title: Darbepoetin-α promotes neovascularization and cell proliferation in established colorectal liver metastases.
abstract: BACKGROUND
  The erythropoietin-analogue darbepoetin-α (DPO) improves liver function and regeneration after hepatectomy (Phx), however, also enhances Phx-induced tumor cell engraftment and neovascularization. Because it is unknown whether DPO also enhances the growth of established tumors, we herein studied the effect of DPO on established colorectal liver metastases after Phx.
  
  
  METHODS
  CT26.WT cells were implanted into the liver of BALB/c mice. Five days after tumor establishment, animals underwent 50% Phx and received 10 μg/kgBW DPO or saline. Non-Phx animals with DPO or saline-treatment served as controls. Seven days after Phx tumors were analyzed regarding blood vessel formation, leukocyte adhesion, cell proliferation, apoptotic cell death, and growth using intravital fluorescence microscopy, histology, and immunohistochemistry.
  
  
  RESULTS
  The growth of established colorectal liver metastases was slightly stimulated after DPO-treatment in hepatectomized and non-hepatectomized animals. However, tumor vessel formation and tumor cell proliferation were significantly enhanced after DPO-treatment in hepatectomized and non-hepatectomized mice compared with controls. Apoptotic cell death and leukocyte-endothelial cell interaction were significantly reduced after DPO-treatment.
  
  
  CONCLUSIONS
  Our study indicates that DPO-treatment promotes neovascularization and cell proliferation in established colorectal liver metastases of hepatectomized and non-hepatectomized mice. DPO-application in patients with colorectal liver metastases might promote tumor progression and should therefore be avoided.
authors.affiliation: Department of General, Visceral, Vascular and Pediatric Surgery, University of Saarland, Homburg/Saar, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Rupertus
authors.forename: Sebastian
authors.initials: S
authors.lastname: Senger
authors.forename: Michael D
authors.initials: MD
authors.lastname: Menger
authors.forename: Martin K
authors.initials: MK
authors.lastname: Schilling
authors.forename: Otto
authors.initials: O
authors.lastname: Kollmar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000473:pathology*; D000075202:Contraindications; D000068256:Darbepoetin alfa; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006397:Hematinics / Q000494:pharmacology; D006498:Hepatectomy; D007962:Leukocytes / Q000187:drug effects; D008102:Liver Circulation / Q000187:drug effects; D008114:Liver Neoplasms, Experimental / Q000098:blood supply* / Q000556:secondary* / Q000601:surgery; D051379:Mice; D008807:Mice, Inbred BALB C; D008833:Microcirculation / Q000187:drug effects; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000139:chemically induced*
chemical_list: D006397:Hematinics; D004921:Erythropoietin; D000068256:Darbepoetin alfa