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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

Tumor xenografts derived from and CXCR6- IGR37 cells.5Ɨ105 CXCR6- sorted cells were injected subcutaneously in five-week-old NOD-SCID mice (3 mice for each experimental condition). CXCR6- cells did not yield tumors.
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pone-0015183-g006: Tumor xenografts derived from and CXCR6- IGR37 cells.5Ɨ105 CXCR6- sorted cells were injected subcutaneously in five-week-old NOD-SCID mice (3 mice for each experimental condition). CXCR6- cells did not yield tumors.

Mentions: IGR37 and IGR39 cell populations exhibited 10.6% and 9.6% frequencies of expression for CXCR6, respectively (Fig. 4). CXCR6+ and CXCR6- subpopulations of IGR37 and IGR39 cells were sorted and injected into NOD-SCID mice (nā€Š=ā€Š3 mice per cohort), as was done for cells sorted on the basis of ABCG2 expression. Surprisingly, as shown in Fig. 5 and Table 2, after only 21 days from the injection of CXCR6+ IGR37 cells, significant tumors appeared that were on average 1.8-fold greater in mass than tumors that arose from unsorted IGR37 cells (p<0.01). Moreover, no tumors were detected from CXCR6- injected cells (Table 2 and Figure 6) after even 2 months. Furthermore, the CXCR6- cells did not show any mass even after 4 months. Similar results were obtained for IGR39 cells. CXCR6+ cells produced tumors with 2.5-fold greater mass compared to unsorted cells; and no mass was detected for the CXCR6- cells (Table 2). As for ABCG2, CXCR6+ cells were also undetectable in tumor xenografts by flow cytometry (data not shown).


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)

Tumor xenografts derived from and CXCR6- IGR37 cells.5Ɨ105 CXCR6- sorted cells were injected subcutaneously in five-week-old NOD-SCID mice (3 mice for each experimental condition). CXCR6- cells did not yield tumors.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0015183-g006: Tumor xenografts derived from and CXCR6- IGR37 cells.5Ɨ105 CXCR6- sorted cells were injected subcutaneously in five-week-old NOD-SCID mice (3 mice for each experimental condition). CXCR6- cells did not yield tumors.
Mentions: IGR37 and IGR39 cell populations exhibited 10.6% and 9.6% frequencies of expression for CXCR6, respectively (Fig. 4). CXCR6+ and CXCR6- subpopulations of IGR37 and IGR39 cells were sorted and injected into NOD-SCID mice (nā€Š=ā€Š3 mice per cohort), as was done for cells sorted on the basis of ABCG2 expression. Surprisingly, as shown in Fig. 5 and Table 2, after only 21 days from the injection of CXCR6+ IGR37 cells, significant tumors appeared that were on average 1.8-fold greater in mass than tumors that arose from unsorted IGR37 cells (p<0.01). Moreover, no tumors were detected from CXCR6- injected cells (Table 2 and Figure 6) after even 2 months. Furthermore, the CXCR6- cells did not show any mass even after 4 months. Similar results were obtained for IGR39 cells. CXCR6+ cells produced tumors with 2.5-fold greater mass compared to unsorted cells; and no mass was detected for the CXCR6- cells (Table 2). As for ABCG2, CXCR6+ cells were also undetectable in tumor xenografts by flow cytometry (data not shown).

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