Nature封面：人类恶性黑素瘤干细胞

生物谷报道：癌症干细胞已经从若干人类肿瘤中被分离了出来。最新发现的是人类恶性黑素瘤引发细胞的一个亚组，科学家根据它们对化学抵抗力调节因子ABCB5的表达将其识别出来。ABCB5+亚组的大小与黑素瘤患者临床病情发展相关，初步证据还表明，这些黑素瘤干细胞可以用针对ABCB5的抗体将其作为特异性目标。这为黑素瘤提供了一个潜在的治疗策略，而且对这种类型细胞进行研究还有可能回答癌症生物学中的重要问题。本期封面所示混合型黑素瘤细胞（电脑增强的荧光显微镜图像合成图）是在活体中所发生的一次人类肿瘤异种移植中形成的，即通过一个ABCB5+黑素瘤干细胞与一种更为分化的ABCB5-肿瘤细胞融合形成。细胞核分别用基因编码的红色（DsRed）和绿色（EYFP）荧光标签作了标记。

生物谷推荐英文原文：

Nature 451, 345-349 (17 January 2008) | doi:10.1038/nature06489; Received 13 June 2007; Accepted 21 November 2007

Identification of cells initiating human melanomas

Tobias Schatton1, George F. Murphy2, Natasha Y. Frank1,3, Kazuhiro Yamaura1, Ana Maria Waaga-Gasser4, Martin Gasser4, Qian Zhan2, Stefan Jordan1, Lyn M. Duncan5, Carsten Weishaupt6, Robert C. Fuhlbrigge6, Thomas S. Kupper6, Mohamed H. Sayegh1 & Markus H. Frank1

Transplantation Research Center, Children's Hospital Boston and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
Department of Pathology and,
Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
Department of Surgery, University of Würzburg Medical School, 97080 Würzburg, Germany
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA

Correspondence to: Markus H. Frank1 Correspondence and requests for materials should be addressed to M.H.F. (Email: mfrank@rics.bwh.harvard.edu).

Abstract

Tumour-initiating cells capable of self-renewal and differentiation, which are responsible for tumour growth, have been identified in human haematological malignancies1, 2 and solid cancers3, 4, 5, 6. 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.