ABSTRACT Cancer develops from normal tissues through the accumulation of genetic alterations that act in concert to confer malignant phenotypes. Although we have now identified some of the

genes that when mutated initiate tumor formation and drive cancer progression, the identity of the cell population(s) susceptible to such transforming events remains undefined for the

majority of human cancers. Recent work indicates that a small population of cells endowed with unique self-renewal properties and tumorigenic potential is present in some, and perhaps all,

tumors. Although our understanding of the biology of these putative cancer stem cells remains rudimentary, the existence of such cells has implications for current conceptualizations of

SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about

institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS CANCERS MAKE THEIR OWN LUCK: THEORIES OF CANCER ORIGINS Article 24 July 2023

TUMOR INITIATION AND EARLY TUMORIGENESIS: MOLECULAR MECHANISMS AND INTERVENTIONAL TARGETS Article Open access 19 June 2024 BREAST CANCER AS AN EXAMPLE OF TUMOUR HETEROGENEITY AND TUMOUR CELL

PLASTICITY DURING MALIGNANT PROGRESSION Article Open access 06 April 2021 REFERENCES * Al-Hajj, M. & Clarke, M.F. Self-renewal and solid tumor stem cells. _Oncogene_ 23, 7274–7282

(2004). CAS  Google Scholar  * Cohnheim, V. Congenitales, quergestreiftes muskelsarkom der nieren. _Virchows Arch. Pathol. Anat. Physiol. Klin. Med._ 65, 64–69 (1875). Google Scholar  *

Makino, S. Further evidence favoring the concept of the stem cell in ascites tumors of rats. _Ann. NY Acad. Sci._ 63, 818–830 (1956). CAS  Google Scholar  * Bruce, W.R. & Van Der Gaag,

H. A Quantitative assay for the number of murine lymphoma cells capable of proliferation _in vivo_. _Nature_ 199, 79–80 (1963). CAS  Google Scholar  * Kleinsmith, L.J. & Pierce, G.B.,

Jr. Multipotentiality of single embryonal carcinoma cells. _Cancer Res._ 24, 1544–1551 (1964). CAS  Google Scholar  * Park, C.H., Bergsagel, D.E. & McCulloch, E.A. Mouse myeloma tumor

stem cells: a primary cell culture assay. _J. Natl. Cancer Inst._ 46, 411–422 (1971). CAS  Google Scholar  * Bishop, J.M. Viral oncogenes. _Cell_ 42, 23–38 (1985). CAS  Google Scholar  *

Weinberg, R.A. The molecular basis of oncogenes and tumor suppressor genes. _Ann. NY Acad. Sci._ 758, 331–338 (1995). CAS  Google Scholar  * Vogelstein, B. & Kinzler, K.W. Cancer genes

and the pathways they control. _Nat. Med._ 10, 789–799 (2004). CAS  Google Scholar  * Masters, J.R. Human cancer cell lines: fact and fantasy. _Nat. Rev. Mol. Cell Biol._ 1, 233–236 (2000).

CAS  Google Scholar  * Fuchs, E. & Raghavan, S. Getting under the skin of epidermal morphogenesis. _Nat. Rev. Genet._ 3, 199–209 (2002). CAS  Google Scholar  * Smalley, M. &

Ashworth, A. Stem cells and breast cancer: a field in transit. _Nat. Rev. Cancer_ 3, 832–844 (2003). CAS  Google Scholar  * Fuchs, E., Tumbar, T. & Guasch, G. Socializing with the

neighbors: stem cells and their niche. _Cell_ 116, 769–778 (2004). CAS  PubMed Central  Google Scholar  * Woodward, W.A., Chen, M.S., Behbod, F. & Rosen, J.M. On mammary stem cells. _J.

Cell Sci._ 118, 3585–3594 (2005). CAS  Google Scholar  * Miller, S.J., Lavker, R.M. & Sun, T.T. Interpreting epithelial cancer biology in the context of stem cells: Tumor properties and

therapeutic implications. _Biochim. Biophys. Acta_ 1756, 25–52 (2005). CAS  Google Scholar  * Crowe, D.L., Parsa, B. & Sinha, U.K. Relationships between stem cells and cancer stem cells.

