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

Abstract

BackgroundA 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+.Methods/FindingsWe 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.Conclusions/SignificanceThe 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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“…Similarly, CXCR6 expression identifies a discrete subpopulation of human melanoma cells with a highly aggressive stem cell phenotype (24). However, contrasting conclusions also existed.…”

Osmotic stress affects functional properties of human melanoma cell lines

“…Human IGR39 and IGR37 cells were obtained from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH and cultured as previously described [27]. IGR39 was derived from a primary amelanotic cutaneous tumour and IGR37 from an inguinal lymph node metastasis in the same patient.…”

Noninvasive near-infrared fluorescent protein-based imaging of tumor progression and metastases in deep organs and intraosseous tissues

“…For this purpose, we used melanoma cells IGR37, originating from a metastatic spread of the primary human melanoma cells IGR39. 21 As shown in Fig. 3(A), injection of iRFPexpressing IGR37 cells in the tail vein resulted in a tumor deposit in the liver [see m1 series and after dissection of the animal Fig.…”