Stem Cell Reviews and Reports

, Volume 5, Issue 1, pp 66–71 | Cite as

Enrichment of Cancer Stem Cells Based on Heterogeneity of Invasiveness



Cancer stem cells (CSCs) have multiple potentials in carcinogenesis and tumor progression. However, it is rather difficult to enrich and amplify CSCs either from tumor cell lines or even primary tumor tissues. Therefore, establishing new methodologies for isolation and enrichment based on the functional properties of CSCs is of great importance for studies on CSCs. According to the findings that CSCs possess more infiltrative capability as compared with their differentiated descendants, we propose a novel strategy based on heterogeneity of cancer cell invasiveness for isolation and enrichment of CSCs from committed cancer cell population. In addition, we hypothesize that existence of CSCs might be the real root of tumor invasion and metastasis.


Cancer stem cell Invasiveness Isolation Migration Extracellular matrix 



This study was supported by grants from the National Basic Research Program of China (973 Program, No.2006CB708503) and the National Natural Science Foundation of China (No. 30725035, 30700863).


  1. 1.
    Reya, T., Morrison, S. J., Clarke, M. F., & Weissman, I. L. (2001). Stem cells, cancer, and cancer stem cells. Nature, 414, 105–111. doi: 10.1038/35102167.PubMedCrossRefGoogle Scholar
  2. 2.
    Polyak, K., & Hahn, W. C. (2006). Roots and stems: stem cells in cancer. Natural Medicines, 12, 296–300. doi: 10.1038/nm1379.CrossRefGoogle Scholar
  3. 3.
    Bao, S., Wu, Q., McLendon, R. E., et al. (2006). Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature, 444, 756–760. doi: 10.1038/nature05236.PubMedCrossRefGoogle Scholar
  4. 4.
    Liu, G., Yuan, X., Zeng, Z., et al. (2006). Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Molecular Cancer, 5, 67. doi: 10.1186/1476-4598-5-67.PubMedCrossRefGoogle Scholar
  5. 5.
    Eramo, A., Lotti, F., Sette, G., et al. (2008). Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death & Differentiation, 15, 504–514. doi: 10.1038/sj.cdd.4402283.CrossRefGoogle Scholar
  6. 6.
    Van, S. A., Van der Pol, M. A., Kok, A., et al. (2003). Differences between the CD34+ and CD34 blast compartments in apoptosis resistance in acute myeloid leukemia. Haematologica, 88, 497–508.Google Scholar
  7. 7.
    Sheridan, C., Kishimoto, H., Fuchs, R. K., et al. (2006). CD44+/CD24 breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis. Breast Cancer Research, 8, R59. doi: 10.1186/bcr1610.PubMedCrossRefGoogle Scholar
  8. 8.
    Bonnet, D., & Dick, J. E. (1997). Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Medicine, 3, 730–737. doi: 10.1038/nm0797-730.PubMedCrossRefGoogle Scholar
  9. 9.
    Tirino, V., Desiderio, V., d, , ’Aquino, R., et al. (2008). Detection and characterization of CD133+ cancer stem cells in human solid tumours. PLoS One, 3, e3469. doi: 10.1371/journal.pone.0003469.PubMedCrossRefGoogle Scholar
  10. 10.
    Baba, T., Convery, P. A., Matsumura, N., et al. (2008). Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells. Oncogene. doi: 10.1038/onc.2008.374.
  11. 11.
    Beier, D., Hau, P., Proescholdt, M., et al. (2007). CD133(+) and CD133(−) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Research, 67, 4010–4015. doi: 10.1158/0008-5472.CAN-06-4180.PubMedCrossRefGoogle Scholar
  12. 12.
