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CD133 + liver tumor‐initiating cells promote tumor angiogenesis, growth, and self‐renewal through neurotensin/interleukin‐8/CXCL1 signaling
Author(s) -
Tang Kwan Ho,
Ma Stephanie,
Lee Terence K.,
Chan Yuen Piu,
Kwan Pak Shing,
Tong Carol M.,
Ng Irene O.,
Man Kwan,
To KaFai,
Lai Paul B.,
Lo ChungMau,
Guan XinYuan,
Chan Kwok Wah
Publication year - 2012
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.24739
Subject(s) - angiogenesis , biology , cancer research , cxcl1 , mapk/erk pathway , matrigel , metastasis , signal transduction , interleukin 8 , cancer stem cell , chemokine , cytokine , stem cell , immunology , cancer , microbiology and biotechnology , immune system , genetics
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. Conclusion : CD133 + liver TICs promote angiogenesis, tumorigenesis, and self‐renewal through NTS‐induced activation of the IL‐8 signaling cascade. (H epatology 2012)