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Hepatic ischemia-reperfusion increases circulating bone marrow-derived progenitor cells and tumor growth in a mouse model of colorectal liver metastases

  • Chetana Lim
    Correspondence
    Corresponding author. Angiogenese et Recherche Translationnelle, INSERM U965, 2 Rue Ambroise Pare, 75475 Paris Cedex 10, France. Tel.: +33 1 49 95 82 58; fax: +33 1 49 95 91 02.
    Affiliations
    Unité INSERM U965 (Université Paris 7), équipe “Angiogénèse et Recherche Translationnelle,” Hôpital Lariboisière, Paris, France
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  • Dong Broqueres-You
    Affiliations
    Unité INSERM U965 (Université Paris 7), équipe “Angiogénèse et Recherche Translationnelle,” Hôpital Lariboisière, Paris, France

    Institut des Vaisseaux et du Sang, Hôpital Lariboisière, Paris, France

    Paris Cardiovascular Research Center (PARCC), INSERM U970, Hôpital Européen Georges Pompidou, Paris, France
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  • Jean-Philippe Brouland
    Affiliations
    Unité INSERM U965 (Université Paris 7), équipe “Angiogénèse et Recherche Translationnelle,” Hôpital Lariboisière, Paris, France

    Service d’Anatomo-pathologie, Hôpital Lariboisière, Paris, France
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  • Tatiana Merkulova-Rainon
    Affiliations
    Unité INSERM U965 (Université Paris 7), équipe “Angiogénèse et Recherche Translationnelle,” Hôpital Lariboisière, Paris, France

    Institut des Vaisseaux et du Sang, Hôpital Lariboisière, Paris, France
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  • Anne-Marie Faussat
    Affiliations
    IFR 65, PlateForme Cytométrie, Hôpital Saint-Antoine, Paris, France
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  • Rose Hilal
    Affiliations
    Unité INSERM U965 (Université Paris 7), équipe “Angiogénèse et Recherche Translationnelle,” Hôpital Lariboisière, Paris, France
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  • Delphine Rouquie
    Affiliations
    Unité INSERM U965 (Université Paris 7), équipe “Angiogénèse et Recherche Translationnelle,” Hôpital Lariboisière, Paris, France
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  • Clarisse Eveno
    Affiliations
    Unité INSERM U965 (Université Paris 7), équipe “Angiogénèse et Recherche Translationnelle,” Hôpital Lariboisière, Paris, France
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  • Raphaëlle Audollent
    Affiliations
    Unité INSERM U965 (Université Paris 7), équipe “Angiogénèse et Recherche Translationnelle,” Hôpital Lariboisière, Paris, France
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  • Bernard I. Levy
    Affiliations
    Unité INSERM U965 (Université Paris 7), équipe “Angiogénèse et Recherche Translationnelle,” Hôpital Lariboisière, Paris, France

    Institut des Vaisseaux et du Sang, Hôpital Lariboisière, Paris, France

    Paris Cardiovascular Research Center (PARCC), INSERM U970, Hôpital Européen Georges Pompidou, Paris, France
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  • Marc Pocard
    Affiliations
    Unité INSERM U965 (Université Paris 7), équipe “Angiogénèse et Recherche Translationnelle,” Hôpital Lariboisière, Paris, France

    Service de Chirurgie Digestive et Cancérologique, Assistance Publique des Hôpitaux de Paris, Hôpital Lariboisière, Paris, France
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      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.

      Materials and 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.

      Keywords

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