Researchers in Japan have developed an experimental blood test that may help identify patients with colorectal cancer who have an aggressive form of the disease and could benefit from additional therapy after surgery.
The test screens the blood for tumor cells that have three molecular markers, including a marker for the protein CD133. This marker is found on some cells that have the properties of stem cells, such as the ability to self renew. Without CD133, the test results were not informative, suggesting to the researchers the importance of this cancer stem cell marker.
Patients whose cells had detectable messenger RNA (mRNA) for the three markers had worse disease-free survival and overall survival than patients whose blood tested negative for these markers. Further work is needed before the test could be used in the clinic, noted the researchers, led by Dr. Hisae Iinuma of the Teikyo University School of Medicine in Tokyo.
The findings appeared online in the Journal of Clinical Oncology on March 21.
“This is really the first study to show that detecting circulating cancer stem cells in blood has a direct clinical correlation,” said Dr. Max Wicha, director of the University of Michigan Comprehensive Cancer Center, who co-authored an editorial about the results.
According to the cancer stem cell hypothesis, tumors include a small fraction of cells that have the ability to self-renew and to give rise to the diverse types of cells within a tumor. Known as tumor-initiating cells or cancer stem cells, these hardy cells may drive the spread of the disease and also resist conventional treatments.
“The message of this study is that cancer stem cells may be important not only because they drive the tumor,” said Dr. Wicha, “but also because we may actually have a way to measure them in blood. And this could help us to assess the efficacy of drugs in our clinical trials.”
The more immediate applications could be to help doctors identify patients at risk of a recurrence of colorectal cancer. Additional (adjuvant) treatments are available following surgery. But new tools are needed to identify patients who may benefit from these treatments, as well as patients with a lower likelihood of relapse who could be spared the toxic effects and costs of the therapy.
For the current study, the researchers created a polymerase chain reaction (PCR)-based test to detect mRNAs for CD133 and two other markers—cytokeratin and carcinoembryonic antigens—in tumor cells circulating in the blood of patients with colorectal cancer.
The test was initially evaluated using archived specimens from 420 patients and, then, in another 315 patients who enrolled in a prospective validation study.
In the editorial, Dr. Wicha and his colleague Dr. Daniel F. Hayes cited the “the rigorous technical and clinical efforts the authors have applied to this prospectively performed study of circulating tumor cells (CTCs).”
A technology for capturing and counting CTCs, called CellSearch, has been cleared by the FDA for use as a prognostic tool in patients with metastatic breast, prostate, and colorectal cancers. CTC counts above certain thresholds (three or more per sample in colorectal cancer) are associated with a poor prognosis and may be an indication that the disease is progressing.
The CellSearch technology detects CTCs using antibodies against the proteins EpCAM (epithelial cell adhesion molecule) and cytokeratin. But these epithelial markers may not be expressed on many cancer stem cells and other tumor cells that undergo a transformation that allows them to escape into the bloodstream and navigate to other parts of the body.
This suggests that the general CTC markers “[might not be] able to detect the most aggressive cells in the circulation,” the study authors wrote. A limitation of the test evaluated in the current study is that it cannot capture single cells, they noted. Still, the technology has the potential to detect some tumor-initiating cells that may be EpCAM-negative.
“The problem with [the CellSearch] test is that it may miss a lot of the cancer stem cells that may be so important in the disease,” said Dr. Wicha. His group is trying to develop tests that could detect multiple markers associated with stem cells on a single cell. Future clinical trials at the University of Michigan will include a component to assess circulating cancer stem cells, Dr. Wicha said.
“The findings really point to our need to develop the technology to find the right cells with the right markers,” he added. “These are still early days.”
—Edward R. Winstead
Biography - Edward Winstead
Edward “Ted” Winstead has written about genes and genomes for more than a decade. He joined the NCI Cancer Bulletin in 2005 after being a reporter for the Genome News Network, where he was introduced to many of the genomic tools now used to study cancer. A graduate of the master’s program in science writing at Johns Hopkins University, Ted stays up to date on the latest developments in cancer research and genomics with help from the scientists and writers he follows on Twitter. You can follow his tweets from @NCIBulletin and @EdwardWinstead.
Biography - Edward Winstead - National Cancer Institute
Further Reading: Putting Circulating Tumor Cells to the Test: NCI Cancer Bulletin for December 15, 2009 - National Cancer Institute
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NCI Cancer Bulletin for March 22, 2011 - National Cancer Institute
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