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

ABSTRACT 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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    ABSTRACT: Malignant melanoma is an aggressive form of skin cancer whose incidence continues to increase worldwide. Increased exposure to sun, ultraviolet radiation, and the use of tanning beds can increase the risk of melanoma. Early detection of melanomas is the key to successful treatment mainly through surgical excision of the primary tumor lesion. But in advanced stage melanomas, once the disease has spread beyond the primary site to distant organs, the tumors are difficult to treat and quickly develop resistance to most available forms of therapy. The advent of molecular and cellular techniques has led to a better characterization of tumor cells revealing the presence of heterogeneous melanoma subpopulations. The discovery of gene mutations and alterations of cell-signaling pathways in melanomas has led to the development of new targeted drugs that show dramatic response rates in patients. Single-agent therapies generally target one subpopulation of tumor cells while leaving others unharmed. The surviving subpopulations will have the ability to repopulate the original tumors that can continue to progress. Thus, a rational approach to target multiple subpopulations of tumor cells with a combination of drugs instead of single-agent therapy will be necessary for long-lasting inhibition of melanoma lesions. In this context, the recent development of immune checkpoint reagents provides an additional armor that can be used in combination with targeted drugs to expand the presence of melanoma reactive T cells in circulation to prevent tumor recurrence.
    Advances in pharmacology (San Diego, Calif.) 09/2012; 65:335-59. DOI:10.1016/B978-0-12-397927-8.00011-7
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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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    ABSTRACT: We investigated the properties of clonally-expanded mouse hair follicle stem cells (HF-SCs) in culture. The expansion method, suppression of asymmetric cell kinetics (SACK), is non-toxic and reversible, allowing evaluation of the cells' asymmetric production of differentiating progeny cells. A tight association was discovered between non-random sister chromatid segregation, a unique property of distributed stem cells (DSCs), like HF-SCs, and a recently described biomarker, Lgr5. We found that nuclear Lgr5 expression was limited to the HF-SC sister of asymmetric self-renewal divisions that retained non-randomly co-segregated chromosomes, which contain the oldest cellular DNA strands, called immortal DNA strands. This pattern-specific Lgr5 association poses a potential highly specific new biomarker for delineation of DSCs. The expanded HF-SCs also maintained the ability to make differentiated hair follicle cells spontaneously, as well as under conditions that induced cell differentiation. In future human cell studies, this capability would improve skin grafts and hair replacement therapies.
    Scientific Reports 11/2011; 1:176. DOI:10.1038/srep00176 · 5.58 Impact Factor
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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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    ABSTRACT: Most cancers contain a small sub-population of cells that are endowed with self-renewal, multipotency, and a unique potential for tumor initiation. These properties are considered hallmarks of cancer stem cells. Here, we provide an overview of the field of cancer stem cells with a focus on head and neck cancers. Cancer stem cells are located in the invasive fronts of head and neck squamous cell carcinomas (HNSCC) close to blood vessels (perivascular niche). Endothelial cell-initiated signaling events are critical for the survival and self-renewal of these stem cells. Markers such as aldehyde dehydrogenase (ALDH), CD133, and CD44 have been successfully used to identify highly tumorigenic cancer stem cells in HNSCC. This review briefly describes the orosphere assay, a method for in vitro culture of undifferentiated head and neck cancer stem cells under low attachment conditions. Notably, recent evidence suggests that cancer stem cells are exquisitely resistant to conventional therapy and are the "drivers" of local recurrence and metastatic spread. The emerging understanding of the role of cancer stem cells in the pathobiology of head and neck squamous cell carcinomas might have a profound impact on the treatment paradigms for this malignancy.
    Journal of dental research 09/2011; 91(4):334-40. DOI:10.1177/0022034511423393 · 4.14 Impact Factor
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