title: Hypoxia induces tumor aggressiveness and the expansion of CD133-positive cells in a hypoxia-inducible factor-1α-dependent manner in pancreatic cancer cells.
abstract: BACKGROUND
  Intratumoral hypoxia is known to lead to increased aggressiveness and distant metastasis. However, the interplay underlying these actions is still unknown.
  
  
  OBJECTIVE
  We explored whether cancer cells might acquire a stem-like phenotype under hypoxia, consequently leading to an aggressive phenotype, including invasiveness and metastasis.
  
  
  METHODS
  Under normoxia (20% O(2)) or hypoxia (1% O(2)), the expression of CD133 (cancer stem cell marker), CXC chemokine receptor 4 (CXCR4) and hypoxia-inducible factor-1α (HIF-1α) was examined by RT-PCR and immunostaining using human pancreatic cancer cell lines. We also examined if hypoxia facilitates the invasiveness of CD133+ cancer cells. Furthermore, we transfected dominant active HIF-1α (HIF-1αΔODD) by the retroviral gene transfer and examined the effects both in vitro and in vivo.
  
  
  RESULTS
  Compared with normoxia, hypoxia elevated the expression of CD133, CXCR4 and HIF-1α. Moreover, hypoxia facilitated the invasiveness of CD133+ pancreatic cancer cells. The behavior of HIF-1αΔODD-transfected cells under normoxia was compatible with that of the parent cells under hypoxia. Furthermore, a xenograft model of HIF-1αΔODD cells showed aggressiveness, including metastasis and highly tumorigenic ability.
  
  
  CONCLUSIONS
  Hypoxia induces tumor aggressiveness associated with the expansion of CD133+ pancreatic cancer cells in a predominantly HIF-1α-dependent manner.
authors.affiliation: Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Okito
authors.initials: O
authors.lastname: Hashimoto
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shimizu
authors.forename: Shuho
authors.initials: S
authors.lastname: Semba
authors.forename: Sachie
authors.initials: S
authors.lastname: Chiba
authors.forename: Yonson
authors.initials: Y
authors.lastname: Ku
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yokozaki
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hori
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D015870:Gene Expression; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014183:Transplantation, Heterologous
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; C527276:CXCR4 protein, human; D017931:DNA Primers; D006023:Glycoproteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4