Selection of tumorigenic melanoma cells using ALDH.
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.
Boonyaratanakornkit
Jim B
JB
Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.
Yue
Lili
L
Strachan
Lauren R
LR
Scalapino
Kenneth J
KJ
LeBoit
Philip E
PE
Lu
Ying
Y
Leong
Stanley P
SP
Smith
Janellen E
JE
Ghadially
Ruby
R
D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D002469:Cell Separation / Q000379:methods; D004195:Disease Models, Animal; D006801:Humans; D008207:Lymphatic Metastasis; D008545:Melanoma / Q000378:metabolism* / Q000556:secondary*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D000444:Aldehyde Dehydrogenase