    Ogden, A. T., Waziri, A. E., Lochhead, R. A., et al. (2008). Identification of A2B5+CD133 tumor-initiating cells in adult human gliomas. Neurosurgery, 62, 505–514. doi: 10.1227/01.neu.0000316019.28421.95.PubMedCrossRefGoogle Scholar
  13. 13.
    Shmelkov, S. V., Butler, J. M., Hooper, A. T., et al. (2008). CD133 expression is not restricted to stem cells, and both CD133+ and CD133 metastatic colon cancer cells initiate tumors. The Journal of Clinical Investigation, 118, 2111–2120.PubMedGoogle Scholar
  14. 14.
    Zheng, X., Shen, G., Yang, X., & Liu, W. (2007). Most C6 cells are cancer stem cells: evidence from clonal and population analyses. Cancer Research, 67, 3691–3697. doi: 10.1158/0008-5472.CAN-06-3912.PubMedCrossRefGoogle Scholar
  15. 15.
    Ho, M. M., Ng, A. V., Lam, S., & Hung, J. Y. (2007). Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Research, 67, 4827–4233. doi: 10.1158/0008-5472.CAN-06-3557.PubMedCrossRefGoogle Scholar
  16. 16.
    Wang, J., Guo, L. P., & Chen, L. Z. (2007). Identification of cancer stem cell-like side population cells in human nasopharyngeal carcinoma cell line. Cancer Research, 67, 3716–3724. doi: 10.1158/0008-5472.CAN-06-4343.PubMedCrossRefGoogle Scholar
  17. 17.
    Kondo, T., Setoguchi, T., & Taga, T. (2004). Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proceedings of the National Academy of Sciences of the United States of America, 101, 781–786. doi: 10.1073/pnas.0307618100.PubMedCrossRefGoogle Scholar
  18. 18.
    Patrawala, L., Calhoun, T., Schneider-Broussard, R., Zhou, J., Claypool, K., & Tang, D. G. (2005). Side population is enriched in tumorigenic, stem-Like cancer cells, whereas ABCG2+ and ABCG2 cancer cells are similarly tumorigenic. Cancer Research, 65, 6207–6219. doi: 10.1158/0008-5472.CAN-05-0592.PubMedCrossRefGoogle Scholar
  19. 19.
    Hirschmann Jax, C., Foster, A. E., Wulf, G. G., et al. (2004). A distinct “side population” of cells with high drug efflux capacity in human tumor cells. Proceedings of the National Academy of Sciences of the United States of America, 101, 14228–14233. doi: 10.1073/pnas.0400067101.PubMedCrossRefGoogle Scholar
  20. 20.
    Hadnagy, A., Gaboury, L., Beaulieu, R., & Balicki, D. (2006). SP analysis may be used to identify cancer stem cell populations. Experimental Cell Research, 312, 3701–3710. doi: 10.1016/j.yexcr.2006.08.030.PubMedCrossRefGoogle Scholar
  21. 21.
    Goodell, M. A., Brose, K., Paradis, G., Conner, A. S., & Mulligan, R. C. (1996). Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. The Journal of Experimental Medicine, 183, 1797–1806. doi: 10.1084/jem.183.4.1797.PubMedCrossRefGoogle Scholar
  22. 22.
    Burkert, J., Otto, W. R., & Wright, N. A. (2008). Side populations of gastrointestinal cancers are not enriched in stem cells. The Journal of Pathology, 214, 564–573. doi: 10.1002/path.2307.PubMedCrossRefGoogle Scholar
  23. 23.
    Yuan, X., Curtin, J., Xiong, Y., et al. (2004). Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene, 23, 9392–9400. doi: 10.1038/sj.onc.1208311.PubMedCrossRefGoogle Scholar
  24. 24.
    Salmaggi, A., Boiardi, A., Gelati, M., et al. (2006). Glioblastoma-derived tumorospheres identify a population of tumor stem-like cells with angiogenic potential and enhanced multidrug resistance phenotype. Glia, 54, 850–860. doi: 10.1002/glia.20414.PubMedCrossRefGoogle Scholar
  25. 25.
