Cancer Chemotherapy and Pharmacology

, Volume 56, Supplement 1, pp 64–68 | Cite as

A self-renewal assay for cancer stem cells



Cancers of epithelial origin are responsible for the majority of cancer-related deaths in the USA. Unfortunately, although chemotherapy and/or radiation therapy can sometimes shrink tumors, metastatic cancers of epithelial origin are essentially incurable. It is clear that new approaches are needed to treat these diseases. Although cancer cell lines provide invaluable information, their biological properties often differ in crucial ways from de novo cancer cells. Our laboratory has developed a novel mouse model that reliably permits individual cancer cells isolated directly from patients’ tumors to be assayed. This will allow the characterization of crucial signaling pathways involved in processes such as self-renewal that are critical for tumor formation by the cancer cells within de novo tumors. These tools should lead to new insights into the cellular and molecular mechanisms that drive human breast cancer growth and invasion.


Stem cells Cancer Self-renewal 


  1. 1.
    Akashi K, Weissman IL (2001) In: Zon LI (ed) Developmental biology of hematopoiesis. Oxford University Press, New YorkGoogle Scholar
  2. 2.
    Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100:3983–3988CrossRefPubMedGoogle Scholar
  3. 3.
    Bafico A, Liu G, Goldin L, Harris V, Aaronson SA (2004) An autocrine mechanism for constitutive Wnt pathway activation in human cancer cells. Cancer Cell 6:497–506CrossRefPubMedGoogle Scholar
  4. 4.
    Bergsagel DE, Valeriote FA (1968) Growth characteristics of a mouse plasma cell tumor. Cancer Res 28:2187–2196PubMedGoogle Scholar
  5. 5.
    Brown JM (1997) NCI’s anticancer drug screening program may not be selecting for clinically active compounds. Oncol Res 9:213–215PubMedGoogle Scholar
  6. 6.
    Bruce WR, Gaag H (1963) A quantitative assay for the number of murine lymphoma cells capable of proliferation in vivo. Nature 199:79–80PubMedCrossRefGoogle Scholar
  7. 7.
    Cadigan KM, Nusse R (1997) Wnt signaling: a common theme in animal development. Genes Dev 11:3286–3305PubMedCrossRefGoogle Scholar
  8. 8.
    Dorrell C, Gan OI, Pereira DS, Hawley RG, Dick JE (2000) Expansion of human cord blood CD34(+)CD38(−) cells in ex vivo culture during retroviral transduction without a corresponding increase in SCID repopulating cell (SRC) frequency: dissociation of SRC phenotype and function. Blood 95:102–110PubMedGoogle Scholar
  9. 9.
    Ethier SP, Mahacek ML, Gullick WJ, Frank TS, Weber BL (1993) Differential isolation of normal luminal mammary epithelial cells and breast cancer cells from primary and metastatic sites using selective media. Cancer Res 53:627–635PubMedGoogle Scholar
  10. 10.
    Furley AJ, Reeves BR, Mizutani S, Altass LJ, Watt SM, Jacob MC, van den Elsen P, Terhorst C, Greaves MF (1986) Divergent molecular phenotypes of KG1 and KG1a myeloid cell lines. Blood 68:1101–1107PubMedGoogle Scholar
  11. 11.
    Gat U, DasGupta R, Degenstein L, Fuchs E (1998) De novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin. Cell 95:605–614CrossRefPubMedGoogle Scholar
  12. 12.
    Hamburger AW, Salmon SE (1977) Primary bioassay of human tumor stem cells. Science 197:461–463PubMedCrossRefGoogle Scholar
  13. 13.
    Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70CrossRefPubMedGoogle Scholar
  14. 14.
    Hedgepeth CM, Deardorff MA, Rankin K, Klein PS (1999) Regulation of glycogen synthase kinase 3beta and downstream Wnt signaling by Axin. Mol Cell Biol 19:7147–7157PubMedGoogle Scholar
  15. 15.
    Hoffman RM (1999) Orthotopic metastatic mouse models for anticancer drug discovery and evaluation: a bridge to the clinic. Invest New Drugs 17:343–359CrossRefPubMedGoogle Scholar
  16. 16.
    Ikeda H, Kanakura Y, Furitsu T, Kitayama H, Sugahara H, Nishiura T, Karasuno T, Tomiyama Y, Yamatodani A, Kanayama Y, Matsuzawa Y (1993) Changes in phenotype and proliferative potential of human acute myeloblastic leukemia cells in culture with stem cell factor. Exp Hematol 21:1686–1694PubMedGoogle Scholar
  17. 17.
    Korinek V, Barker N, Moerer P, van Donselaar E, Huls G, Peters PJ, Clevers H (1998) Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet 19:379–383CrossRefPubMedGoogle Scholar
