title: Hypoxia and metastasis in an orthotopic cervix cancer xenograft model.
abstract: BACKGROUND
  Hypoxia can promote tumor metastasis by mechanisms that are believed to result from changes in gene expression. The current study examined the role of putative metastatic genes regulated by cyclic hypoxia in relation to metastasis formation in orthotopic models of cervix cancer.
  
  
  METHODS
  Orthotopic tumors derived from ME180 human cervix cancer cells or from early generation human cervix cancer xenografts were exposed to cyclic hypoxic conditions during growth in vivo and tumor growth and lymphnode metastases were monitored. Expression of the chemokine receptor CXCR4 and various genes in the Hedgehog (Hh) pathway were inhibited using genetic (inducible shRNA vs CXCR4) small molecule (AMD3100) or antibody (5E1) treatment (CXCR4 and Hh genes, respectively) during tumor growth.
  
  
  RESULTS
  As reported previously, exposure of tumor bearing mice to cyclic hypoxia caused a reduction of tumor growth but a large increase in metastasis. Inhibition of CXCR4 or Hh gene activity during tumor growth further reduced primary tumor size and reduced lymphatic metastasis to levels below those seen in control mice exposed to normoxic conditions.
  
  
  CONCLUSIONS
  Blocking CXCR4 or Hh gene expression are potential therapeutic pathways for improving cervix cancer treatment.
authors.affiliation: Ontario Cancer Institute/Princess Margaret Cancer Centre and The Campbell Family Institute for Cancer Research, Toronto, Canada.
authors.forename: Naz
authors.initials: N
authors.lastname: Chaudary
authors.forename: Hilda
authors.initials: H
authors.lastname: Mujcic
authors.forename: Bradly G
authors.initials: BG
authors.lastname: Wouters
authors.forename: Richard P
authors.initials: RP
authors.lastname: Hill
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D054377:Chemokine CXCL12 / Q000502:physiology; D005260:Female; D053823:Hedgehog Proteins / Q000235:genetics / Q000502:physiology; D064593:Heterografts; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D008207:Lymphatic Metastasis; D051379:Mice; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000502:physiology; D002583:Uterine Cervical Neoplasms / Q000473:pathology* / Q000628:therapy
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; C497442:HIF1A protein, human; D053823:Hedgehog Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019718:Receptors, CXCR4
keywords: CXCR4; Cervix; Cyclic hypoxia; Hedgehog; Metastasis