_Histol. Histopathol._ 19, 505–509 (2004). CAS  Google Scholar  * Young, H.E. et al. Adult reserve stem cells and their potential for tissue engineering. _Cell Biochem. Biophys._ 40, 1–80

(2004). CAS  Google Scholar  * Beachy, P.A., Karhadkar, S.S. & Berman, D.M. Tissue repair and stem cell renewal in carcinogenesis. _Nature_ 432, 324–331 (2004). CAS  Google Scholar  *

Valk-Lingbeek, M.E., Bruggeman, S.W. & van Lohuizen, M. Stem cells and cancer: the polycomb connection. _Cell_ 118, 409–418 (2004). CAS  Google Scholar  * Tsai, R.Y. A molecular view of

stem cell and cancer cell self-renewal. _Int. J. Biochem. Cell Biol._ 36, 684–694 (2004). CAS  Google Scholar  * Goodell, M.A. Multipotential stem cells and 'side population'

cells. _Cytotherapy_ 4, 507–508 (2002). CAS  Google Scholar  * Lapidot, T. et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. _Nature_ 367, 645–648

(1994). CAS  Google Scholar  * Dontu, G. et al. _In vitro_ propagation and transcriptional profiling of human mammary stem/progenitor cells. _Genes Dev._ 17, 1253–1270 (2003). CAS  PubMed

Central  Google Scholar  * Dontu, G., Al-Hajj, M., Abdallah, W.M., Clarke, M.F. & Wicha, M.S. Stem cells in normal breast development and breast cancer. _Cell Prolif._ 36 Suppl 1, 59–72

(2003). CAS  Google Scholar  * Kim, C.F. et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. _Cell_ 121, 823–835 (2005). CAS  PubMed Central  Google Scholar

  * Al-Hajj, M., Wicha, M.S., Benito-Hernandez, A., Morrison, S.J. & Clarke, M.F. Prospective identification of tumorigenic breast cancer cells. _Proc. Natl. Acad. Sci. USA_ 100,

3983–3988 (2003). CAS  Google Scholar  * Setoguchi, T., Taga, T. & Kondo, T. Cancer stem cells persist in many cancer cell lines. _Cell Cycle_ 3, 414–415 (2004). CAS  Google Scholar  *

Kondo, T., Setoguchi, T. & Taga, T. Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. _Proc. Natl. Acad. Sci. USA_ 101, 781–786 (2004). CAS 

Google Scholar  * Singh, S.K. et al. Identification of a cancer stem cell in human brain tumors. _Cancer Res._ 63, 5821–5828 (2003). CAS  Google Scholar  * Hirschmann-Jax, C. et al. A

distinct “side population” of cells with high drug efflux capacity in human tumor cells. _Proc. Natl. Acad. Sci. USA_ 101, 14228–14233 (2004). CAS  Google Scholar  * Locke, M., Heywood, M.,

Fawell, S. & Mackenzie, I.C. Retention of intrinsic stem cell hierarchies in carcinoma-derived cell lines. _Cancer Res._ 65, 8944–8950 (2005). CAS  Google Scholar  * Patrawala, L. et al.

Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2- cancer cells are similarly tumorigenic. _Cancer Res._ 65, 6207–6219 (2005). CAS  Google Scholar

  * Passegue, E., Jamieson, C.H., Ailles, L.E. & Weissman, I.L. Normal and leukemic hematopoiesis: are leukemias a stem cell disorder or a reacquisition of stem cell characteristics?

