title: Volatile anesthetics reduce invasion of colorectal cancer cells through down-regulation of matrix metalloproteinase-9.
abstract: BACKGROUND
  Invasion of extracellular matrix is a hallmark of malignant tumors. Clamping maneuvers during cancer surgery reduce blood loss, but trigger reperfusion injury (RI). RI increases cancer recurrence in the reperfused organ through up-regulation of matrix metalloproteinase-9 (MMP-9). Interleukin-8 is an important cytokine in RI promoting accumulation of neutrophils, a major source of MMP-9. Volatile anesthetics were demonstrated to reduce RI. We hypothesized that these anesthetics might attenuate MMP-9 up-regulation and consequently tumor cell invasion in RI.
  
  
  METHODS
  Isolated human neutrophils (n = 6) were preconditioned with sevoflurane or desflurane, followed by stimulation with interleukin-8, phorbol myristate acetate, or chemokine CXC-ligand 1 (CXCL1) to differentiate intracellular pathways. MMP-9 release and activity were quantified by enzyme-linked immunosorbent assay and zymography, respectively. CXC-receptor-2 (CXCR2) expression and phosphorylation of extracellular signal-regulated kinases 1/2 were assessed by flow cytometry. The impact of MMP-9 on the invasion of neutrophils and MC-38 colon cancer cells was assessed using Matrigel-coated filters (n = 6).
  
  
  RESULTS
  Preconditioning reduced interleukin-8-induced MMP-9-release by 41% (±13, 5%, sevoflurane) and 40% (±13%, desflurane). This was also evident following stimulation of CXCR2 with CXCL1. No impact on phosphorylation of extracellular signal-regulated kinases 1/2 and MMP-9 release was observed with receptor-independent stimulation of protein kinase C with phorbol myristate acetate. Preconditioning reduced transmigration of neutrophils and MC-38 tumor cells to baseline levels.
  
  
  CONCLUSIONS
  Volatile anesthetics impair neutrophil MMP-9 release and interfere with pathways downstream of CXCR2, but upstream of protein kinase C. Through down-regulation of MMP-9, volatile anesthetics decrease Matrigel breakdown and reduce subsequent migration of cancer cells in vitro.
authors: Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland.
authors: Björn
authors: B
authors: Müller-Edenborn
authors: Birgit
authors: B
authors: Roth-Zʼgraggen
authors: Kamila
authors: K
authors: Bartnicka
authors: Alain
authors: A
authors: Borgeat
authors: Alexandra
authors: A
authors: Hoos
authors: Lubor
authors: L
authors: Borsig
authors: Beatrice
authors: B
authors: Beck-Schimmer
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000378:metabolism*; D000077335:Desflurane; D015536:Down-Regulation / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D066298:In Vitro Techniques; D007530:Isoflurane / Q000031:analogs & derivatives / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects* / Q000378:metabolism*; D008738:Methyl Ethers / Q000494:pharmacology; D023063:Receptors, Interleukin-8B / Q000187:drug effects / Q000378:metabolism; D015427:Reperfusion Injury / Q000517:prevention & control*; D000077149:Sevoflurane; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D023063:Receptors, Interleukin-8B; D000077149:Sevoflurane; D000077335:Desflurane; D007530:Isoflurane; D048049:Extracellular Signal-Regulated MAP Kinases; D020780:Matrix Metalloproteinase 9