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May 16, 2014

Cancer Stem Cells Found by Backtracking Mutations in Human Patients

Cancer Stem Cells Found by Backtracking Mutations in Human Patients

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  • A source of controversy for many years, the cancer stem cell concept is looking stronger now that genetic analysis of a particular kind of cancer—myelodysplastic syndrome—has revealed that rare multipotent cancer stem cells not only exist in human patients, they also sit atop a hierarchy of lineage-restricted progenitors. In other words, mutations in myelodysplastic syndrome (MDS) have been found to originate exclusively in a subset of MDS cells, a population of rare and distinct MDS stem cells.

    The cancer stem cell concept suggests that at the root of any cancer there is a small subset of cancer cells that are solely responsible for driving the growth and evolution of a patient’s cancer. These cancer stem cells replenish themselves and produce the other types of cancer cells, as normal stem cells produce other normal tissues.

    The concept is attractive because it provides an explanation for cancer recurrence. That is, cancer stem cells could resist treatment, persist in human tissues, and continue to self-renew. If cancer indeed recurs this way, rather like a weed that grows back after it has been pulled, cancer stem cells would have to be specially targeted. In other words, cancer would have to be attacked at its roots. If cancer stem cells could be eliminated, the remaining cancer cells might wither away.

    Findings in support of the cancer stem cell concept recently emerged from work carried out by scientists at the University of Oxford and the Karolinska Institutet. These scientists, led by Professor Sten Eirik W. Jacobsen at the MRC Molecular Haematology Unit and the Weatherall Institute for Molecular Medicine at the University of Oxford, investigated malignant cells in the bone marrow of patients with myelodysplastic syndrome (MDS) and followed them over time.

    The scientists published the results of their work in Cancer Cell, in an article entitled “Myelodysplastic Syndromes Are Propagated by Rare and Distinct Human Cancer Stem Cells In Vivo.” “All identified somatically acquired genetic lesions were backtracked to distinct MDS-SCs, establishing their distinct MDS-propagating function in vivo,” the authors wrote. “In isolated del(5q)-MDS, acquisition of del(5q) preceded diverse recurrent driver mutations. Sequential analysis in del(5q)-MDS revealed genetic evolution in MDS-SCs and MDS-progenitors prior to leukemic transformation.”

    “This is conclusive evidence for the existence of cancer stem cells in myelodysplastic syndromes,” said first author Petter Woll of the MRC Weatherall Institute for Molecular Medicine at the University of Oxford. “We have identified a subset of cancer cells, shown that these rare cells are invariably the cells in which the cancer originates, and also are the only cancer-propagating cells in the patients. It is a vitally important step because it suggests that if you want to cure patients, you would need to target and remove these cells at the root of the cancer—but that would be sufficient, that would do it.”

    The existence of cancer stem cells has already been reported in a number of human cancers, explained Professor Jacobsen, but previous findings have remained controversial since the lab tests used to establish the identity of cancer stem cells have been shown to be unreliable and, in any case, do not reflect the "real situation" in an intact tumor in a patient.

    “In our studies we avoided the problem of unreliable lab tests by tracking the origin and development of cancer-driving mutations in MDS patients,” noted Professor Jacobsen, who also holds a guest professorship at the Karolinska Institutet.

    “We can’t offer patients today new treatments with this knowledge,” added Dr. Woll. “What it does is give us a target for development of more efficient and cancer stem cell specific therapies to eliminate the cancer.”

    “We need to understand more about what makes these cancer stem cells unique, what makes them different to all the other cancer cells. If we can find biological pathways that are specifically dysregulated in cancer stem cells, we might be able to target them with new drugs.”


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