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CXCR6, a newly defined biomarker of tissue-specific stem cell asymmetric self-renewal, identifies more aggressive human melanoma cancer stem cells.

Taghizadeh R, Noh M, Huh YH, Ciusani E, Sigalotti L, Maio M, Arosio B, Nicotra MR, Natali P, Sherley JL, La Porta CA - PLoS ONE (2010)

Bottom Line: 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.We defined CXCR6 as a new biomarker for tissue-specific stem cell asymmetric self-renewal.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.

View Article: PubMed Central - PubMed

Affiliation: Programs in Regenerative Biology and Cancer Biology, Adult Stem Cell Technology Center, Boston Biomedical Research Institute, Watertown, Massachusetts, United States of America.

ABSTRACT

Background: 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+.

Methods/findings: 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.

Conclusions/significance: 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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Related in: MedlinePlus

Flow cytometry detection of CXCR6+/ABCG2+ subpopulations from human melanoma biopsy.Flow cytometry analysis of a human melanoma biopsy specimen for a CXCR6+/ABCG2+ subfraction. A metastatic melanoma biopsy specimen was processed as described in Material and Methods and immediately analyzed by flow cytometry. Left panel, bivariate fluorescence intensity analyses with respective APC- and FITC-conjugated isotype (IgG) control antibodies. Right panel, bivariate fluorescence intensity analyses with respective APC- and FITC-conjugated CXCR6-specific and ABCG2-specific antibodies. Numbers, percent of total evaluated cells.
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pone-0015183-g009: Flow cytometry detection of CXCR6+/ABCG2+ subpopulations from human melanoma biopsy.Flow cytometry analysis of a human melanoma biopsy specimen for a CXCR6+/ABCG2+ subfraction. A metastatic melanoma biopsy specimen was processed as described in Material and Methods and immediately analyzed by flow cytometry. Left panel, bivariate fluorescence intensity analyses with respective APC- and FITC-conjugated isotype (IgG) control antibodies. Right panel, bivariate fluorescence intensity analyses with respective APC- and FITC-conjugated CXCR6-specific and ABCG2-specific antibodies. Numbers, percent of total evaluated cells.

Mentions: Although the evaluated melanoma cell lines were derived from human tumor tissues, the newly described CXCR6+/ABCG2+ cell phenotype might have been limited to cultured tumor cells. Therefore, we investigated 4 uncultured human melanoma positive lymph node biopsy specimens for the presence of cells with the CXCR6+/ABCG2+ phenotype. All the four biopsy speciments contained a small subpopulation of cells ABCG2+ (12,2%, 8,4%, 2,65%, >0,1%). One of these three also contained a small population CXCR6+ (0.25%) and a small population double positive ABCG2+/CXCR6+ (0,3%). Fig. 9 shows the results of the flow cytometry analysis of the CXCR6+/ABCG2+ positive specimens.


CXCR6, a newly defined biomarker of tissue-specific stem cell asymmetric self-renewal, identifies more aggressive human melanoma cancer stem cells.

Taghizadeh R, Noh M, Huh YH, Ciusani E, Sigalotti L, Maio M, Arosio B, Nicotra MR, Natali P, Sherley JL, La Porta CA - PLoS ONE (2010)

Flow cytometry detection of CXCR6+/ABCG2+ subpopulations from human melanoma biopsy.Flow cytometry analysis of a human melanoma biopsy specimen for a CXCR6+/ABCG2+ subfraction. A metastatic melanoma biopsy specimen was processed as described in Material and Methods and immediately analyzed by flow cytometry. Left panel, bivariate fluorescence intensity analyses with respective APC- and FITC-conjugated isotype (IgG) control antibodies. Right panel, bivariate fluorescence intensity analyses with respective APC- and FITC-conjugated CXCR6-specific and ABCG2-specific antibodies. Numbers, percent of total evaluated cells.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3008677&req=5

pone-0015183-g009: Flow cytometry detection of CXCR6+/ABCG2+ subpopulations from human melanoma biopsy.Flow cytometry analysis of a human melanoma biopsy specimen for a CXCR6+/ABCG2+ subfraction. A metastatic melanoma biopsy specimen was processed as described in Material and Methods and immediately analyzed by flow cytometry. Left panel, bivariate fluorescence intensity analyses with respective APC- and FITC-conjugated isotype (IgG) control antibodies. Right panel, bivariate fluorescence intensity analyses with respective APC- and FITC-conjugated CXCR6-specific and ABCG2-specific antibodies. Numbers, percent of total evaluated cells.
Mentions: Although the evaluated melanoma cell lines were derived from human tumor tissues, the newly described CXCR6+/ABCG2+ cell phenotype might have been limited to cultured tumor cells. Therefore, we investigated 4 uncultured human melanoma positive lymph node biopsy specimens for the presence of cells with the CXCR6+/ABCG2+ phenotype. All the four biopsy speciments contained a small subpopulation of cells ABCG2+ (12,2%, 8,4%, 2,65%, >0,1%). One of these three also contained a small population CXCR6+ (0.25%) and a small population double positive ABCG2+/CXCR6+ (0,3%). Fig. 9 shows the results of the flow cytometry analysis of the CXCR6+/ABCG2+ positive specimens.

Bottom Line: 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.We defined CXCR6 as a new biomarker for tissue-specific stem cell asymmetric self-renewal.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.

View Article: PubMed Central - PubMed

Affiliation: Programs in Regenerative Biology and Cancer Biology, Adult Stem Cell Technology Center, Boston Biomedical Research Institute, Watertown, Massachusetts, United States of America.

ABSTRACT

Background: 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+.

Methods/findings: 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.

Conclusions/significance: 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.

Show MeSH
Related in: MedlinePlus