1 Department of Internal Medicine, University of California Davis Medical Center , Sacramento, California.
Stem Cells Dev. 2015 Apr 15;24(8):1008-21. doi: 10.1089/scd.2014.0405. Epub 2015 Jan 26.
CD34(+) stem cells play an important role during liver development and regeneration. Thus, we hypothesized that some human liver carcinomas (HLCs) might be derived from transformed CD34(+) stem cells. Here, we determined that a population of CD34(+) cells isolated from PLC/PRF/5 hepatoma cells (PLC) appears to function as liver cancer stem cells (LCSCs) by forming HLCs in immunodeficient mice with as few as 100 cells. Moreover, the CD34(+) PLC subpopulation cells had an advantage over CD34(-) PLCs at initiating tumors. Three types of HLCs were generated from CD34(+) PLC: hepatocellular carcinomas (HCCs); cholangiocarcinomas (CC); and combined hepatocellular cholangiocarcinomas (CHCs). Tumors formed in mice transplanted with 12 subpopulations and 6 progeny subpopulations of CD34(+) PLC cells. Interestingly, progenies with certain surface antigens (CD133, CD44, CD90, or EPCAM) predominantly yielded HCCs. CD34(+) PLCs that also expressed OV6 and their progeny OV6(+) cells primarily produced CHC and CC. This represents the first experiment to demonstrate that the OV6(+) antigen is associated with human CHC and CC. CD34(+) PLCs that also expressed CD31 and their progeny CD31(+) cells formed CHCs. Gene expression patterns and tumor cell populations from all xenografts exhibited diverse patterns, indicating that tumor-initiating cells (TICs) with distinct antigenic profiles contribute to cancer cell heterogeneity. Therefore, we identified CD34(+) PLC cells functioning as LCSCs generating three types of HLCs. Eighteen subpopulations from one origin had the capacity independently to initiate tumors, thus functioning as TICs. This finding has broad implications for better understanding of the multistep model of tumor initiation and progression. Our finding also indicates that CD34(+) PLCs that also express OV6 or CD31 result in types of HLCs. This is the first report that PLC/PRF/5 subpopulations expressing CD34 in combination with particular antigens defines categories of HLCs, implicating a diversity of origins for HLC.
CD34(+) 干细胞在肝脏发育和再生过程中发挥重要作用。因此，我们假设一些人类肝癌（HLC）可能来源于转化的 CD34(+) 干细胞。在这里，我们确定从 PLC/PRF/5 肝癌细胞（PLC）中分离的 CD34(+) 细胞群体似乎通过在免疫缺陷小鼠中形成 HLC 而发挥肝癌干细胞（LCSC）的作用，只需 100 个细胞即可。此外，CD34(+) PLC 亚群细胞在启动肿瘤方面比 CD34(-) PLC 具有优势。从 CD34(+) PLC 中产生了三种类型的 HLC：肝细胞癌（HCC）；胆管癌（CC）；和肝细胞胆管癌（CHC）。将 12 个亚群和 6 个祖细胞亚群的 CD34(+) PLC 细胞移植到小鼠中形成肿瘤。有趣的是，具有某些表面抗原（CD133、CD44、CD90 或 EPCAM）的祖细胞主要产生 HCC。也表达 OV6 的 CD34(+) PLC 及其 OV6(+) 细胞后代主要产生 CHC 和 CC。这是第一个证明 OV6(+) 抗原与人类 CHC 和 CC 相关的实验。还表达 CD31 的 CD34(+) PLC 及其后代 CD31(+) 细胞形成 CHC。所有异种移植物的基因表达模式和肿瘤细胞群体表现出不同的模式，表明具有不同抗原表型的肿瘤起始细胞（TIC）有助于癌症细胞异质性。因此，我们确定 CD34(+) PLC 作为 LCSC 产生三种类型的 HLC。一个起源的 18 个亚群具有独立启动肿瘤的能力，因此作为 TIC 发挥作用。这一发现对更好地理解肿瘤起始和进展的多步模型具有广泛的意义。我们的发现还表明，也表达 OV6 或 CD31 的 CD34(+) PLC 导致 HLC 类型。这是第一个报告表明 PLC/PRF/5 亚群与特定抗原结合表达 CD34 定义了 HLC 类别，暗示 HLC 具有多种起源。
