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

Authors

  • Kwan Ho Tang,

    Corresponding author
    1. Department of Pathology, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong
    • Department of Pathology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Queen Mary Hospital, 102 Pok Fu Lam Road, Pok Fu Lam, Hong Kong
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    • fax: 852-2872-5197

  • Stephanie Ma,

    Corresponding author
    1. Department of Pathology, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong
    2. State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong
    • Department of Pathology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Room 56, 10/F, Laboratory Block, 21 Sassoon Road, Pok Fu Lam, Hong Kong
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    • fax: 852-2218-5244

  • Terence K. Lee,

    1. Department of Pathology, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong
    2. State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong
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  • Yuen Piu Chan,

    1. Department of Pathology, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong
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  • Pak Shing Kwan,

    1. Department of Pathology, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong
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  • Carol M. Tong,

    1. Department of Pathology, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong
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  • Irene O. Ng,

    1. Department of Pathology, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong
    2. State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong
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  • Kwan Man,

    1. State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong
    2. Department of Surgery, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong
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  • Ka-Fai To,

    1. Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong
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  • Paul B. Lai,

    1. Department of Surgery, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong
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  • Chung-Mau Lo,

    1. State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong
    2. Department of Surgery, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong
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  • Xin-Yuan Guan,

    Corresponding author
    1. State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong
    2. Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong
    • Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Room 56, 10/F, Laboratory Block, 21 Sassoon Road, Pok Fu Lam, Hong Kong
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    • fax: 852-2816-9126

  • Kwok Wah Chan

    1. Department of Pathology, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong
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  • Potential conflict of interest: Nothing to report.

  • Funded by: Sir Michael and Lady Kadoorie Funded Research into Cancer Genetics, Research Grant Council General Research Fund, Research Grant Council Collaborative Research Fund (HKU 1/06C, HKU 5/CRF/08 and HKU 7/CRG/09) and the University of Hong Kong Strategic Research Theme in Cancer.

Abstract

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)

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