CXCR6, a newly defined biomarker of tissue-specific stem cell asymmetric self-renewal, identifies more aggressive human melanoma cancer stem cells.
CXCR6, a newly defined biomarker of tissue-specific stem cell asymmetric self-renewal, identifies more aggressive human melanoma cancer stem cells.
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DOI：
10.1371/journal.pone.0015183
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发表时间：
2010-12-22
期刊：
影响因子：
3.7
通讯作者：
La Porta CA
中科院分区：
文献类型：
--
作者：
Taghizadeh R;Noh M;Huh YH;Ciusani E;Sigalotti L;Maio M;Arosio B;Nicotra MR;Natali P;Sherley JL;La Porta CA
癌症研究中的一个基本问题是确定能够维持肿瘤生长的细胞类型及其来自正常组织细胞的起源。最近对多种肿瘤类型的研究表明，表型可识别和可分离的细胞亚组分具有肿瘤形成能力。在本论文中，使用两个谱系相关的人黑色素瘤细胞系，原发性黑色素瘤细胞系IGR 39及其转移性衍生细胞系IGR 37，报告了两个主要观察结果。第一个是支持黑色素瘤癌症干细胞（CSC）起源于突变的组织特异性干细胞的第一个表型证据;第二个是鉴定出黑色素瘤中更具侵袭性的CSC亚群为CXCR 6+。我们将CXCR 6定义为组织特异性干细胞不对称自我更新的新生物标志物。因此，研究了黑色素瘤形成与ABCG 2和CXCR 6表达之间的关系。与其非转移性特征一致，未分选的IGR 39细胞形成的肿瘤显著小于未分选的IGR 37细胞。此外，ABCG 2+细胞产生的肿瘤比未分选细胞或ABCG 2-细胞产生的肿瘤质量大2倍。CXCR 6+细胞产生更具侵袭性的肿瘤。CXCR 6鉴定了培养的人黑素瘤细胞的更离散的亚群，其具有比仅基于ABCG 2+表型选择的细胞更侵袭性的MCSC表型。更具侵袭性的肿瘤表型与不对称自我更新表型的关联揭示了肿瘤细胞生理学的一个先前未被认识的方面。也就是说，一些组织特异性干细胞属性的保留，如不对称自我更新的能力，影响了人类肿瘤发展的自然史。了解肿瘤发展和进展的这一新方面可能为癌症预防和治疗提供新的靶点。
A fundamental problem in cancer research is identifying the cell type that is capable of sustaining neoplastic growth and its origin from normal tissue cells. Recent investigations of a variety of tumor types have shown that phenotypically identifiable and isolable subfractions of cells possess the tumor-forming ability. In the present paper, using two lineage-related human melanoma cell lines, primary melanoma line IGR39 and its metastatic derivative line IGR37, two main observations are reported. The first one is the first phenotypic evidence to support the origin of melanoma cancer stem cells (CSCs) from mutated tissue-specific stem cells; and the second one is the identification of a more aggressive subpopulation of CSCs in melanoma that are CXCR6+. We defined CXCR6 as a new biomarker for tissue-specific stem cell asymmetric self-renewal. Thus, the relationship between melanoma formation and ABCG2 and CXCR6 expression was investigated. Consistent with their non-metastatic character, unsorted IGR39 cells formed significantly smaller tumors than unsorted IGR37 cells. In addition, ABCG2+ cells produced tumors that had a 2-fold greater mass than tumors produced by unsorted cells or ABCG2- cells. CXCR6+ cells produced more aggressive tumors. CXCR6 identifies a more discrete subpopulation of cultured human melanoma cells with a more aggressive MCSC phenotype than cells selected on the basis of the ABCG2+ phenotype alone. The association of a more aggressive tumor phenotype with asymmetric self-renewal phenotype reveals a previously unrecognized aspect of tumor cell physiology. Namely, the retention of some tissue-specific stem cell attributes, like the ability to asymmetrically self-renew, impacts the natural history of human tumor development. Knowledge of this new aspect of tumor development and progression may provide new targets for cancer prevention and treatment.