Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized.
Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized.
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DOI：
10.1016/j.ccr.2010.10.012
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发表时间：
2010-11-16
期刊：
影响因子：
50.3
通讯作者：
Morrison SJ
中科院分区：
文献类型：
--
作者：
Quintana E;Shackleton M;Foster HR;Fullen DR;Sabel MS;Johnson TM;Morrison SJ
我们研究了黑色素瘤是否分层组织成表型不同的致瘤细胞和非致瘤细胞亚群，或者大多数黑色素瘤细胞是否保留致瘤能力，无论其表型如何。我们发现28%的直接从患者获得的单个黑素瘤细胞在NOD/SCID IL 2 R γ敲除小鼠中形成肿瘤。直接从患者身上获得的所有II、III和IV期黑色素瘤都有共同的致瘤细胞。所有的致瘤细胞似乎有无限的致瘤能力后，连续移植。我们无法找到任何大的黑色素瘤细胞亚群，缺乏致瘤潜力。包括CD 271和ABCB 5在内的22种异源表达标志物均未富集致瘤细胞。一些黑色素瘤在小鼠中转移，无论它们是否来自CD 271-或CD 271+细胞。许多标志物似乎是可逆地表达的致瘤性黑色素瘤细胞。在遵循干细胞模型的癌症中，表型不同的致瘤细胞以类似于正常干细胞分化的分级方式形成丰富且表型多样的非致瘤子代。与此模型相反，我们的研究结果表明，原发性皮肤或转移性黑色素瘤患者有共同的和表型多样的致瘤细胞，在体内发生可逆的表型变化。因此，黑色素瘤中的大多数表型异质性与致瘤潜力的丧失无关，也与稳定的层次结构无关。这些数据表明一个表型可塑性模型，其中表型异质性主要由致瘤细胞谱系内的可逆变化驱动，而不是由不可逆的表观遗传或遗传变化驱动。
We investigated whether melanoma is hierarchically organized into phenotypically distinct subpopulations of tumorigenic and non-tumorigenic cells, or whether most melanoma cells retain tumorigenic capacity, irrespective of their phenotype. We found 28% of single melanoma cells obtained directly from patients formed tumors in NOD/SCID IL2Rγnull mice. All stage II, III, and IV melanomas obtained directly from patients had common tumorigenic cells. All tumorigenic cells appeared to have unlimited tumorigenic capacity upon serial transplantation. We were unable to find any large subpopulation of melanoma cells that lacked tumorigenic potential. None of 22 heterogeneously-expressed markers, including CD271 and ABCB5, enriched tumorigenic cells. Some melanomas metastasized in mice, irrespective of whether they arose from CD271- or CD271+ cells. Many markers appeared to be reversibly expressed by tumorigenic melanoma cells. In cancers that follow a stem cell model, phenotypically distinct tumorigenic cells form abundant and phenotypically diverse non-tumorigenic progeny in a hierarchical manner that resembles normal stem cell differentiation. In contrast to this model, our results indicate that primary cutaneous or metastatic melanomas from patients have common and phenotypically diverse tumorigenic cells that undergo reversible phenotypic changes in vivo. Most of the phenotypic heterogeneity in melanoma is therefore not associated with a loss of tumorigenic potential or organized in stable hierarchies. These data suggest a phenotypic plasticity model in which phenotypic heterogeneity is driven largely by reversible changes within lineages of tumorigenic cells rather than by irreversible epigenetic or genetic changes.
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影响因子：
5.2
作者：
Schatton T;Frank MH
通讯作者：
Frank MH
影响因子：
64.5
作者：
Roesch A;Fukunaga-Kalabis M;Schmidt EC;Zabierowski SE;Brafford PA;Vultur A;Basu D;Gimotty P;Vogt T;Herlyn M
通讯作者：
Herlyn M
影响因子：
11.2
作者：
Held MA;Curley DP;Dankort D;McMahon M;Muthusamy V;Bosenberg MW
通讯作者：
Bosenberg MW
影响因子：
158.5
作者：
Jamieson, CHM;Ailles, LE;Weissman, IL
通讯作者：
Weissman, IL
影响因子：
4.8
作者：
Frank, NY;Pendse, SS;Frank, MH
通讯作者：
Frank, MH