Department of Pathology, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong.
Hepatology. 2012 Mar;55(3):807-20. doi: 10.1002/hep.24739. Epub 2012 Jan 13.
A novel theory in the field of tumor biology postulates that cancer growth is driven by a population of stem-like cells, called tumor-initiating cells (TICs). We previously identified a TIC population derived from hepatocellular carcinoma (HCC) that is characterized by membrane expression of CD133. Here, we describe a novel mechanism by which these cells mediate tumor growth and angiogenesis by systematic comparison of the gene expression profiles between sorted CD133 liver subpopulations through genome-wide microarray analysis. A significantly dysregulated interleukin-8 (IL-8) signaling network was identified in CD133(+) liver TICs obtained from HCC clinical samples and cell lines. IL-8 was found to be overexpressed at both the genomic and proteomic levels in CD133(+) cells isolated from HCC cell lines or clinical samples. Functional studies found enhanced IL-8 secretion in CD133(+) liver TICs to exhibit a greater ability to self-renew, induce tumor angiogenesis, and initiate tumors. In further support of these observations, IL-8 repression in CD133(+) liver TICs by knockdown or neutralizing antibody abolished these effects. Subsequent studies of the IL-8 functional network identified neurotensin (NTS) and CXCL1 to be preferentially expressed in CD133(+) liver TICs. Addition of exogenous NTS resulted in concomitant up-regulation of IL-8 and CXCL1 with simultaneous activation of p-ERK1/2 and RAF-1, both key components of the mitogen-activated protein kinase (MAPK) pathway. Enhanced IL-8 secretion by CD133(+) liver TICs can in turn activate an IL-8-dependent feedback loop that signals through the MAPK pathway. Further, in its role as a liver TIC marker CD133 also plays a functional part in regulating tumorigenesis of liver TICs by way of regulating NTS, IL-8, CXCL1, and MAPK signaling.
CD133(+) liver TICs promote angiogenesis, tumorigenesis, and self-renewal through NTS-induced activation of the IL-8 signaling cascade.
肿瘤生物学领域的一个新理论假设，癌症的生长是由一群称为肿瘤起始细胞（TICs）的干细胞样细胞驱动的。我们之前从肝细胞癌（HCC）中鉴定出一个 TIC 群体，其特征是细胞膜表达 CD133。在这里，我们通过对从 HCC 临床样本和细胞系中分离的 CD133 肝亚群进行全基因组微阵列分析，系统比较其基因表达谱，描述了这些细胞通过何种新机制介导肿瘤生长和血管生成。在从 HCC 细胞系或临床样本中分离的 CD133+细胞中，发现白细胞介素-8（IL-8）信号网络显著失调。在 CD133+细胞中，基因组和蛋白质组水平均发现 IL-8 过度表达。功能研究发现，CD133+肝 TIC 中 IL-8 的分泌增强，使其具有更强的自我更新、诱导肿瘤血管生成和启动肿瘤的能力。进一步支持这些观察结果的是，通过敲低或中和抗体抑制 CD133+肝 TIC 中的 IL-8 表达，消除了这些效应。对 IL-8 功能网络的后续研究表明，神经降压素（NTS）和 CXCL1 优先在 CD133+肝 TIC 中表达。添加外源性 NTS 导致 IL-8 和 CXCL1 的同时上调，同时激活丝裂原活化蛋白激酶（MAPK）通路的关键组成部分 p-ERK1/2 和 RAF-1。CD133+肝 TIC 的增强的 IL-8 分泌反过来可以激活通过 MAPK 通路信号的 IL-8 依赖性反馈回路。此外，作为肝 TIC 标志物的 CD133 还通过调节 NTS、IL-8、CXCL1 和 MAPK 信号通路，在调节肝 TIC 的肿瘤发生中发挥功能作用。
CD133+肝 TIC 通过 NTS 诱导的 IL-8 信号级联激活促进血管生成、肿瘤发生和自我更新。
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