  18. 18.
    Krasna L, Dudorkinova D, Vedralova J, Vesely P, Pokorna E, Kudlackova I, Chaloupkova A, Petruzelka L, Danes J, Matouskova E (2002) Large expansion of morphologically heterogeneous mammary epithelial cells, including the luminal phenotype, from human breast tumours. Breast Cancer Res Treat 71:219–235CrossRefPubMedGoogle Scholar
  19. 19.
    Lagasse E, Weissman IL (1994) bcl-2 inhibits apoptosis of neutrophils but not their engulfment by macrophages. J Exp Med 179:1047–1052CrossRefPubMedGoogle Scholar
  20. 20.
    Leglise MC, Dent GA, Ayscue LH, Ross DW (1988) Leukemic cell maturation: phenotypic variability and oncogene expression in HL60 cells: a review. Blood Cells 13:319–337PubMedGoogle Scholar
  21. 21.
    Morrison SJ, Qian D, Jerabek L, Thiel BA, Park IK, Ford PS, Kiel MJ, Schork NJ, Weissman IL, Clarke MF (2002) A genetic determinant that specifically regulates the frequency of hematopoietic stem cells. J Immunol 168:635–642PubMedGoogle Scholar
  22. 22.
    Muller-Sieburg CE, Cho RH, Sieburg HB, Kupriyanov S, Riblet R (2000) Genetic control of hematopoietic stem cell frequency in mice is mostly cell autonomous. Blood 95:2446–2448PubMedGoogle Scholar
  23. 23.
    Nusse R, Brown A, Papkoff J, Scambler P, Shackleford G, McMahon A, Moon R, Varmus H (1991) A new nomenclature for int-1 and related genes: the Wnt gene family. Cell 64:231CrossRefPubMedGoogle Scholar
  24. 24.
    Park CH, Bergsagel DE, McCulloch EA (1971) Mouse myeloma tumor stem cells: a primary cell culture assay. J Natl Cancer Inst 46:411–422PubMedGoogle Scholar
  25. 25.
    Phillips RL, Reinhart AJ, Van Zant G (1992) Genetic control of murine hematopoietic stem cell pool sizes and cycling kinetics. Proc Natl Acad Sci USA 89:11607–11611PubMedCrossRefGoogle Scholar
  26. 26.
    Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111CrossRefPubMedGoogle Scholar
  27. 27.
    Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K, Hintz L, Nusse R, Weissman IL (2003) A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 423:409–414CrossRefPubMedGoogle Scholar
  28. 28.
    Schlosshauer PW, Brown SA, Eisinger K, Yan Q, Guglielminetti ER, Parsons R, Ellenson LH, Kitajewski J (2000) APC truncation and increased beta-catenin levels in a human breast cancer cell line. Carcinogenesis 21:1453–1456CrossRefPubMedGoogle Scholar
  29. 29.
    Southam C, Brunschwig A (1961) Quantitative studies of autotransplantation of human cancer. Cancer 14:971–978CrossRefGoogle Scholar
  30. 30.
    Spink KE, Polakis P, Weis WI (2000) Structural basis of the Axin-adenomatous polyposis coli interaction. Embo J 19:2270–2279CrossRefPubMedGoogle Scholar
  31. 31.
    Taipale J, Beachy PA (2001) The hedgehog and Wnt signalling pathways in cancer. Nature 411:349–354CrossRefPubMedGoogle Scholar
  32. 32.
    Tsukamoto AS, Grosschedl R, Guzman RC, Parslow T, Varmus HE (1988) Expression of the int-1 gene in transgenic mice is associated with mammary gland hyperplasia and adenocarcinomas in male and female mice. Cell 55:619–625CrossRefPubMedGoogle Scholar
  33. 33.
    van de Wetering M, Sancho E, Verweij C, de Lau W, Oving I, Hurlstone A, van der Horn K, Batlle E, Coudreuse D, Haramis AP, Tjon-Pon-Fong M, Moerer P, van den Born M, Soete G, Pals S, Eilers M, Medema R, Clevers H (2002) The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111:241–250CrossRefPubMedGoogle Scholar
  34. 34.
    Weidmann E, Brieger J, Karakas T, Maurer U, Pascheberg U, Hoelzer D, Mitrou PS, Bergmann L (1997) Establishment and characterization of a new, factor-independent acute myeloid leukemia line designated Ei501. Leukemia 11:709–713CrossRefPubMedGoogle Scholar
  35. 35.
    Wodinsky I, Swiniarski J, Kensler CJ (1967) Spleen colony studies of leukemia L1210.I. Growth kinetics of lymphocytic L1210 cells in vivo as determined by spleen colony assay. Cancer Chemother Rep 51:415–421Google Scholar
  36. 36.
    Yamashita YM, Jones DL, Fuller MT (2003) Orientation of asymmetric stem cell division by the APC tumor suppressor and centrosome. Science 301:1547–1550CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  1. 1.University of Michigan Medical SchoolAnn ArborUSA

Personalised recommendations