Cancer Stem Cells in Human Tumors

Recently, the cancer stem cell (CSC) theory has had a meteoric rise in popularity, partly as this theory offers a potential explanation for the relapse and resistance that occurs in many tumors after therapy. The theory states that tumors are heterogeneous and that the growth of the tumor is driven by a discrete subpopulation of cells. Currently a CSC is defined as a tumorigenic cell that has the ability to recapitulate a heterogeneous tumor upon transplantation, and also has the ‘stem cell-specific’ property of self-renewal. This definition resembles that of normal stem cells, and distinguishes CSCs from tumor-initiating cells (T-ICs) and tumor cell of origin (see Figure 1).

Drosophila melanogaster

Figure 1. Emergence of a CSC and distinction from normal stem cells (NSC), cancer cell of origin and T-ICs. (Adapted from [1])

CLINICAL SIGNIFICANCE

The CSC model has clinical implications, in that CSC's have been shown to contribute to resistance to chemo/radiotherapeutics, predominantly through increased ABC transporters to efflux toxic drugs, enhanced levels of DNA repair activity and slow cell cycle kinetics. Determining if a disease follows the CSC model will dictate whether a minority of cells, the bulk of the tumor, or both need to be targeted.


FUNCTIONAL CHARACTERIZATION OF CSC

At present, the gold standard assay to demonstrate the existence of a CSC in human tumours involves using fluorescence-activated cell sorting to isolate phenotypically distinct subsets of tumor cells and then demonstrating that tumor formation upon transplantation into immune-deficient recipient mice is restricted to a subset of cells. This approach has worked well in haematological malignancies (CD34+CD38-[2] ), however the data in solid tumors is the subject of much debate. To date, CSCs have been shown to exist in at least nine human solid tumor types using this methodology. These are: Brain (CD133+[3, 4] ); Breast (EpCAM+CD44+CD24-/low[5]); Colon (CD133+[6, 7] , EpCAMhiCD44+[8] ); Ovary (CD44+CD117+[9]); Head and Neck (CD44+[10]); Pancreas (EpCAM+CD44+CD24+[11] , CD133+[12]); Liver (CD90+[13] ); Lung (EpCAM+CD133+[14] ); Melanoma (ABCB5+[15] , CD271+[16,17] ). However, recent evidence [18] argues against the existence of CSC hierarchy in melanoma.


IMPORTANT UNRESOLVED ISSUES IN CSC BIOLOGY

  • It is not known if there are patient-to-patient and temporal differences in whether or not a tumor will follow a CSC model.
  • It will be important to define the intra- and inter-tumoral heterogeneity of CSCs with regards to therapeutic strategies.
  • It will become important to formally demonstrate in a primary human or mouse solid tumor the existence of CSCs in situ.


Author Credits:

Dr Alasdair Russell
Dr Amel Saadi and Dr Mona Shehata
Department of Oncology
Cancer Research UK Cambridge Research Institute

References

  1. Visvader, J.E., Cells of origin in cancer. Nature, 2011. 469(7330): p. 314-22. [PMID: 21248838]
  2. Bonnet, D. and J.E. Dick, Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med, 1997. 3(7): p. 730-7. [PMID: 21248838]
  3. Singh, S.K., et al., Identification of a cancer stem cell in human brain tumors. Cancer Res, 2003. 63(18): p. 5821-8. [PMID: 14522905]
  4. Bao, S., et al., Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res, 2006. 66(16): p. 7843-8. [PMID: 16912155]
  5. Al-Hajj, M., et al., Prospective identification of tumorigenic breast cancer cells. ProcNatlAcadSci U S A, 2003. 100(7): p. 3983-8. [PMID: 12629218]
  6. O'Brien, C.A., et al., A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature, 2007. 445(7123): p. 106-10. [PMID: 17122772]
  7. Ricci-Vitiani, L., et al., Identification and expansion of human colon-cancer-initiating cells. Nature, 2007. 445(7123): p. 111-5. [PMID: 17122771]
  8. Dalerba, P., et al., Phenotypic characterization of human colorectal cancer stem cells. ProcNatlAcadSci U S A, 2007. 104(24): p. 10158-63. [PMID: 17548814]
  9. Zhang, S., et al., Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res, 2008. 68(11): p. 4311-20. [PMID: 18519691]
  10. Prince, M.E., et al., Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. ProcNatlAcadSci U S A, 2007. 104(3): p. 973-8. [PMID: 17210912]
  11. Li, C., et al., Identification of pancreatic cancer stem cells. Cancer Res, 2007. 67(3): p. 1030-7. [PMID:    17283135]
  12. Hermann, P.C., et al., Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell, 2007. 1(3): p. 313-23. [PMID: 18371365]
  13. Yang, Z.F., et al., Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell, 2008. 13(2): p. 153-66. [PMID: 18242515]
  14. Eramo, A., et al., Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ, 2008. 15(3): p. 504-14. [PMID: 18049477]
  15. Schatton, T., et al., Identification of cells initiating human melanomas. Nature, 2008. 451(7176): p. 345-9. [PMID: 18202660]
  16. Boiko, A.D., et al., Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271. Nature, 2010. 466(7302): p. 133-7. [PMID: 20596026]
  17. Civenni, G., et al., Human CD271-positive melanoma stem cells associated with metastasis establish tumor heterogeneity and long-term growth. Cancer Res, 2011. 71(8): p. 3098-109. [PMID: 21393506]
  18. Quintana E, et al., Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized.Cancer Cell. 2010 Nov 16;18(5):p.510-23. [PMID:21075313]