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Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271
Alexander D. Boiko1, Olga V. Razorenova2, Matt van de Rijn3, Susan M. Swetter4,5, Denise L. Johnson6,9, Daphne P. Ly6,7, Paris D. Butler6,7, George P. Yang5,6,7, Benzion Joshua8, Michael J. Kaplan8, Michael T. Longaker1,6,7 & Irving L. Weissman1,3
The question of whether tumorigenic cancer stem cells exist in human melanomas has arisen in the last few years1. 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 transplantation1, 2. 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?/?γc?/? 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?/?γc?/? 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.
1Institute for Stem Cell Biology and Regenerative Medicine, Stanford Cancer Center, Stanford University School of Medicine, Stanford, California 94304-5542, USA
2Department of Radiation Oncology, Stanford University Medical Center, Stanford Cancer Center, Stanford, California 94305-5118, USA
3Department of Pathology, Stanford University Medical Center, Stanford Cancer Center, Stanford, California 94305-5118, USA
4Department of Dermatology, Pigmented Lesion and Melanoma Program, Stanford University Medical Center, Stanford Cancer Center, Stanford, California 94305-5118, USA
5Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304, USA
6Department of Surgery, Stanford University Medical Center, Stanford Cancer Center, Stanford, California 94305-5118, USA
7Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California 94305-5118, USA
8Department of Otolaryngology-Head and Neck Surgery, Stanford University Medical Center, Stanford Cancer Center, Stanford, California 94305-5118, USA
