title: Darbepoetin-α accelerates neovascularization and engraftment of extrahepatic colorectal metastases.
abstract: OBJECTIVE
  Erythropoietin and its analogue darbepoetin (DPO)-α have been shown to improve liver function and regeneration after partial hepatectomy (Phx). However, previous experimental studies have also shown that DPO significantly enhances Phx-induced engraftment of colorectal liver metastases by increasing neovascularization and tumor cell proliferation. Therefore, the present study analyzed whether DPO affects engraftment and neovascularization of extrahepatic colorectal metastases after major hepatectomy.
  
  
  METHODS
  Green fluorescent protein-transfected CT26.WT colorectal cancer cells were implanted into dorsal skinfold chambers of syngeneic BALB/c mice. Animals received a single dose of DPO (10 µg/kg body weight) at the day of tumor cell implantation (day 0). Phosphate-buffered saline-treated animals served as controls. To study whether the effect of DPO is influenced by Phx, additional animals with and without DPO treatment underwent 70% Phx at day 0. Tumor vascularization and growth as well as tumor cell migration, proliferation and apoptosis were studied repetitively over 14 days using intravital fluorescence microscopy, histology and immunohistochemistry.
  
  
  RESULTS
  In nonhepatectomized animals, DPO significantly accelerated tumor cell engraftment and slightly enhanced tumor neovascularization. Tumor cell migration and host tissue infiltration were not affected by DPO. In hepatectomized animals, DPO slightly enhanced tumor growth and significantly accelerated tumor neovascularization, but did not affect tumor cell migration and infiltration.
  
  
  CONCLUSIONS
  The present study indicates that DPO accelerates extrahepatic engraftment of colorectal cancer cells, most probably by stimulating the process of neovascularization.
authors.affiliation: Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Senger
authors.forename: Otto
authors.initials: O
authors.lastname: Kollmar
authors.forename: Michael D
authors.initials: MD
authors.lastname: Menger
authors.forename: Martin K
authors.initials: MK
authors.lastname: Schilling
authors.forename: Kathrin
authors.initials: K
authors.lastname: Rupertus
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000473:pathology*; D000068256:Darbepoetin alfa; D004921:Erythropoietin / Q000009:adverse effects / Q000031:analogs & derivatives*; D005260:Female; D006397:Hematinics / Q000009:adverse effects*; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000139:chemically induced*; D011897:Random Allocation
chemical_list: D006397:Hematinics; D004921:Erythropoietin; D000068256:Darbepoetin alfa