title: OV6⁺ tumor-initiating cells contribute to tumor progression and invasion in human hepatocellular carcinoma.
abstract: OBJECTIVE
  Accumulating evidence suggests the involvement of tumor-initiating cells (T-ICs) in cancer genesis, but whether liver T-ICs contribute to HCC invasion and metastasis remains unclear.
  
  
  METHODS
  OV6(+) T-ICs were isolated from SMMC7721 and HuH7 cell lines by magnetic sorting. Characteristics of T-ICs were assessed by in vitro and mouse xenograft assays. Expression of OV6 was determined by immunostaining in specimens from 218 HCC patients, and Kaplan-Meier survival analysis was used to determine the correlation of OV6 expression with prognosis.
  
  
  RESULTS
  OV6(+) T-ICs isolated from HCC cell lines not only possess a higher capacity to form tumor spheroids in vitro, but also had a greater potential to form tumors when implanted in non-obese diabetic/severe combined immunodeficient mice, suggesting their elevated self-renewal capacity and tumorigenicity. Moreover, OV6(+) T-ICs exhibited more invasive and metastatic potentials both in vitro and in vivo. Patients with more OV6(+) tumor cells were associated with aggressive clinicopathologic features and poor prognosis. CXCR4 is expressed at higher levels in OV6(+) cells. Recombinant stromal cell-derived factor-1 (SDF-1) treatment expanded the OV6(+) HCC T-ICs population, by sustaining the stem cell property of OV6(+) cells. The SDF-1 effect was blocked by a specific CXCR4 inhibitor, AMD3100, or transfection of siRNA targeting CXCR4.
  
  
  CONCLUSIONS
  OV6(+) HCC cells may represent a subpopulation of T-ICs with augmented invasion and metastasis potential, which contribute to progression and metastasis of HCC. The SDF-1/CXCR4 axis also provides therapeutic targets for elimination of liver T-ICs.
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, PR China.
authors.forename: Wen
authors.initials: W
authors.lastname: Yang
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Lin
authors.forename: Qiong
authors.initials: Q
authors.lastname: Liu
authors.forename: Le-xing
authors.initials: LX
authors.lastname: Yu
authors.forename: Liang
authors.initials: L
authors.lastname: Tang
authors.forename: He-Xin
authors.initials: HX
authors.lastname: Yan
authors.forename: Jing
authors.initials: J
authors.lastname: Fu
authors.forename: Yao
authors.initials: Y
authors.lastname: Chen
authors.forename: Hui-Lu
authors.initials: HL
authors.lastname: Zhang
authors.forename: Liang
authors.initials: L
authors.lastname: Tang
authors.forename: Long-Yi
authors.initials: LY
authors.lastname: Zheng
authors.forename: Ya-Qin
authors.initials: YQ
authors.lastname: He
authors.forename: Yu-Qiong
authors.initials: YQ
authors.lastname: Li
authors.forename: Fu-Quan
authors.initials: FQ
authors.lastname: Wu
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Zou
authors.forename: Zhong
authors.initials: Z
authors.lastname: Li
authors.forename: Meng-Chao
authors.initials: MC
authors.lastname: Wu
authors.forename: Gen-Sheng
authors.initials: GS
authors.lastname: Feng
authors.forename: Hong-Yang
authors.initials: HY
authors.lastname: Wang
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000943:Antigens, Differentiation / Q000378:metabolism*; D000951:Antigens, Neoplasm / Q000378:metabolism; D001596:Benzylamines; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000556:secondary*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000378:metabolism; D000080027:Cyclams; D018450:Disease Progression; D018572:Disease-Free Survival; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D055785:Gene Knockdown Techniques; D006023:Glycoproteins / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000556:secondary; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D011379:Prognosis; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018874:Spheroids, Cellular
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; D001596:Benzylamines; C527276:CXCR4 protein, human; D015815:Cell Adhesion Molecules; D054377:Chemokine CXCL12; D000080027:Cyclams; D000071858:Epithelial Cell Adhesion Molecule; D006023:Glycoproteins; D006571:Heterocyclic Compounds; D010455:Peptides; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; C115011:oval cell marker OV-6; C088327:plerixafor