title: Luminal and basal-like breast cancer cells show increased migration induced by hypoxia, mediated by an autocrine mechanism.
abstract: BACKGROUND
  Some breast cancer patients receiving anti-angiogenic treatment show increased metastases, possibly as a result of induced hypoxia. The effect of hypoxia on tumor cell migration was assessed in selected luminal, post-EMT and basal-like breast carcinoma cell lines.
  
  
  METHODS
  Migration was assessed in luminal (MCF-7), post-EMT (MDA-MB-231, MDA-MB-435S), and basal-like (MDA-MB-468) human breast carcinoma cell lines under normal and oxygen-deprived conditions, using a collagen-based assay. Cell proliferation was determined, secreted cytokine and chemokine levels were measured using flow-cytometry and a bead-based immunoassay, and the hypoxic genes HIF-1α and CA IX were assessed using PCR. The functional effect of tumor-cell conditioned medium on the migration of neutrophil granulocytes (NG) was tested.
  
  
  RESULTS
  Hypoxia caused increased migratory activity but not proliferation in all tumor cell lines, involving the release and autocrine action of soluble mediators. Conditioned medium (CM) from hypoxic cells induced migration in normoxic cells. Hypoxia changed the profile of released inflammatory mediators according to cell type. Interleukin-8 was produced only by post-EMT and basal-like cell lines, regardless of hypoxia. MCP-1 was produced by MDA-MB-435 and -468 cells, whereas IL-6 was present only in MDA-MB-231. IL-2, TNF-α, and NGF production was stimulated by hypoxia in MCF-7 cells. CM from normoxic and hypoxic MDA-MB-231 and MDA-MB-435S cells and hypoxic MCF-7 cells, but not MDA-MB-468, induced NG migration.
  
  
  CONCLUSIONS
  Hypoxia increases migration by the autocrine action of released signal substances in selected luminal and basal-like breast carcinoma cell lines which might explain why anti-angiogenic treatment can worsen clinical outcome in some patients.
authors.affiliation: Institute of Immunology, ZBAF, Witten/Herdecke University, Stockumer Str, 10, 58448 Witten, Germany.
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Voss
authors.forename: Mischa F
authors.initials: MF
authors.lastname: Möller
authors.forename: Desmond G
authors.initials: DG
authors.lastname: Powe
authors.forename: Bernd
authors.initials: B
authors.lastname: Niggemann
authors.forename: Kurt S
authors.initials: KS
authors.lastname: Zänker
authors.forename: Frank
authors.initials: F
authors.lastname: Entschladen
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D019898:Autocrine Communication / Q000502:physiology*; D001943:Breast Neoplasms / Q000473:pathology*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects
chemical_list: D000951:Antigens, Neoplasm; D017077:Culture Media, Conditioned; D016207:Cytokines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases