Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-64387
Müller-Edenborn, Björn; Roth-Z'graggen, Birgit; Bartnicka, Kamila; Borgeat, Alain; Hoos, Alexandra; Borsig, Lubor; Beck-Schimmer, Beatrice (2012). Volatile anesthetics reduce invasion of colorectal cancer cells through down-regulation of matrix metalloproteinase-9. Anesthesiology, 117(2):293-301.
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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.
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).
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.
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.
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|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > Balgrist University Hospital, Swiss Spinal Cord Injury Center
04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
04 Faculty of Medicine > Center for Integrative Human Physiology
04 Faculty of Medicine > University Hospital Zurich > Institute of Anesthesiology
|DDC:||570 Life sciences; biology
610 Medicine & health
|Deposited On:||04 Sep 2012 12:49|
|Last Modified:||29 Nov 2013 21:24|
|Publisher:||Lippincott Wiliams & Wilkins|
|Funders:||Swiss National Research Foundation, Grant 320030_141216, Swiss Society of Anesthesiology and Reanimation, Baxter Schweiz AG, Volketswil, Switzerland|
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