Tumour-initiating cells capable of self-renewal and differentiation, which are responsible for tumour growth, have been identified in human haematological malignancies 1,2 and solid cancers [3][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 malignantmelanoma-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 humanto-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 + sub-populations for selfrenewal 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

SummaryChemotactic factors are postulated to direct emigration of lymphocytes from the blood stream into sites of inflammation. Members of a family ofchemotactic cytokines, termed chemokines, have been shown to attract lymphocytes but efficacy, i.e., the maximal percentage of attracted cells, has been low. We have identified a highly efficacious lymphocyte chemotactic activity in the supernatants of the murine bone marrow stroma cell line MS-5 which attracts 10-fold more lymphocytes in vitro than currently described lymphocyte chemoattractants. Purification of this chemotactic activity revealed identity to stromal cell-derived factor 1 (SDF-1). SDF-1 acts on lymphocytes and monocytes but not neutrophils in vitro and is both a highly efficacious and highly potent mononuclear cell attractant in vivo. In addition, SDF-1 induces intracellular actin polymerization in lymphocytes, a process that is thought to be a prerequisite for cell motility. Since SDF-1 is expressed constitutively in a broad range of tissues it may have a role in immune surveillance and in basal extravasation of lymphocytes and monocytes rather than in inflammation.L Ymphocytes function as the reservoir of immunological memory. In contrast to neutrophils and monocytes, lymphocytes may leave tissues through lymphatics, emigrate from the blood stream into lymphoid and non-lymphoid tissues, and recirculate multiple times during their life history (for review see reference 1). Chemoattractants are postulated to help direct lymphocyte traffic into sites of inflammation and into lymphoid and non-lymphoid tissues during recirculation (1, 2). The best lymphocyte chemoattractants identified to date are members of a family of small, 60 to 80 amino acid chemotactic cytokines termed chemokines. The chemokines can be divided into two subfamilies, the CXC-and the CC-chemokines. The members of each subfamily are more homologous to one another than to members of the other subfamily, and differ in the spacing of the first two cysteines. The two subfamilies differ in their chromosomal localization and cluster on chromosome 4 (CXC-chemokines) and chromosome 17 (CC-chemokines), respectively. While CXC-chemokines, e.g., interleukin 8 (IL-8), act mostly on neutrophils, members of the CC-chemokines, e.g., monocyte chemoattractant protein 1 (MCP-1) 1, regulated on activation normal T cell expressed 1Abbreviations used in this paper: MCP-1, monocyte chemoattractant protein 1; MIP-10t, macrophage inflammatory protein lce; RANTES, regulated on activation normal T cell expressed and secreted; SDF, stromal cellderived factor. and secreted (RANTES), and macrophage inflammatory protein lcl (MIP-lo0, have been shown to exert function on monocytes, eosinophils and lymphocytes (2, 3). However, the efficacy, i.e., the percent of attracted ceils, of lymphocyte chemoattractants described so far is low, whereas chemokines active on monocytes, neutrophils, and eosinophils are highly efficacious (2).The bone marrow not only produces precursor and immature lymphocytes, but also harbors m...

No abstract