CD133 + liver tumor-initiating cells promote tumor angiogenesis, growth, and self-renewal through neurotensin/interleukin-8/CXCL1 signaling

Kwan Ho Tang, Stephanie Ma, Kin Wah Lee, Yuen Piu Chan, Pak Shing Kwan, Carol M. Tong, Irene O. Ng, Kwan Man, Ka Fai To, Paul B. Lai, Chung Mau Lo, Xin Yuan Guan, Kwok Wah Chan

Research output: Journal article publicationJournal articleAcademic researchpeer-review

176 Citations (Scopus)


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. (Hepatology 2012)
Original languageEnglish
Pages (from-to)807-820
Number of pages14
Issue number3
Publication statusPublished - 1 Mar 2012
Externally publishedYes

ASJC Scopus subject areas

  • Hepatology


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