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. Discussion 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.

Preconditioning of Mesenchymal Stem Cells by Sevoflurane to Improve Their Therapeutic Potential

“…The Chamber was flushed with an air/5% CO 2 -mixture for 5 min and then augmented with 2 vol% of sevoflurane for 2 h [22]. Volatile anesthetic concentrations were measured by using the Ohmeda 5330 Agent Monitor (Coast to Coast Medical, Fall River, MA).…”

Natural history of hepatic metastases from colorectal cancer - pathobiological pathways with clinical significance

“…These multi-functional degrading enzymes play a critical role in carcinogenesis but also in other stages of the invasion-metastasis cascade. CRC cells may induce the expression of MMP-2 and -9 by stromal cells, either directly or via a paracrine mechanism, thus modifying ECM and promoting tumour development [56][57][58] .…”

Perioperative Interventions During Cancer Surgery: Can Anesthetic and Analgesic Techniques Influence Outcome?

“…It is unclear how these findings will translate to humans especially when we consider the fact that all research in this area to date has been carried out under normoxic conditions (21 % O 2 ), however, many tumor environments are relatively hypoxic which has been shown to alter the expression of HIF-1a. On the contrary, there is data to suggest that sevoflurane and desflurane may actually decrease migration of colon cancer cells by reducing the production of matrix-metalloproteinase by neutrophils [25]. Also sevoflurane may increase the migration of these tumor cells, however, the research was carried out in an oxygen rich atmosphere and the difference in the results may be directly attributable to this [17].…”