The new england journal of medicine n engl j med 355;12 www.nejm.org september 21, 2006 1253 review article Mechanisms of Disease Cancer Stem Cells Craig T. Jordan, Ph.D., Monica L. Guzman, Ph.D., and Mark Noble, Ph.D. From the James P. Wilmot Cancer Center (C.T.J., M.L.G.) and the Department of Biomedical Genetics (M.N.), University of Rochester School of Medicine, Roch- ester, NY. Address reprint requests to Dr. Jordan at the University of Rochester School of Medicine, 601 Elmwood Ave., Box 703, Rochester, NY 14642, or at craig_jordan@urmc.rochester.edu. N Engl J Med 2006;355:1253-61. Copyright © 2006 Massachusetts Medical Society. T he deepening of our understanding of normal biology has made it clear that stem cells have a critical role not only in the generation of com- plex multicellular organisms, but also in the development of tumors. Recent findings support the concept that cells with the properties of stem cells are integral to the development and perpetuation of several forms of human cancer. 1-3 Eradica- tion of the stem-cell compartment of a tumor also may be essential to achieve stable, long-lasting remission, and even a cure, of cancer. 4,5 Advances in our knowledge of the properties of stem cells have made specific targeting and eradication of cancer stem cells a topic of considerable interest. In this article, we discuss the properties of cancer stem cells, outline initial therapeutic strategies against them, and present challenges for the future. Background and Definitions Stem cells occur in many different somatic tissues and are important participants in their physiology (Fig. 1). Populations of cells that derive from stem cells are or- ganized in a hierarchical fashion, with the stem cell residing at the apex of the developmental pathway (Fig. 2). Stem cells have three distinctive properties: self- renewal (i.e., at cell division, one or both daughter cells retain the same biologic properties as the parent cell), the capability to develop into multiple lineages, and the potential to proliferate extensively. The combination of these three properties makes stem cells unique. The attribute of self-renewal is especially notable, because its subversion is highly relevant to oncogenesis and malignancy. 6,7 Aberrantly in- creased self-renewal, in combination with the intrinsic growth potential of stem cells, may account for much of what is considered a malignant phenotype. Many studies performed over the past 30 to 40 years, when viewed collectively, have shown that the characteristics of stem-cell systems, the specific stem-cell properties described above, or both, are relevant to some forms of human can- cer. 3,4,8,9 Biologically distinct and relatively rare populations of “tumor-initiating” cells have been identified in cancers of the hematopoietic system, brain, and breast. 10-13 Cells of this type have the capacity for self-renewal, the potential to develop into any cell in the overall tumor population, and the proliferative ability to drive continued expansion of the population of malignant cells. Accordingly, the properties of tumor-initiating cells closely parallel the three features that de- fine normal stem cells. Malignant cells with these functional properties have been termed “cancer stem cells” (Fig. 2). Given these features, it is possible that cancer stem cells arise by mutation from normal stem cells. However, several lines of evidence indicate that cancer stem cells can also arise from mutated progenitor cells. 14-17 Such progenitors (also known as “transit-amplifying cells”) can possess substantial replicative ability, but they do not usually have the self-renewal capacity of stem cells. To become a cancer stem Downloaded from www.nejm.org on January 21, 2007 . Copyright © 2006 Massachusetts Medical Society. All rights reserved.