Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271.
The question of whether tumorigenic cancer stem cells exist in human melanomas has arisen in the last few years. Here we show that in melanomas, tumour stem cells (MTSCs, for melanoma tumour stem cells) can be isolated prospectively as a highly enriched CD271(+) MTSC population using a process that maximizes viable cell transplantation. The tumours sampled in this study were taken from a broad spectrum of sites and stages. High-viability cells isolated by fluorescence-activated cell sorting and re-suspended in a matrigel vehicle were implanted into T-, B- and natural-killer-deficient Rag2(-/-)gammac(-/-) mice. The CD271(+) subset of cells was the tumour-initiating population in 90% (nine out of ten) of melanomas tested. Transplantation of isolated CD271(+) melanoma cells into engrafted human skin or bone in Rag2(-/-)gammac(-/-) mice resulted in melanoma; however, melanoma did not develop after transplantation of isolated CD271(-) cells. We also show that in mice, tumours derived from transplanted human CD271(+) melanoma cells were capable of metastatsis in vivo. CD271(+) melanoma cells lacked expression of TYR, MART1 and MAGE in 86%, 69% and 68% of melanoma patients, respectively, which helps to explain why T-cell therapies directed at these antigens usually result in only temporary tumour shrinkage.
Boiko
Alexander D
AD
Institute for Stem Cell Biology and Regenerative Medicine, Stanford Cancer Center, Stanford University School of Medicine, Stanford, California 94304-5542, USA. aboiko@stanford.edu
Razorenova
Olga V
OV
van de Rijn
Matt
M
Swetter
Susan M
SM
Johnson
Denise L
DL
Ly
Daphne P
DP
Butler
Paris D
PD
Yang
George P
GP
Joshua
Benzion
B
Kaplan
Michael J
MJ
Longaker
Michael T
MT
Weissman
Irving L
IL
D000818:Animals; D000951:Antigens, Neoplasm / Q000032:analysis / Q000378:metabolism; D016025:Bone Transplantation; D001842:Bone and Bones / Q000473:pathology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology*; D058950:Melanoma-Specific Antigens; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000032:analysis / Q000378:metabolism; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology* / Q000637:transplantation; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009432:Neural Crest / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D017475:Receptors, Nerve Growth Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000473:pathology; D016038:Skin Transplantation; D014183:Transplantation, Heterologous / Q000473:pathology
D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D058950:Melanoma-Specific Antigens; C484065:NGFR protein, human; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; C499308:Rag2 protein, mouse; D017475:Receptors, Nerve Growth Factor