title: Hepatic ischemia-reperfusion increases circulating bone marrow-derived progenitor cells and tumor growth in a mouse model of colorectal liver metastases.
abstract: BACKGROUND
  Hepatic pedicle clamping is often required to reduce blood loss and transfusion during liver resection. However, the question remains whether use of hepatic pedicle clamping promotes tumor growth. Endothelial progenitor cells (EPCs) are mobilized from bone marrow in response to tissue ischemia, which allows neovascularization of ischemic tissue. It has been suggested that EPCs are involved in tumor progression. We hypothesized that hepatic ischemia reperfusion (I/R)-induced mobilization of EPCs could enhance growth of microscopic tumor, therefore promoting liver metastasis in a mouse model of colorectal cancer.
  
  
  METHODS
  We used mouse models of hepatic I/R and hind limb ischemia. For comparison, we studied mice that underwent limb ischemia as positive controls of EPC mobilization. At day 0, we divided 40 mice into four groups: hepatic I/R, hind limb ischemia, combined hepatic I/R and hind limb ischemia, and control (sham midline incision laparotomy). At day 2, we induced liver metastasis in all mice by injecting CT-26 cells into the spleen. Time-dependent circulating EPCs were determined by flow cytometry. We evaluated liver metastasis and microvascular density on day 21.
  
  
  RESULTS
  The number of circulating progenitor cells increased rapidly in the ischemic groups compared with the control group. Hepatic I/R significantly increased tumor outgrowth compared with the control group. Increased tumor growth was associated with enhanced CD31-positive microvascular density in liver tissue.
  
  
  CONCLUSIONS
  Hepatic I/R leads to mobilization of bone marrow-derived EPCs and enhanced intra-hepatic angiogenesis, which is associated with increased tumor burden in an animal model of colorectal liver metastasis.
authors.affiliation: Unité INSERM U965 (Université Paris 7), équipe "Angiogénèse et Recherche Translationnelle," Hôpital Lariboisière, Paris, France. Electronic address: chetana.lim@gmail.com.
authors.forename: Chetana
authors.initials: C
authors.lastname: Lim
authors.forename: Dong
authors.initials: D
authors.lastname: Broqueres-You
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Brouland
authors.forename: Tatiana
authors.initials: T
authors.lastname: Merkulova-Rainon
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Faussat
authors.forename: Rose
authors.initials: R
authors.lastname: Hilal
authors.forename: Delphine
authors.initials: D
authors.lastname: Rouquie
authors.forename: Clarisse
authors.initials: C
authors.lastname: Eveno
authors.forename: Raphaëlle
authors.initials: R
authors.lastname: Audollent
authors.forename: Bernard I
authors.initials: BI
authors.lastname: Levy
authors.forename: Marc
authors.initials: M
authors.lastname: Pocard
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology*; D002452:Cell Count; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000097:blood; D015179:Colorectal Neoplasms / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D008099:Liver / Q000098:blood supply*; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D015427:Reperfusion Injury / Q000503:physiopathology*
chemical_list: D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse
keywords: Angiogenesis; Bone marrow–derived progenitor cells; CT-26 colon cancer cells; Colorectal liver metastasis; Ischemia-reperfusion; Mobilization