_Proc. Natl. Acad. Sci. USA_ 100 Suppl 1, 11842–11849 (2003). CAS  Google Scholar  * Spradling, A., Drummond-Barbosa, D. & Kai, T. Stem cells find their niche. _Nature_ 414, 98–104

(2001). CAS  Google Scholar  * Tumbar, T. et al. Defining the epithelial stem cell niche in skin. _Science_ 303, 359–363 (2004). CAS  PubMed Central  Google Scholar  * Brabletz, T., Jung,

A., Spaderna, S., Hlubek, F. & Kirchner, T. Opinion: migrating cancer stem cells - an integrated concept of malignant tumour progression. _Nat. Rev. Cancer_ 5, 744–749 (2005). CAS 

Google Scholar  * Pardal, R., Clarke, M.F. & Morrison, S.J. Applying the principles of stem-cell biology to cancer. _Nat. Rev. Cancer_ 3, 895–902 (2003). CAS  Google Scholar  *

Vitale-Cross, L., Amornphimoltham, P., Fisher, G., Molinolo, A.A. & Gutkind, J.S. Conditional expression of K-ras in an epithelial compartment that includes the stem cells is sufficient

to promote squamous cell carcinogenesis. _Cancer Res._ 64, 8804–8807 (2004). CAS  Google Scholar  * Caussinus, E. & Gonzalez, C. Induction of tumor growth by altered stem-cell asymmetric

division in _Drosophila melanogaster_. _Nat Genet_ (2005). * Lininger, R.A., Fujii, H., Man, Y.G., Gabrielson, E. & Tavassoli, F.A. Comparison of loss heterozygosity in primary and

recurrent ductal carcinoma _in situ_ of the breast. _Mod. Pathol._ 11, 1151–1159 (1998). CAS  Google Scholar  * Prindull, G. Hypothesis: cell plasticity, linking embryonal stem cells to

adult stem cell reservoirs and metastatic cancer cells? _Exp. Hematol._ 33, 738–746 (2005). CAS  Google Scholar  * Bates, R.C. & Mercurio, A.M. The epithelial-mesenchymal transition

(EMT) and colorectal cancer progression. _Cancer Biol. Ther._ 4, 365–370 (2005). CAS  Google Scholar  * Kai, T. & Spradling, A. Differentiating germ cells can revert into functional stem

cells in _Drosophila melanogaster_ ovaries. _Nature_ 428, 564–569 (2004). CAS  Google Scholar  * Cozzio, A. et al. Similar MLL-associated leukemias arising from self-renewing stem cells and

short-lived myeloid progenitors. _Genes Dev._ 17, 3029–3035 (2003). CAS  PubMed Central  Google Scholar  * Harley, C.B. et al. Telomerase, cell immortality, and cancer. _Cold Spring Harb.

Symp. Quant. Biol._ 59, 307–315 (1994). CAS  PubMed Central  Google Scholar  * Hahn, W.C. Role of telomeres and telomerase in the pathogenesis of human cancer. _J. Clin. Oncol._ 21,

2034–2043 (2003). CAS  Google Scholar  * Morrison, S.J., Prowse, K.R., Ho, P. & Weissman, I.L. Telomerase activity in hematopoietic cells is associated with self-renewal potential.

_Immunity_ 5, 207–216 (1996). CAS  Google Scholar  * Molofsky, A.V. et al. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. _Nature_ 425, 962–967

(2003). CAS  PubMed Central  Google Scholar  * Sherr, C.J. The ink4a/arf network in tumour suppression. _Nat. Rev. Mol. Cell Biol._ 2, 731–737 (2001). CAS  Google Scholar  * Reya, T. &

Clevers, H. Wnt signalling in stem cells and cancer. _Nature_ 434, 843–850 (2005). CAS  Google Scholar  * Allsopp, R.C., Cheshier, S. & Weissman, I.L. Telomere shortening accompanies

increased cell cycle activity during serial transplantation of hematopoietic stem cells. _J. Exp. Med._ 193, 917–924 (2001). CAS  PubMed Central  Google Scholar  * Flores, I., Cayuela, M.L.

