Identification of cells initiating human melanomas

Abstract

Cancer stem cells have been isolated from a number of human tumours. The latest example is a subpopulation of human malignant melanoma initiating cells, identified by their expression of the chemoresistance mediator ABCB5. The size of the ABCB5+ subpopulations correlates with clinical disease progression in patients with melanomas, and preliminary evidence also suggests that these melanoma stem cells can be specifically targeted with antibodies against ABCB5. This offers a potential therapeutic strategy against melanomas, and the study of cells of this type could help answer important questions in cancer biology. The hybrid melanoma cell shown on the cover, depicted as a merged, computer-enhanced fluorescent microscopy image, arose in vivo in a human tumour xenograft through fusion of an ABCB5+ melanoma stem cell with a more differentiated, ABCB5− tumour cell. Nuclei are marked by genetically encoded red (DsRed) and green (EYFP) fluorescent labels, respectively. The isolation of tumour-initiating cells from human melanomas is reported, with preliminary evidence suggesting that these melanoma stem cells can be specifically targeted with antibodies targeted against ABCB5, which offers a potential therapeutic strategy against melanomas. Tumour-initiating cells capable of self-renewal and differentiation, which are responsible for tumour growth, have been identified in human haematological malignancies1,2 and solid cancers3,4,5,6. If such minority populations are associated with tumour progression in human patients, specific targeting of tumour-initiating cells could be a strategy to eradicate cancers currently resistant to systemic therapy. Here we identify a subpopulation enriched for human malignant-melanoma-initiating cells (MMIC) defined by expression of the chemoresistance mediator ABCB5 (refs 7, 8) and show that specific targeting of this tumorigenic minority population inhibits tumour growth. ABCB5+ tumour cells detected in human melanoma patients show a primitive molecular phenotype and correlate with clinical melanoma progression. In serial human-to-mouse xenotransplantation experiments, ABCB5+ melanoma cells possess greater tumorigenic capacity than ABCB5- bulk populations and re-establish clinical tumour heterogeneity. In vivo genetic lineage tracking demonstrates a specific capacity of ABCB5+ subpopulations for self-renewal and differentiation, because ABCB5+ cancer cells generate both ABCB5+ and ABCB5- progeny, whereas ABCB5- tumour populations give rise, at lower rates, exclusively to ABCB5-cells. In an initial proof-of-principle analysis, designed to test the hypothesis that MMIC are also required for growth of established tumours, systemic administration of a monoclonal antibody directed at ABCB5, shown to be capable of inducing antibody-dependent cell-mediated cytotoxicity in ABCB5+ MMIC, exerted tumour-inhibitory effects. Identification of tumour-initiating cells with enhanced abundance in more advanced disease but susceptibility to specific targeting through a defining chemoresistance determinant has important implications for cancer therapy.