Evidence of distinct tumour-propagating cell populations with different properties in primary human hepatocellular carcinoma.
Evidence of distinct tumour-propagating cell populations with different properties in primary human hepatocellular carcinoma.
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DOI：
10.1371/journal.pone.0021369
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Porretti L
中科院分区：
文献类型：
--
作者：
Colombo F;Baldan F;Mazzucchelli S;Martin-Padura I;Marighetti P;Cattaneo A;Foglieni B;Spreafico M;Guerneri S;Baccarin M;Bertolini F;Rossi G;Mazzaferro V;Cadamuro M;Maggioni M;Agnelli L;Rebulla P;Prati D;Porretti L
越来越多的证据表明，一些恶性肿瘤的特点是肿瘤细胞异质性最近已公布，但仍然缺乏有关肝癌的数据。本研究的目的是研究和鉴定人肝细胞癌（HCC）中的肿瘤增殖细胞（TPC）。经过长期培养，我们在一个HCC标本中鉴定出三种形态学不同的肿瘤细胞群，并通过流式细胞术、荧光显微镜、核型分析和微阵列分析、单细胞克隆和NOD/SCID/IL 2 R γ−/−小鼠异种移植对其进行了广泛的表征。原代细胞群（hcc-1、hcc-2和hcc-3）和通过从hcc-1有限稀释产生的两个克隆（克隆-1/7和-1/8）不同地表达许多肿瘤相关干细胞标志物，包括EpCAM、CD 49 f、CD 44、CD 133、CD 56、Thy-1、ALDH和CK 19，并且还显示出不同的倍增时间、耐药性和致瘤潜力。此外，我们发现ALDH表达，结合CD 44或Thy-1阴性或CD 56阳性，分别鉴定了hcc-1、hcc-2和hcc-3原代细胞群中具有较高克隆形成潜力的亚群。核型分析揭示了原发性肿瘤内细胞群和克隆的克隆进化。重要的是，具有最大致瘤潜力和耐药性的原发性肿瘤细胞群显示出比其他细胞更多的染色体改变，并且包含具有上皮和间充质特征的克隆。单个HCC可以具有不同的自我更新致瘤细胞类型，表达多种形态和表型标记、核型进化和不同的基因表达谱。这表明，肝癌发生的模型应考虑TPC异质性，由于肿瘤内的克隆进化。
Increasing evidence that a number of malignancies are characterised by tumour cell heterogeneity has recently been published, but there is still a lack of data concerning liver cancers. The aim of this study was to investigate and characterise tumour-propagating cell (TPC) compartments within human hepatocellular carcinoma (HCC). After long-term culture, we identified three morphologically different tumour cell populations in a single HCC specimen, and extensively characterised them by means of flow cytometry, fluorescence microscopy, karyotyping and microarray analyses, single cell cloning, and xenotransplantation in NOD/SCID/IL2Rγ−/− mice. The primary cell populations (hcc-1, -2 and -3) and two clones generated by means of limiting dilutions from hcc-1 (clone-1/7 and -1/8) differently expressed a number of tumour-associated stem cell markers, including EpCAM, CD49f, CD44, CD133, CD56, Thy-1, ALDH and CK19, and also showed different doubling times, drug resistance and tumorigenic potential. Moreover, we found that ALDH expression, in combination with CD44 or Thy-1 negativity or CD56 positivity identified subpopulations with a higher clonogenic potential within hcc-1, hcc-2 and hcc-3 primary cell populations, respectively. Karyotyping revealed the clonal evolution of the cell populations and clones within the primary tumour. Importantly, the primary tumour cell population with the greatest tumorigenic potential and drug resistance showed more chromosomal alterations than the others and contained clones with epithelial and mesenchymal features. Individual HCCs can harbor different self-renewing tumorigenic cell types expressing a variety of morphological and phenotypical markers, karyotypic evolution and different gene expression profiles. This suggests that the models of hepatic carcinogenesis should take into account TPC heterogeneity due to intratumour clonal evolution.
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影响因子：
25.7
作者：
Marquardt JU;Factor VM;Thorgeirsson SS
通讯作者：
Thorgeirsson SS
影响因子：
--
作者：
BIGNER, SH;MARK, J;BIGNER, DD
通讯作者：
BIGNER, DD
影响因子：
50.3
作者：
Chen, Ruihuan;Nishimura, Merry C.;Phillips, Heidi S.
通讯作者：
Phillips, Heidi S.
DOI：
10.1073/pnas.0703478104
发表时间：
2007-06-12
影响因子：
11.1
作者：
Dalerba, Piero;Dylla, Scott J.;Clarke, Michael F.
通讯作者：
Clarke, Michael F.
影响因子：
11.2
作者：
Kim Y;Lin Q;Zelterman D;Yun Z
通讯作者：
Yun Z