TY - JOUR
T1 - Identification of cells initiating human melanomas
AU - Schatton, Tobias
AU - Murphy, George F.
AU - Frank, Natasha Y.
AU - Yamaura, Kazuhiro
AU - Waaga-Gasser, Ana Maria
AU - Gasser, Martin
AU - Zhan, Qian
AU - Jordan, Stefan
AU - Duncan, Lyn M.
AU - Weishaupt, Carsten
AU - Fuhlbrigge, Robert C.
AU - Kupper, Thomas S.
AU - Sayegh, Mohamed H.
AU - Frank, Markus H.
N1 - Funding Information:
Acknowledgements We thank D. Herlyn and M. Herlyn for providing fresh melanoma tissue specimen for our studies. The construction of the tissue microarray was possible only through the collaborative assistance of P. Van Belle, D. Elder, V. Prieto and A. Lazar. The tissue microarrays were performed with the technical assistance of R. Kim, K. Lamb and L. Biagini. We thank A. Baldor for technical assistance with tumour xenotransplantation experiments, and M. Grimm for tissue sectioning and immunohistochemistry. We thank D. Scadden for comments on the manuscript. This work was supported by the NCI/NIH (M.H.F.), a NCI/NIH Specialized Program of Research Excellence (SPORE) in Skin Cancer (T.S.K.) and the Department of Defense (M.H.F.).
PY - 2008/1/17
Y1 - 2008/1/17
N2 - Tumour-initiating cells capable of self-renewal and differentiation, which are responsible for tumour growth, have been identified in human haematological malignancies and solid cancers. If such minority populations are associated with tumour progression in human patients, specific targeting of tumour-initiating cells could be a strategy to eradicate cancers currently resistant to systemic therapy. Here we identify a subpopulation enriched for human malignant-melanoma-initiating cells (MMIC) defined by expression of the chemoresistance mediator ABCB5 (refs 7, 8) and show that specific targeting of this tumorigenic minority population inhibits tumour growth. ABCB5+ tumour cells detected in human melanoma patients show a primitive molecular phenotype and correlate with clinical melanoma progression. In serial human-to-mouse xenotransplantation experiments, ABCB5+ melanoma cells possess greater tumorigenic capacity than ABCB5- bulk populations and re-establish clinical tumour heterogeneity. In vivo genetic lineage tracking demonstrates a specific capacity of ABCB5+ subpopulations for self-renewal and differentiation, because ABCB5+ cancer cells generate both ABCB5+ and ABCB5- progeny, whereas ABCB5- tumour populations give rise, at lower rates, exclusively to ABCB5- cells. In an initial proof-of-principle analysis, designed to test the hypothesis that MMIC are also required for growth of established tumours, systemic administration of a monoclonal antibody directed at ABCB5, shown to be capable of inducing antibody-dependent cell-mediated cytotoxicity in ABCB5+ MMIC, exerted tumour-inhibitory effects. Identification of tumour-initiating cells with enhanced abundance in more advanced disease but susceptibility to specific targeting through a defining chemoresistance determinant has important implications for cancer therapy.
AB - Tumour-initiating cells capable of self-renewal and differentiation, which are responsible for tumour growth, have been identified in human haematological malignancies and solid cancers. If such minority populations are associated with tumour progression in human patients, specific targeting of tumour-initiating cells could be a strategy to eradicate cancers currently resistant to systemic therapy. Here we identify a subpopulation enriched for human malignant-melanoma-initiating cells (MMIC) defined by expression of the chemoresistance mediator ABCB5 (refs 7, 8) and show that specific targeting of this tumorigenic minority population inhibits tumour growth. ABCB5+ tumour cells detected in human melanoma patients show a primitive molecular phenotype and correlate with clinical melanoma progression. In serial human-to-mouse xenotransplantation experiments, ABCB5+ melanoma cells possess greater tumorigenic capacity than ABCB5- bulk populations and re-establish clinical tumour heterogeneity. In vivo genetic lineage tracking demonstrates a specific capacity of ABCB5+ subpopulations for self-renewal and differentiation, because ABCB5+ cancer cells generate both ABCB5+ and ABCB5- progeny, whereas ABCB5- tumour populations give rise, at lower rates, exclusively to ABCB5- cells. In an initial proof-of-principle analysis, designed to test the hypothesis that MMIC are also required for growth of established tumours, systemic administration of a monoclonal antibody directed at ABCB5, shown to be capable of inducing antibody-dependent cell-mediated cytotoxicity in ABCB5+ MMIC, exerted tumour-inhibitory effects. Identification of tumour-initiating cells with enhanced abundance in more advanced disease but susceptibility to specific targeting through a defining chemoresistance determinant has important implications for cancer therapy.
UR - http://www.scopus.com/inward/record.url?scp=38349165576&partnerID=8YFLogxK
U2 - 10.1038/nature06489
DO - 10.1038/nature06489
M3 - Article
C2 - 18202660
AN - SCOPUS:38349165576
SN - 0028-0836
VL - 451
SP - 345
EP - 349
JO - Nature
JF - Nature
IS - 7176
ER -