title: Cycling hypoxia induces a specific amplified inflammatory phenotype in endothelial cells and enhances tumor-promoting inflammation in vivo.
abstract: Abnormal architecture of the tumor blood network, as well as heterogeneous erythrocyte flow, leads to temporal fluctuations in tissue oxygen tension exposing tumor and stromal cells to cycling hypoxia. Inflammation is another feature of tumor microenvironment and is considered as a new enabling characteristic of tumor progression. As cycling hypoxia is known to participate in tumor aggressiveness, the purpose of this study was to evaluate its role in tumor-promoting inflammation. Firstly, we assessed the impact of cycling hypoxia in vitro on endothelial inflammatory response induced by tumor necrosis factor α. Results showed that endothelial cells exposed to cycling hypoxia displayed an amplified proinflammatory phenotype, characterized by an increased expression of inflammatory cytokines, namely, interleukin (IL)-6 and IL-8; by an increased expression of adhesion molecules, in particular intercellular adhesion molecule-1 (ICAM-1); and consequently by an increase in THP-1 monocyte adhesion. This exacerbation of endothelial inflammatory phenotype occurs through nuclear factor-κB overactivation. Secondly, the role of cycling hypoxia was studied on overall tumor inflammation in vivo in tumor-bearing mice. Results showed that cycling hypoxia led to an enhanced inflammation in tumors as prostaglandin-endoperoxide synthase 2 (PTGS2), IL-6, CXCL1 (C-X-C motif ligand 1), and macrophage inflammatory protein 2 (murine IL-8 functional homologs) mRNA expression was increased and as a higher leukocyte infiltration was evidenced. Furthermore, cycling hypoxia-specific inflammatory phenotype, characterized by a simultaneous (baculoviral inhibitor of apoptosis repeat-containing 5)(low)/PTGS2(high)/ICAM-1(high)/IL-6(high)/IL-8(high) expression, is associated with a poor prognosis in human colon cancer. This new phenotype could thus be used in clinic to more precisely define prognosis for colon cancer patients. In conclusion, our findings evidenced for the first time the involvement of cycling hypoxia in tumor-promoting inflammation amplification.
authors.affiliation: Unit of Biochemistry and Cellular Biology (URBC), Namur Research Institute for LIfe Sciences (NARILIS), University of Namur (UNamur), 61 Rue de Bruxelles, B-5000 Namur, Belgium.
authors.forename: Céline
authors.initials: C
authors.lastname: Tellier
authors.affiliation: Unit of Biochemistry and Cellular Biology (URBC), Namur Research Institute for LIfe Sciences (NARILIS), University of Namur (UNamur), 61 Rue de Bruxelles, B-5000 Namur, Belgium.
authors.forename: Déborah
authors.initials: D
authors.lastname: Desmet
authors.affiliation: Unit of Pharmacology and Therapeutics (FATH 5349), University of Louvain Medical School (UCL), 52 Avenue Mounier, B-1200 Bruxelles, Belgium.
authors.forename: Laurenne
authors.initials: L
authors.lastname: Petit
authors.affiliation: Biobank, CHU Dinant-Mont-Godinne, UCL, 1 Avenue Docteur G.Thérasse, B-5530 Yvoir, Belgium.
authors.forename: Laure
authors.initials: L
authors.lastname: Finet
authors.affiliation: Biobank, CHU Dinant-Mont-Godinne, UCL, 1 Avenue Docteur G.Thérasse, B-5530 Yvoir, Belgium.
authors.forename: Carlos
authors.initials: C
authors.lastname: Graux
authors.affiliation: Unit of Biochemistry and Cellular Biology (URBC), Namur Research Institute for LIfe Sciences (NARILIS), University of Namur (UNamur), 61 Rue de Bruxelles, B-5000 Namur, Belgium.
authors.forename: Martine
authors.initials: M
authors.lastname: Raes
authors.affiliation: Unit of Pharmacology and Therapeutics (FATH 5349), University of Louvain Medical School (UCL), 52 Avenue Mounier, B-1200 Bruxelles, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Feron
authors.affiliation: Unit of Biochemistry and Cellular Biology (URBC), Namur Research Institute for LIfe Sciences (NARILIS), University of Namur (UNamur), 61 Rue de Bruxelles, B-5000 Namur, Belgium. Electronic address: carine.michiels@unamur.be.
authors.forename: Carine
authors.initials: C
authors.lastname: Michiels
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D010641:Phenotype; D011379:Prognosis
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B