia, scientists say.
At issue is the hard-to-control runaway growth of cancer cells in the blood of people who have chronic myeloid leukemia (CML). A new study suggests that targeting certain cells could stop a cascade of cancerous growth, just like killing a queen bee will devastate a hive by eliminating offspring.
“It opens a second line of investigation that we believe will lead to new therapies, whether they’re pharmaceutical or immune-based,” said study co-author Dr. Irving Weissman, a professor of cancer biology at Stanford University.
CML, one of four major types of the blood cancer known as leukemia, strikes about 4,400 Americans a year and eventually kills half of them. The cancer disrupts white blood cells, a vital part of the immune system, and the cells eventually lose their ability to fight invaders. In the most serious cases, the ineffective cells overwhelm the circulatory system.
While the new drug called Gleevec helps patients in the early, “smoldering” stages of the disease, doctors are still trying to find ways to effectively treat those in the later, deadly stages, Weissman said.
Weissman and his colleagues have been exploring so-called “stem cells” that normally play a routine role in the creation of blood cells. When leukemia strikes, cancerous stem cells help spread the disease.
In the new study, published in the Aug. 12 issue of the New England Journal of Medicine, the researchers describe their discovery of the stem cells, which have been found in a handful of other types of cancer. Among other things, they discovered that the cancerous stem cells are created when normal cells mutate. They’re not, as some had suspected, the product of renegade stem cells.
The next step is to ask drug companies to develop medications that inhibit the genetic process that produces the deadly cancer stem cells, Weissman said. Combined with the use of Gleevec, “then you could think of a one-two punch for treating this disease,” he added.
The findings suggest that “it’s time to start looking for the cancer stem cell in other cancers and leukemias to see if the same kind of information can be obtained and new targets for therapies developed,” he said.
The new research holds promise for future patients with chronic myeloid leukemia, according to Alan Kinniburgh, senior vice president of research at the Leukemia and Lymphoma Society.
“We’ve further defined how to treat leukemia” by learning which cancerous cells are most dangerous, he said.
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