Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271

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  • A Corrigendum to this article was published on 16 February 2011

Abstract

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.

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Figure 1: Isolation of melanoma tumour stem cells (MTSCs) expressing CD271 P75(NGFR) from melanoma patients.
Figure 2: MTSCs induce tumours in humanized mouse models.
Figure 3: Most melanomas contain CD271 + tumour cells that either completely or partially lack expression of melanoma tumour antigens.

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Acknowledgements

We thank J. Bueno and S. Hicks for obtaining patient consent and specimens; K. Montgomery for immunohistochemistry analyses; D. Kim for NSG bone-grafted mice; K. Chan, L. Ailles and C. Park for advice and help in FACS and tumour transplantation assays; L. Cohen for MAGE antibodies; L. Jerabek, T. Storm and A. Mosley for laboratory and mouse management; P. Lovelace for FACS management; A. Olson for help with microscopy; all members of the Weissman Laboratory for experimental suggestions; and M. Clarke and members of his laboratory for critical discussions and reading. This research was initially supported in part by the American Cancer Society fellowship and in part by NIH F32 CA126252 NRSA fellowship to A.D.B.; the Virginia & D.K. Ludwig Fund for Cancer Research to I.L.W.; NIH/NCRR CTSA grant UL1 RR025744 to Stanford Spectrum M.v.d.R.; The Oak Foundation and NIH 1RC2 DE02077-01 to M.T.L.; the Oak Foundation and Ellenburg Faculty Scholar Endowment to G.P.Y.

Author information

A.D.B., M.T.L. and I.L.W. designed research; A.D.B. and O.V.R. performed research; M.v.d.R. and A.D.B. performed immunohistochemical and pathological analysis; S.M.S. provided clinical information; D.L.J., B.J. and M.J.K. provided human surgical melanoma tissues; D.P.L., P.D.B., G.P.Y. and M.T.L. provided humanized skin mouse model; A.D.B. and O.V.R. analysed the data; A.D.B. and I.L.W. wrote the paper.

Correspondence to Alexander D. Boiko or Irving L. Weissman.

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Competing interests

I.L.W. was a member of the scientific advisory board of Amgen and owns significant Amgen stock; he co-founded and consulted for Systemix; he is a co-founder and director of Stem Cells, Inc.; and co-founded Cellerant, Inc. None of these companies is in the cancer stem cell field, at least while I.L.W. was an advisor or held the stock.

Supplementary information

Supplementary Information

This file contains Supplementary Tables 1-3, Supplementary Figures 1-28 and a list of the antibodies that were used in FACS analysis and cell sorting. The Supplementary Information file was corrected on 17 February 2011 (PDF 16088 kb)

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