    Reynolds, B. A., & Weiss, S. (1996). Clonal and population analyses demonstrate that an EGF-responsive mammalian embryonic CNS precursor is a stem cell. Developments of Biological, 175, 1–13. doi: 10.1006/dbio.1996.0090.CrossRefGoogle Scholar
  26. 26.
    Yu, F., Yao, H., Zhu, P., et al. (2007). let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell, 131, 1109–1123. doi: 10.1016/j.cell.2007.10.054.PubMedCrossRefGoogle Scholar
  27. 27.
    Li, H. Z., Yi, T. B., & Wu, Z. Y. (2008). Suspension culture combined with chemotherapeutic agents for sorting of breast cancer stem cells. BioMed Central Cancer, 8, 135. doi: 10.1186/1471-2407-8-135.PubMedGoogle Scholar
  28. 28.
    Dean, M., Fojo, T., & Bates, S. (2005). Tumour stem cells and drug resistance. Nature Reviews Cancer, 5, 275–284. doi: 10.1038/nrc1590.PubMedCrossRefGoogle Scholar
  29. 29.
    Eramo, A., Ricci-Vitiani, L., Zeuner, A., et al. (2006). Chemotherapy resistance of glioblastoma stem cells. Cell Death & Differentiation, 13, 1238–1241. doi: 10.1038/sj.cdd.4401872.CrossRefGoogle Scholar
  30. 30.
    Ghods, A. J., Irvin, D., Liu, G., et al. (2007). Spheres isolated from 9L gliosarcoma rat cell line possess chemoresistant and aggressive cancer stem-like cells. Stem Cells, 25, 1645–1653. doi: 10.1634/stemcells.2006-0624.PubMedCrossRefGoogle Scholar
  31. 31.
    Pellegatta, S., Poliani, P. L., Corno, D., et al. (2006). Neurospheres enriched in cancer stem-like cells are highly effective in eliciting a dendritic cell-mediated immune response against malignant gliomas. Cancer Research, 66, 10247–10252. doi: 10.1158/0008-5472.CAN-06-2048.PubMedCrossRefGoogle Scholar
  32. 32.
    Rak, J. (2006). Is cancer stem cell a cell, or a multicellular unit capable of inducing angiogenesis? Medical Hypotheses, 66, 601–604. doi: 10.1016/j.mehy.2005.09.004.PubMedCrossRefGoogle Scholar
  33. 33.
    Shen, R., Ye, Y., Chen, L., Yan, Q., Barsky, S. H., & Gao, J. X. (2008). Precancerous stem cells can serve as tumor vasculogenic progenitors. PLoS One, 3, e1652. doi: 10.1371/journal.pone.0001652.PubMedCrossRefGoogle Scholar
  34. 34.
    Locke, M., Heywood, M., Fawell, S., & Mackenzie, I. C. (2005). Retention of intrinsic stem cell hierarchies in carcinoma-derived cell lines. Cancer Research, 65, 8944–8950. doi: 10.1158/0008-5472.CAN-05-0931.PubMedCrossRefGoogle Scholar
  35. 35.
    Yu, S. C., Ping, Y. F., Yi, L., et al. (2008). Isolation and characterization of cancer stem cells from a human glioblastoma cell line U87. Cancer Letters, 265, 124–134. doi: 10.1016/j.canlet.2008.02.010.PubMedCrossRefGoogle Scholar
  36. 36.
    Lee, J., Kotliarova, S., Kotliarov, Y., et al. (2006). Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell, 9, 391–403. doi: 10.1016/j.ccr.2006.03.030.PubMedCrossRefGoogle Scholar
  37. 37.
    Brabletz, T., Jung, A., Spaderna, S., Hlubek, F., & Kirchner, T. (2005). Opinion: migrating cancer stem cells—an integrated concept of malignant tumour progression. Nature Review Cancer, 5, 744–749. doi: 10.1038/nrc1694.CrossRefGoogle Scholar
  38. 38.
    Li, F., Tiede, B., Massagué, J., & Kang, Y. (2007). Beyond tumorigenesis: cancer stem cells in metastasis. Cell Research, 17, 3–14. doi: 10.1038/ Scholar

Copyright information

© Springer Science + Business Media 2008

Authors and Affiliations

  1. 1.Institute of Pathology and Southwest Cancer Center, Southwest HospitalThird Military Medical UniversityChongqingP. R. China

Personalised recommendations