Identification of cyclooxygenase-2 as a major actor of the transcriptomic adaptation of endothelial and tumor cells to cyclic hypoxia: effect on angiogenesis and metastases.
[en] Purpose: Cyclic hypoxia in tumors originates from heterogeneities in RBC flux and influences not only tumor cells but also endothelial cells lining tumor blood vessels. Whether pO2 fluctuations, particularly transient reoxygenation periods, alter the well-known hypoxia-inducible factor (HIF)–dependent gene program is largely unknown.
Experimental Design: We compared the transcriptomic profiles of endothelial and tumor cells exposed to cyclic hypoxia versus continuous hypoxia to uncover a possible differential effect on angiogenesis and metastases.
Results: Microarray analyses identified early genes that were selectively induced by cyclic hypoxia in endothelial cells. Among them, we focused on PTGS2 because the observed increase in mRNA expression led to a significant increase in the expression and activity of cyclooxygenase-2 (COX-2; the protein product of PTGS2). HIF-1α was shown to be stabilized by cyclic hypoxia (despite reoxygenation periods) and to favor COX-2 induction as validated by the use of echinomycin and HIF-1α targeting small interfering RNA. Using a specific COX-2 inhibitor and a dedicated COX-2 targeting small interfering RNA, we documented that COX-2 accounted for the higher endothelial cell survival and angiogenic potential conferred by cyclic hypoxia. Cyclic hypoxia also led to a preferential COX-2 induction in tumor cells and, contrary to continuous hypoxia, fostered a higher metastatic take of prechallenged tumor cells.
Conclusions: Our study documents that PTGS2/COX-2 is part of a cyclic hypoxia gene signature and largely accounts for the unique phenotype of endothelial and tumor cells exposed to fluctuations in pO2, thereby offering new perspectives for the clustering of tumors expressing COX-2 together with other cyclic hypoxia-responsive genes. Clin Cancer Res; 16(2); 410–9 [fr] OBJECTIF: hypoxie cycliques dans les tumeurs proviennent de l'hétérogénéité dans le flux de RBC et influence non seulement les cellules tumorales mais également des cellules endothéliales qui tapissent les vaisseaux sanguins tumoraux. Whether pO(2) fluctuations, particularly transient reoxygenation periods, alter the well-known hypoxia-inducible factor (HIF)-dependent gene program is largely unknown. Que Po (2) les fluctuations, en particulier réoxygénation des périodes transitoires, de modifier l'hypoxie bien connue-inducible factor (HIF)-programme des gènes dépendant est largement inconnue. EXPERIMENTAL DESIGN: We compared the transcriptomic profiles of endothelial and tumor cells exposed to cyclic hypoxia versus continuous hypoxia to uncover a possible differential effect on angiogenesis and metastases. EXPERIMENTAL DESIGN: Nous avons comparé les profils transcriptomiques de endothéliales et les cellules tumorales exposées à l'hypoxie cyclique par rapport à l'hypoxie continue de découvrir un effet différentiel possible sur l'angiogénèse et les métastases. RESULTS: Microarray analyses identified early genes that were selectively induced by cyclic hypoxia in endothelial cells. RÉSULTATS: Les analyses de biopuces identifié les gènes précoces qui ont été sélective induite par l'hypoxie cyclique dans les cellules endothéliales. Among them, we focused on PTGS2 because the observed increase in mRNA expression led to a significant increase in the expression and activity of cyclooxygenase-2 (COX-2; the protein product of PTGS2). Parmi eux, nous nous sommes concentrés sur PTGS2 parce que l'augmentation observée dans l'expression des ARNm conduit à une augmentation significative de l'expression et l'activité de la cyclooxygénase-2 (COX-2, la protéine produite par PTGS2). HIF-1alpha was shown to be stabilized by cyclic hypoxia (despite reoxygenation periods) and to favor COX-2 induction as validated by the use of echinomycin and HIF-1alpha targeting small interfering RNA. HIF-1alpha a été montré pour être stabilisé par l'hypoxie cyclique (en dépit de réoxygénation périodes) et à favoriser la COX-2 induction tels que validés par l'utilisation de echinomycin et HIF-1alpha destiné aux petits ARN interférents. Using a specific COX-2 inhibitor and a dedicated COX-2 targeting small interfering RNA, we documented that COX-2 accounted for the higher endothelial cell survival and angiogenic potential conferred by cyclic hypoxia. L'utilisation d'un spécifiques de la COX-2 et un inhibiteur de la COX-2 dédié destiné aux petits ARN interférents, nous avons documenté que la COX-2 ont représenté pour la survie plus élevé de cellules endothéliales et le potentiel angiogénique conférés par l'hypoxie cyclique. Cyclic hypoxia also led to a preferential COX-2 induction in tumor cells and, contrary to continuous hypoxia, fostered a higher metastatic take of prechallenged tumor cells. Cyclic hypoxie a également conduit à la COX-2 induction préférentielle dans les cellules tumorales et, contrairement à l'hypoxie en continu, a favorisé une plus prendre métastatique des cellules tumorales prechallenged. CONCLUSIONS: Our study documents that PTGS2/COX-2 is part of a cyclic hypoxia gene signature and largely accounts for the unique phenotype of endothelial and tumor cells exposed to fluctuations in pO(2), thereby offering new perspectives for the clustering of tumors expressing COX-2 together with other cyclic hypoxia-responsive genes. CONCLUSIONS: Notre étude montre que PTGS2/COX-2 fait partie d'une signature cyclique hypoxie génique et explique en grande partie le phénotype unique de endothéliales et les cellules tumorales exposées à des fluctuations de Po (2), offrant ainsi de nouvelles perspectives pour le regroupement des tumeurs exprimant COX-2, ainsi que l'hypoxie cyclique autres gènes sensibles.
Disciplines :
Oncology
Author, co-author :
Daneau, Géraldine; Université Catholique de Louvain - UCL > Pharmacology and Therapeutics
Boidot, Romain; Université catholique de Louvain > Pharmacology and Therapeutics
MARTINIVE, Philippe ; Centre Hospitalier Universitaire de Liège - CHU > Radiothérapie
Feron, Olivier; Pharmacology and Therapeutics
Language :
English
Title :
Identification of cyclooxygenase-2 as a major actor of the transcriptomic adaptation of endothelial and tumor cells to cyclic hypoxia: effect on angiogenesis and metastases.
Alternative titles :
[en] Identification de la cyclooxygénase-2 comme un acteur majeur de l'adaptation du transcriptome d'effet endothéliales et les cellules tumorales à l'hypoxie cyclique: sur l'angiogénèse et les métastases.
Publication date :
15 January 2010
Journal title :
Clinical Cancer Research
ISSN :
1078-0432
eISSN :
1557-3265
Publisher :
American Association for Cancer Research, Inc. (AACR), Birmingham, United States - Alabama
Volume :
16
Issue :
2
Pages :
410-419
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
Informations complémentaires
Departement : Département: UCL - "MD/MINT - Département de médecine interne" UCL - "MD / MINT - Département de Médecine Interne"
Type : Type: Article de périodique (Journal article) Article de périodique (Journal article)
Source : Source: "Clinical cancer research : an official journal of the American Association for Cancer Research" - Vol. «La recherche clinique sur le cancer: une revue officielle de l'American Association for Cancer Research" - Vol. 16, no. 16, no. 2 p. 2 p. 410-9 (2010) 410-9 (2010)
issn : ISSN: 1078-0432 1078-0432
Date de publication : Date de publication: 2010 2010
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