title: CXCR6, a newly defined biomarker of tissue-specific stem cell asymmetric self-renewal, identifies more aggressive human melanoma cancer stem cells.
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+.
  
  
  RESULTS
  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
  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.
authors.affiliation: Programs in Regenerative Biology and Cancer Biology, Adult Stem Cell Technology Center, Boston Biomedical Research Institute, Watertown, Massachusetts, United States of America.
authors.forename: Rouzbeh
authors.initials: R
authors.lastname: Taghizadeh
authors.forename: Minsoo
authors.initials: M
authors.lastname: Noh
authors.forename: Yang Hoon
authors.initials: YH
authors.lastname: Huh
authors.forename: Emilio
authors.initials: E
authors.lastname: Ciusani
authors.forename: Luca
authors.initials: L
authors.lastname: Sigalotti
authors.forename: Michele
authors.initials: M
authors.lastname: Maio
authors.forename: Beatrice
authors.initials: B
authors.lastname: Arosio
authors.forename: Maria R
authors.initials: MR
authors.lastname: Nicotra
authors.forename: PierGiorgio
authors.initials: P
authors.lastname: Natali
authors.forename: James L
authors.initials: JL
authors.lastname: Sherley
authors.forename: Caterina A M
authors.initials: CA
authors.lastname: La Porta
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D008545:Melanoma / Q000378:metabolism*; D051379:Mice; D008967:Molecular Biology / Q000379:methods; D009154:Mutation; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000166:cytology*; D054387:Receptors, CXCR / Q000378:metabolism*; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine / Q000378:metabolism*; D011991:Receptors, Virus / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D014408:Biomarkers, Tumor; C106330:CXCR6 protein, human; C482906:Cxcr6 protein, mouse; D009363:Neoplasm Proteins; D054387:Receptors, CXCR; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine; D011991:Receptors, Virus