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cancer stem cells

Friday 2 July 2004

The cancer stem-cell model

Like stem cells, cancer cells are able to proliferate indefinitely. There is increasing evidence that the clonal population of neoplastic cells exhibit marked heterogeneity with respect to proliferation and differentiation and cancer cells arise in cells with the characteristics of stem cells. This hypothesis that a subset of cells drives tumorigenesis suggests targeting elimination of stem cell-like population of cancer cells as a new therapeutic strategy.

Most cancers comprise a heterogenous population of cells with marked differences in their proliferative potential as well as the ability to reconstitute the tumor upon transplantation.

Cancer stem cells are a minor population of tumor cells that possess the stem cell property of self-renewal. In addition, dysregulation of stem cell self-renewal is a likely requirement for the development of cancer.

Strategies aimed at efficient targeting of CSCs are becoming important for monitoring the progress of cancer therapy and for evaluating new therapeutic approaches.

A clinically detectable tumor contains a heterogeneous population of cells, which originated from the clonal growth of the progeny of a single cell. Yet, it has been difficult to identify cancer stem cells, that is, the cells within a tumor that have the capacity to initiate and sustain the tumor.

Recently, cancer stem cells (called tumor-initiating cells, or T-IC) were identified in breast tumors and acute myeloid leukemia.7,8 T-ICs constitute less than 2% of the cells in breast tumors and 0.1% to 1% of cells in acute myeloid leukemia.9 To maintain their self-renewing capacity, leukemic T-ICs require the expression of the BMI1 gene, which represses the cell-cycle inhibitors p161NK4a and p14ARF (these inhibitors are discussed later in conjunction with the cell cycle).

There is also strong experimental support for the idea that, in these leukemias, cancer stem cells are the initial targets for transformation. These findings have important implications for cancer treatment aimed at the elimination of proliferating cells.

Apparently, cancer stem cells, similar to their normal counterparts, have a low rate of replication. If this is the case, cancer therapies that may efficiently kill the replicating progeny of cancer stem cells would leave in place the cells capable of generating the tumor.

Under these circumstances, tumors can easily recur after treatment. Whether such cancer stem cells exist in all tumors is not yet clear.

References

- The developing cancer stem-cell model: clinical challenges and opportunities. Vermeulen L, de Sousa e Melo F, Richel DJ, Medema JP. Lancet Oncol. 2012 Feb;13(2):e83-9. doi : 10.1016/S1470-2045(11)70257-1 PMID: 22300863

- Klonisch T, Wiechec E, Hombach-Klonisch S, Ande SR, Wesselborg S, Schulze-Osthoff K, Los M. Cancer stem cell markers in common cancers - therapeutic implications. Trends Mol Med. 2008 Sep 3. PMID: 18775674

- Stingl J, Caldas C. Molecular heterogeneity of breast carcinomas and the cancer stem cell hypothesis. Nat Rev Cancer. 2007 Oct;7(10):791-9. PMID: 17851544

- Gilbertson RJ, Rich JN. Making a tumour’s bed: glioblastoma stem cells and the vascular niche. Nat Rev Cancer. 2007 Oct;7(10):733-6. PMID: 17882276

- Widschwendter M, Fiegl H, Egle D, Mueller-Holzner E, Spizzo G, Marth C, Weisenberger DJ, Campan M, Young J, Jacobs I, Laird PW. Epigenetic stem cell signature in cancer. Nat Genet. 2007 Feb;39(2):157-8. PMID: 17200673

- Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006 Sep 21;355(12):1253-61. PMID: 16990388

- 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. 2005 Sep;5(9):744-9. PMID: 16148886

- Wang JC, Dick JE. Cancer stem cells: lessons from leukemia. Trends Cell Biol. 2005 Sep;15(9):494-501. PMID: 16084092

- Bjerkvig R, Tysnes BB, Aboody KS, Najbauer J, Terzis AJ. Opinion: the origin of the cancer stem cell: current controversies and new insights. Nat Rev Cancer. 2005 Nov;5(11):899-904. PMID: 16327766

- Al-Hajj M, Becker MW, Wicha M, Weissman I, Clarke MF. Therapeutic implications of cancer stem cells. Curr Opin Genet Dev. 2004 Feb;14(1):43-7. PMID: 15108804

- Dick JE: Breast cancer stem cells revealed. Proc Natl Acad Sci U S A 100:3547, 2003.