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

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.

Conclusion: CD133(+) liver TICs promote angiogenesis, tumorigenesis, and self-renewal through NTS-induced activation of the IL-8 signaling cascade.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AC133 Antigen
  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Carcinoma, Hepatocellular / blood supply
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / surgery
  • Cell Line, Tumor
  • Cell Proliferation*
  • Cells, Cultured
  • Chemokine CXCL1 / physiology*
  • Feedback, Physiological
  • Glycoproteins / deficiency
  • Glycoproteins / genetics
  • Glycoproteins / metabolism*
  • Hepatectomy
  • Humans
  • Interleukin-8 / deficiency
  • Interleukin-8 / genetics
  • Interleukin-8 / physiology*
  • Liver / blood supply
  • Liver / pathology
  • Liver / surgery
  • Liver Neoplasms / blood supply
  • Liver Neoplasms / pathology*
  • Liver Neoplasms / surgery
  • Mice
  • Mice, Nude
  • Mitogen-Activated Protein Kinase Kinases
  • Neoplastic Stem Cells / immunology
  • Neoplastic Stem Cells / physiology*
  • Neovascularization, Pathologic / physiopathology*
  • Neurotensin / pharmacology
  • Neurotensin / physiology*
  • Peptides / deficiency
  • Peptides / genetics
  • Peptides / metabolism*
  • Signal Transduction / physiology*
  • Xenograft Model Antitumor Assays


  • AC133 Antigen
  • Antigens, CD
  • CXCL1 protein, human
  • Chemokine CXCL1
  • Glycoproteins
  • Interleukin-8
  • PROM1 protein, human
  • Peptides
  • Prom1 protein, mouse
  • Neurotensin
  • Mitogen-Activated Protein Kinase Kinases

Associated data

  • GEO/GSE23450
  • GEO/GSE23451