title: CD133(+)  liver tumor-initiating cells promote tumor angiogenesis, growth, and self-renewal through neurotensin/interleukin-8/CXCL1 signaling.
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.
  
  
  CONCLUSIONS
  CD133(+) liver TICs promote angiogenesis, tumorigenesis, and self-renewal through NTS-induced activation of the IL-8 signaling cascade.
authors: Department of Pathology, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong. kwchan@pathology.hku.hk
authors: Kwan Ho
authors: KH
authors: Tang
authors: Stephanie
authors: S
authors: Ma
authors: Terence K
authors: TK
authors: Lee
authors: Yuen Piu
authors: YP
authors: Chan
authors: Pak Shing
authors: PS
authors: Kwan
authors: Carol M
authors: CM
authors: Tong
authors: Irene O
authors: IO
authors: Ng
authors: Kwan
authors: K
authors: Man
authors: Ka-Fai
authors: KF
authors: To
authors: Paul B
authors: PB
authors: Lai
authors: Chung-Mau
authors: CM
authors: Lo
authors: Xin-Yuan
authors: XY
authors: Guan
authors: Kwok Wah
authors: KW
authors: Chan
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000473:pathology / Q000601:surgery; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000502:physiology*; D025461:Feedback, Physiological; D006023:Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006498:Hepatectomy; D006801:Humans; D016209:Interleukin-8 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000098:blood supply / Q000473:pathology / Q000601:surgery; D008113:Liver Neoplasms / Q000098:blood supply / Q000473:pathology* / Q000601:surgery; D051379:Mice; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D009496:Neurotensin / Q000494:pharmacology / Q000502:physiology*; D010455:Peptides / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D006023:Glycoproteins; D016209:Interleukin-8; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D009496:Neurotensin; D020929:Mitogen-Activated Protein Kinase Kinases