& Blasco, M.A. Effects of telomerase and telomere length on epidermal stem cell behavior. _Science_ 309, 1253–1256 (2005). CAS  Google Scholar  * Sarin, K.Y. et al. Conditional

telomerase induction causes proliferation of hair follicle stem cells. _Nature_ 436, 1048–1052 (2005). CAS  PubMed Central  Google Scholar  * Masutomi, K. et al. The telomerase reverse

transcriptase regulates chromatin state and DNA damage responses. _Proc. Natl. Acad. Sci. USA_ 102, 8222–8227 (2005). CAS  Google Scholar  * Kinzler, K.W. & Vogelstein, B. Lessons from

hereditary colorectal cancer. _Cell_ 87, 159–170 (1996). CAS  PubMed Central  Google Scholar  * Vogelstein, B. et al. Genetic alterations during colorectal-tumor development. _N. Engl. J.

Med._ 319, 525–532 (1988). CAS  Google Scholar  * Al-Hajj, M., Becker, M.W., Wicha, M., Weissman, I. & Clarke, M.F. Therapeutic implications of cancer stem cells. _Curr. Opin. Genet.

Dev._ 14, 43–47 (2004). CAS  Google Scholar  * Brenton, J.D., Carey, L.A., Ahmed, A.A. & Caldas, C. Molecular classification and molecular forecasting of breast cancer: ready for

clinical application? _J. Clin. Oncol._ 23, 7350–7360 (2005). CAS  Google Scholar  * Dean, M., Fojo, T. & Bates, S. Tumour stem cells and drug resistance. _Nat. Rev. Cancer_ 5, 275–284

(2005). CAS  Google Scholar  * Abraham, B.K. et al. Prevalence of CD44+/CD24-/low cells in breast cancer may not be associated with clinical outcome but may favor distant metastasis. _Clin.

Cancer Res._ 11, 1154–1159 (2005). CAS  Google Scholar  * Glinsky, G.V., Berezovska, O. & Glinskii, A.B. Microarray analysis identifies a death-from-cancer signature predicting therapy

failure in patients with multiple types of cancer. _J. Clin. Invest._ 115, 1503–1521 (2005). CAS  PubMed Central  Google Scholar  * Bosl, G.J. & Motzer, R.J. Testicular germ-cell cancer.

_N. Engl. J. Med._ 337, 242–253 (1997). CAS  Google Scholar  * Bhatia, R. et al. Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete

cytogenetic remission following imatinib mesylate treatment. _Blood_ 101, 4701–4707 (2003). CAS  Google Scholar  Download references ACKNOWLEDGEMENTS We apologize to our colleagues whose

work could not be cited due to space limitations. We thank R. Weinberg, C. Kim, K. Cichowski, C. Sawyers, M. Brown and B. Vogelstein for comments and discussion. We recognize support from

the US National Institutes of Health (R01 CA94074, P50 CA89393, K01 94223 and R01 AG23145), the Tisch Family Fund for Research in Solid Tumors, the US Army Medical Research and Material

Command (DAMD17 02 1 0692 and W8IXWH-04-1-0452) and the American Cancer Society (RSG-05-154-01-MGO). The authors are consultants for Novartis Pharmaceuticals, Inc. AUTHOR INFORMATION AUTHORS

AND AFFILIATIONS * Department of Medical Oncology, Dana-Farber Cancer Institute, Kornelia Polyak & William C Hahn * Departments of Medicine, Harvard Medical School and Brigham and

Women's Hospital, Boston, 02115, Massachusetts, USA Kornelia Polyak & William C Hahn * Broad Institute of Harvard and MIT, Cambridge, 02139, Massachusetts, USA William C Hahn

Authors * Kornelia Polyak View author publications You can also search for this author inPubMed Google Scholar * William C Hahn View author publications You can also search for this author

inPubMed Google Scholar ETHICS DECLARATIONS COMPETING INTERESTS Kornelia Polyak and William C. Hahn are consultants for Novartis Pharmaceuticals, Inc. RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Polyak, K., Hahn, W. Roots and stems: stem cells in cancer. _Nat Med_ 12, 296–300 (2006). https://doi.org/10.1038/nm1379 Download citation *

Published: 06 March 2006 * Issue Date: 01 March 2006 * DOI: https://doi.org/10.1038/nm1379 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get

shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative