Identification of cells initiating human melanomas

Abstract

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

Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells

“…[5][6][7][8][9] As shown in Figure 1b, all cell lines generated tumorospheres, and flow cytometry analyses showed that CD44 þ CD24 À population was highly enriched in tumorospheres (Supplementary Figure S1A). We sorted CD44 þ CD24 À cells from spheres of prostate and breast cancer using fluorescence-activated cell sorting (FACS) and achieved a purity of 495% as judged by postsorting flow analysis (Figure 1c).…”

“…Collectively, our data suggest that both CSCs and spheres exhibited diverse stem cell-associated characteristics, consistent with previous reports. [5][6][7][8][9] CSCs overexpressed BAD with elevated phosphorylation. As CSCs are resistant to drugs 11 and phosphorylated BAD correlates with drug resistance in cancer patients, 25 we determined the level of BAD expression and phosphorylation in CSCs and tumorospheres.…”

“…1,2 Subsequently, CSCs have been identified in several cancers. [3][4][5][6][7][8][9][10] Accumulating evidence suggests that current cancer therapies can only shrink tumors as they target and kill the differentiated cancer (DC) cells, but are unable to target the rare CSC population. 11,12 Thus, despite a wealth of information on DC cells, the active survival and self-renewal pathways in CSCs have not been characterized thoroughly.…”

Three Roots of Melanoma

“…To this end, stem cell research has opened up new and intriguing horizons that may enable better understanding of development of cancer in general and melanoma in particular. [6][7][8][9] Stem cells are slowly proliferating self-renewing cells that are able to differentiate into cell types of multiple lineages (ie, multipotent stem cells) or of one lineage (ie, unipotent stem cells). Researchers have identified stem cells of melanocytic lineage in the human hair follicle, the epidermis, and recently also in the dermis.…”

Towards novel paradigms for cancer therapy

“…When acute myeloid leukemia patients are re-examined after chemotherapy, the persistence of CD34 þ CD38 À cells (proposed to be LICs) predicts a high risk of relapse (van Rhenen et al, 2005). Similarly, the presence of stemness markers within the tumor cells of melanoma and breast cancer patients (ABCB5 þ and CD44 þ , respectively) correlates with a higher rate of cancer progression and poor prognosis (Shipitsin et al, 2007;Schatton et al, 2008). As highlighted above, the eradication of LICs in APL upon treatment with retinoic acid and arsenic supports the concept that agents targeting TICs will lead to complete cure.…”