Selection of Tumorigenic Melanoma Cells Using ALDH

Abstract

Despite increasing knowledge regarding melanoma-initiating cells (MICs), questions persist regarding the number and phenotypic nature of cells with tumor-generating capability. Evidence for a phenotypically distinct human MIC has been found in NOD/SCID (non-obese diabetic/severe combined immunodeficiency) mice. However, a phenotypically distinct human MIC was not found in the NOD/SCIDIl2rg−/− (NSG) mouse model. The demonstration of a distinct population of human melanoma cells responsible for tumorigenesis and tumor cell self-renewal would provide an important target for new melanoma therapies. In this study, we show a 100-fold range in MIC frequency in human melanoma (1 in 18,000 to 1 in 1,851,000 cells) in the NOD/SCID mouse. In this model, human melanoma cells with high aldehyde dehydrogenase (ALDH) activity were enriched 16.8-fold in tumorigenic cells over unfractionated (UNF) cells, such that 1 in 21,000 cells was a MIC. In the NSG mouse, the ALDH expressing cell population was enriched 100-fold in tumorigenic cells over UNF cells, such that one in four cells was a MIC. Xenograft melanomas that developed from ALDH+ cells displayed robust self-renewal, whereas those from ALDH− cells showed minimal self-renewal in vitro. Thus, ALDH+ melanoma cells have enhanced tumorigenicity over ALDH− cells and superior self-renewal ability.

Melanoma stem cells: not rare, but well done

“…75 In another report, a rare subpopulation of melanoma cells identified by high aldehyde dehydrogenase (ALDH) activity displayed enhanced tumorigenicity and capacity for selfrenewal over ALDH-negative cells when serially transplanted into NOD/SCID and IL-2Rg À/À NOD/SCID mice. 76 The existence of a stem cell-like population in melanoma was additionally fortified by a recent study of the effect of the ECM glycoprotein tenascin-C on melanoma progression; these data demonstrated that tenascin-C in the microenvironment encouraged manifestation of a stem cell-like phenotype in melanoma cells that included the expression of ABCB5. 77 Most recently, melanoma cells that expressed the receptor activator of NF-kB (RANK) demonstrated enhanced tumorigenicity compared with RANK-negative melanoma cells in IL-2Rg À/À NOD/SCID mice.…”

Cancer Stem Cells: Formidable Allies of Cancer

“…Subsequent studies have suggested that increased ALDH activity might be a universal marker since it identifies CSCs in liver [42], colon [43], lung [44], melanoma [45], head and neck [46], prostate [47], bladder [48], thyroid [49], glioblastoma [50] and osteosarcoma [51]. The aldefluor assay is used to measure ALDH activity and also allow FACS sorting of ALDH +/high cells.…”

Novel biomarkers and therapeutic targets for optimizing the therapeutic management of melanomas

“…More specifically, highly tumorigenic melanoma stem/progenitor cells have been identified in situ and isolated from primary and secondary melanoma tumors, circulating melanoma cells and established melanoma cell lines [20,21,[50][51][52][53][54][55][56][57][58][59][60][61][62][63][64] . Melanoma stem/progenitor cells may express different stem cell-like markers such as CD133, nestin, aldehyde dehydrogenase (ALDHhigh ), CD166, neural crest nerve growth factor receptor (CD271) and/or ATP-binding cassette (ABC) multidrug resistance transporters such as multidrug resistance-1 encoding P-glycoprotein (P-gp), ABCG2 and ABCB5.…”

“…Melanoma stem/progenitor cells may express different stem cell-like markers such as CD133, nestin, aldehyde dehydrogenase (ALDHhigh ), CD166, neural crest nerve growth factor receptor (CD271) and/or ATP-binding cassette (ABC) multidrug resistance transporters such as multidrug resistance-1 encoding P-glycoprotein (P-gp), ABCG2 and ABCB5. It has been shown that highly tumorigenic melanoma stem/progenitor cells can give arise to the total tumor cell mass in vivo with the phenotypic features resembling to original patient's melanomas and metastasize at distant sites [50][51][52][53][54][55][56][57][58]60,61,[63][64][65] . In this matter, we review the most recent advancements on the gene products that are often altered during melanoma initiation and progression to locally invasive and metastatic disease states and which may be exploited to develop novel multiplex biomarker detection methods for optimizing diagnosis and prognosis and multitargeted therapies for a more effective management of melanoma patients.…”