(Ivanhoe Newswire) " For the first time it is hypothesized that some cancers spring from and are replenished by a small dense population of self-renewing stem cells, therefore leukemia patients whose cancers express higher levels of genes associated with cancer stem cell have significantly poorer prognosis than patients with lower levels of the gene.
"The clinical implications of this concept are huge," acting assistant professor of oncology Ash Alizadeh, MD, was quoted as saying. "If we're not able to design therapies to target this self-renewing population of chemotherapy-resistant cells, the patients will continue to have a tendency to relapse." And yet, although much laboratory evidence exists to support the idea, clinical evidence to support the cancer stem cell hypothesis has until now been sparse.
Senior researcher and first author Andrew Gentles, PhD, along with gentles co-senior author, teamed up with assistant professor of hematology Ravindra Majeti, MD, PhD and co-senior author, and associate professor of radiology Sylvia Plevritis, PhD, to conduct a retrospective analysis of more than 1,000 patients with acute myeloid leukemia who were treated at centers in the Netherlands, Germany, Japan, and the U.S.
The cancer stem cell hypothesis- which posits that some cancers spring from and are replenished by a small, hardy population of self-renewing cells- has gained increasing credibility as researchers from around the world have identified subpopulations of cells in a variety of solid and blood cancers that resist treatment and contribute to relapse in animal models. Many believe that terminating these stem cells could be a complete cure. However, studies in animals are still several steps removed from proving the idea's worth in humans.
"What's been lacking is clinical evidence that these observations in mice impact actual outcomes in human patients independently of existing prognostic factors," Majeti was quoted as saying. "We wanted to know, 'Do genes associated with leukemia stem cells confer a bad prognosis for a patient?'"
In this study, the researchers were interested in learning whether leukemia stem cells play a similarly important role in acute myeloid leukemia, which is one of the most aggressive blood cancers in adults."We've made very little progress in the treatment of AML over the past 40 years," Alizadeh was quoted as saying. "We're still using the same drugs and therapies we've always used, even though about 70 percent of patients with AML die within five years of diagnosis."
The team used two cell surface markers formerly shown to identify leukemia stem cells to isolate these cells from tumor samples from seven patients. They then compared the overall gene expression patterns of the stem cells to other cells in the tumors and identified a total of 52 genes whose expression varies between the tumor stem cells and non-stem cells.
The gene expression pattern is similar to that found on normal blood stem cells, which give rise to blood cells and the immune system. This similarity implies that the cancer stem cells not only can self-renew, but also that they, like normal stem cells, don't divide unless they're needed. Infrequent division may be one way the cancer stem cells escape many conventional treatments that target rapidly dividing cells."It's as if these cells are lurking in the background, waiting to pounce after chemotherapy has wiped out most of the other cells," said Alizadeh.
When the researchers compared the levels of expression of these new leukemia stem-cell-associated genes among tumor samples from four groups with a total of more than 1,000 people with acute myeloid leukemia, they found a strong correlation between high levels of expression and a poor outcome for the patients. In one group from Germany, patients with high levels of gene expression had an absolute risk of death within three years of 78 percent, versus 57 percent for patients with lower levels of expression. High-expressing patients fared similarly poorly in comparisons of "event-free survival," or likelihood of relapse within a certain time period, and in how strongly their disease resisted initial rounds of treatment.
"The stronger the leukemia stem cell signal, the worse the patients did," Gentles, who is a member of the Stanford Center for Cancer Systems Biology, was quoted as saying. "Their lives were shorter, they relapsed sooner and they were less able to respond to therapy." The center was established with a $12 million grant from the National Institutes of Health to stimulate the application of computer modeling to cancer research. Plevritis is the director of the center and a co-author of the research.
Plevritis and Gentles plan to study the gene expression pattern in the leukemia stem cells to identify important regulatory pathways that might be driving the cellular hierarchy in the cancer. The researchers are also working to develop ways to make their findings more useful in the clinic.
Finally, the team will continue to study the data to determine which treatments are most effective for patients with the high-expressing gene signature. "We'd like to know whether a group of patients with a high leukemic stem cell burden would respond well to certain types of therapy," said Gentles, "and which should be avoided. For example, bone marrow transplant can sometimes be an effective way to treat AML. But transplant itself carries significant risks for the patient. If it is not likely to help someone with high levels of expression of these genes, then we can try other approaches."
SOURCE: Journal of the American Medical Association, published online December 22, 2010
Source: Ivanhoe Newswire
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