title: Liver resection-associated macrophage inflammatory protein-2 stimulates engraftment but not growth of colorectal metastasis at extrahepatic sites.
abstract: BACKGROUND
  Previous studies have shown that liver resection enhances intrahepatic engraftment of CXCR-2-expressing colorectal cancer cells by the action of the CXC chemokine macrophage inflammatory protein (MIP)-2. Herein we studied how liver resection-associated MIP-2 affects extrahepatic tumor cell engraftment and whether MIP-2 also stimulates the growth of already established metastases.
  
  
  METHODS
  Green fluorescent protein-transfected CT26.WT colorectal cancer cells were implanted into dorsal skinfold chambers of syngeneic BALB/c mice. Additionally, all animals underwent a 30% hepatectomy. To study MIP-2 in extrahepatic tumor cell engraftment, animals were treated with an anti-MIP-2 antibody, starting at the day of tumor cell implantation. To study MIP-2 in established metastases, anti-MIP-2 treatment was initiated at day 5 after tumor cell implantation. Hepatectomized animals without neutralization of MIP-2 served as controls. Tumor vascularization and growth as well as tumor cell migration, proliferation, apoptosis, and CXCR-2 expression were studied over 14 days using intravital fluorescence microscopy, histology, and immunohistochemistry.
  
  
  RESULTS
  Functional inhibition of MIP-2 significantly delayed extrahepatic tumor cell engraftment but not the growth of established metastases. The initial delay of engraftment was associated with a compensatory stimulation of vascularization and tumor cell migration when compared to controls (P < 0.05). Further, inhibition of tumor cell engraftment by initial anti-MIP-2 treatment was associated with a significant (P < 0.05) reduction of CXCR-2 expression and tumor cell apoptosis.
  
  
  CONCLUSIONS
  Our study indicates that MIP-2 is involved in extrahepatic engraftment of CT.26 colorectal cancer cells. The MIP-2/CXCR-2 signaling pathway may be a promising target for early antitumor therapy in patients undergoing liver resection.
authors.affiliation: Department of General, Visceral, Vascular and Pediatric Surgery, University of Saarland, Homburg/Saar, Germany. otto.kollmar@uniklinikum-saarland.de
authors.forename: Otto
authors.initials: O
authors.lastname: Kollmar
authors.forename: Bastian
authors.initials: B
authors.lastname: Junker
authors.forename: Kathrin
authors.initials: K
authors.lastname: Rupertus
authors.forename: Claudia
authors.initials: C
authors.lastname: Scheuer
authors.forename: Michael D
authors.initials: MD
authors.lastname: Menger
authors.forename: Martin K
authors.initials: MK
authors.lastname: Schilling
mesh_terms: D000230:Adenocarcinoma / Q000556:secondary*; D000818:Animals; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D054426:Chemokine CXCL2 / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000473:pathology*; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins / Q000235:genetics; D006498:Hepatectomy; D008115:Liver Regeneration / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008833:Microcirculation / Q000502:physiology; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D012878:Skin Neoplasms / Q000556:secondary*
chemical_list: D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D023063:Receptors, Interleukin-8B; D049452:Green Fluorescent Proteins