title: Inhibition of tumor necrosis factor alpha reduces the outgrowth of hepatic micrometastasis of colorectal tumors in a mouse model of liver ischemia-reperfusion injury.
abstract: BACKGROUND
  Patients with colorectal cancer (CRC) often develop liver metastases, in which case surgery is considered the only potentially curative treatment option. However, liver surgery is associated with a risk of ischemia-reperfusion (IR) injury, which is thought to promote the growth of colorectal liver metastases. The influence of IR-induced tumor necrosis factor alpha (TNF-α) elevation in the process still is unknown. To investigate the role of TNF-α in the growth of pre-existing micrometastases in the liver following IR, we used a mouse model of colorectal liver metastases. In this model, mice received IR treatment seven days after intrasplenic injections of colorectal CT26 cells. Prior to IR treatment, either TNF-α blocker Enbrel or low-dose TNF-α, which could inhibit IR-induced TNF-α elevation, was administered by intraperitoneal injection.
  
  
  RESULTS
  Hepatic IR treatment significantly promoted CT26 tumor growth in the liver, but either Enbrel or low-dose TNF-α pretreatment reversed this trend. Further studies showed that the CT26 + IR group prominently increased the levels of ALT and AST, liver necrosis, inflammatory infiltration and the expressions of hepatic IL-6, MMP9 and E-selectin compared to those of CT26 group. Inhibition of TNF-α elevation remarkably attenuated the increases of these liver inflammatory damage indicators and tumor-promoting factors.
  
  
  CONCLUSIONS
  These findings suggested that inhibition of TNF-α elevation delayed the IR-enhanced outgrowth of colorectal liver metastases by reducing IR-induced inflammatory damage and the formation of tumor-promoting microenvironments. Both Enbrel and low-dose TNF-α represented the potential therapeutic approaches for the protection of colorectal liver metastatic patients against IR injury-induced growth of liver micrometastases foci.
authors.forename: Shu-Fan
authors.initials: SF
authors.lastname: Jiao
authors.forename: Kai
authors.initials: K
authors.lastname: Sun
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Chen
authors.forename: Xue
authors.initials: X
authors.lastname: Zhao
authors.forename: Ning
authors.initials: N
authors.lastname: Cai
authors.forename: Yan-Jun
authors.initials: YJ
authors.lastname: Liu
authors.forename: Long-Mei
authors.initials: LM
authors.lastname: Xu
authors.affiliation: Medical Sciences Research Center, Renji hospital, School of Medicine, Shanghai Jiaotong University, 1630 Dongfang Road, Shanghai 200127, China. xianmingk@163.com.
authors.forename: Xian-Ming
authors.initials: XM
authors.lastname: Kong
authors.forename: Li-Xin
authors.initials: LX
authors.lastname: Wei
mesh_terms: D000818:Animals; D015179:Colorectal Neoplasms / Q000150:complications / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D000068800:Etanercept; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage; D008099:Liver / Q000293:injuries / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology* / Q000556:secondary / Q000601:surgery; D051379:Mice; D061206:Neoplasm Micrometastasis / Q000235:genetics / Q000473:pathology / Q000628:therapy; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage; D015427:Reperfusion Injury / Q000601:surgery / Q000628:therapy; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000627:therapeutic use
chemical_list: D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept