CXCR6, a Newly Defined Biomarker of Tissue-Specific Stem Cell Asymmetric Self-Renewal, Identifies More Aggressive Human Melanoma Cancer Stem Cells

Programs in Regenerative Biology and Cancer Biology, Adult Stem Cell Technology Center, Boston Biomedical Research Institute, Watertown, Massachusetts, United States of America.
PLoS ONE (Impact Factor: 3.23). 12/2010; 5(12):e15183. DOI: 10.1371/journal.pone.0015183
Source: PubMed


A fundamental problem in cancer research is identifying the cell type that is capable of sustaining neoplastic growth and its origin from normal tissue cells. Recent investigations of a variety of tumor types have shown that phenotypically identifiable and isolable subfractions of cells possess the tumor-forming ability. In the present paper, using two lineage-related human melanoma cell lines, primary melanoma line IGR39 and its metastatic derivative line IGR37, two main observations are reported. The first one is the first phenotypic evidence to support the origin of melanoma cancer stem cells (CSCs) from mutated tissue-specific stem cells; and the second one is the identification of a more aggressive subpopulation of CSCs in melanoma that are CXCR6+.
We defined CXCR6 as a new biomarker for tissue-specific stem cell asymmetric self-renewal. Thus, the relationship between melanoma formation and ABCG2 and CXCR6 expression was investigated. Consistent with their non-metastatic character, unsorted IGR39 cells formed significantly smaller tumors than unsorted IGR37 cells. In addition, ABCG2+ cells produced tumors that had a 2-fold greater mass than tumors produced by unsorted cells or ABCG2- cells. CXCR6+ cells produced more aggressive tumors. CXCR6 identifies a more discrete subpopulation of cultured human melanoma cells with a more aggressive MCSC phenotype than cells selected on the basis of the ABCG2+ phenotype alone.
The association of a more aggressive tumor phenotype with asymmetric self-renewal phenotype reveals a previously unrecognized aspect of tumor cell physiology. Namely, the retention of some tissue-specific stem cell attributes, like the ability to asymmetrically self-renew, impacts the natural history of human tumor development. Knowledge of this new aspect of tumor development and progression may provide new targets for cancer prevention and treatment.

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    • "Using immunodeficient SCID mice, the authors showed that ABCB5+ cells were more tumorigenic than ABCB5 negative melanoma cells. The CD133+ melanoma subpopulation that is chemoresistant is known to co-expresses ABCG2 (Monzani, et al., 2007; Taghizadeh, et al., 2011). Given the selective expression of ABCG2 in a minor subpopulation of CD133+ cells, its expression in melanoma tissue sections has not yet been confirmed. "
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    • "Therefore, in culture, asymmetric self-renewal can be defined by cell divisions in which continued cycling by the stem cell sister is denoted by nuclear cyclin A expression, and the arrest of non-stem cell sisters is noted by a lack of nuclear cyclin A expression (e.g., Fig. 1f, CyA)1121. Symmetric self-renewal divisions are defined by sister cells that both show nuclear cyclin A expression1121 (e.g., Fig. 1j, CyA). "
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    • "CD271+ cells sorted from melanomas generated more tumors than the CD271-cells, supporting the cancer stem cell hypothesis (Civenni et al., 2011). In another independent study, CXCR6+ cells created more aggressive tumors than CXCR6-cells in melanoma models (Taghizadeh et al., 2010). This suggests the existence of primitive melanoma cells capable of phenotypic plasticity, self-renewal, and immune evasion (Girouard and Murphy, 2011). "
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