Editors' ChoiceCANCER STEM CELLS

Removing the Veil from Cancer Stem Cells

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Science Translational Medicine  04 Jun 2014:
Vol. 6, Issue 239, pp. 239ec98
DOI: 10.1126/scitranslmed.3009416

Integrating the concept that tumors contain a self-renewing, tumorigenic cancer stem cell (CSC) into cancer models has the potential to provide insight into tumor progression and therapeutic resistance. However, the existence of CSCs remains controversial. CSCs have been functionally validated in many tumors on the basis of their ability to selectively engraft into immunocompromised mice, and the first generation of anti-CSC therapies is entering clinical trials. Nevertheless, the presence of CSCs that generate an entire tumor in human patients has yet to be demonstrated. Woll and colleagues used samples from patients with myelodysplastic syndromes (MDSs) to provide evidence for an in vivo cellular hierarchy driven by a self-renewing CSC.

MDSs are clonal disorders, and the authors confirmed that all lineages were present in MDS samples and observed an increase in the stem cell compartment (Lineage/CD34+/CD38/CD90+/CD45RA) compared with non-MDS patient controls. The authors used in vivo transplantation assays in mice to show that only CSCs were capable of engrafting and generating lineage-restricted progenitor cells. On the basis of the rationale that hematopoietic cells are short-lived and that stable mutations would be acquired in self-renewing cells, the authors evaluated driver mutations in MDS patients and found that every key mutation could be tracked back to CSCs. Del(5q) is the most common mutation in MDS, and genetic tracing studies revealed that this mutation preceded other driver mutations and was detected even in low and intermediate-risk MDS patients. The authors validated their genetic lineage analysis by sequencing patients’ blood cells during disease progression and confirmed that driver mutations present in CSCs were not eliminated over time in patients with stable disease or in those that had progressed.

This analysis provides evidence that a population of tumor cells can drive tumor progression, supporting the existence of CSCs. Integrating such analytical approaches in the context of therapy will help the targeting of CSCs reach its full potential.

P. S. Woll et al., Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo. Cancer Cell 10.1016/j.ccr.2014.03.036 (2014). [Abstract]

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