Université catholique de Louvain, Unit of Pharmacology and Therapeutics (UCL-FATH 5349), Brussels, Belgium.
Clin Cancer Res. 2010 Jan 15;16(2):410-9. doi: 10.1158/1078-0432.CCR-09-0583. Epub 2010 Jan 12.
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 pO(2) fluctuations, particularly transient reoxygenation periods, alter the well-known hypoxia-inducible factor (HIF)-dependent gene program is largely unknown.
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.
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-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. 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.
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.
肿瘤中的循环缺氧源于 RBC 流量的异质性，不仅影响肿瘤细胞，还影响肿瘤血管内皮细胞。pO2 波动，特别是短暂的再氧合期，是否会改变众所周知的缺氧诱导因子（HIF）依赖性基因程序，在很大程度上尚不清楚。
我们比较了暴露于周期性缺氧与持续缺氧的内皮细胞和肿瘤细胞的转录组谱，以揭示对血管生成和转移的可能的差异影响。
微阵列分析鉴定了内皮细胞中由周期性缺氧选择性诱导的早期基因。其中，我们专注于 PTGS2，因为观察到的 mRNA 表达增加导致环氧化酶-2（COX-2；PTGS2 的蛋白产物）的表达和活性显著增加。已经表明，HIF-1alpha 被周期性缺氧稳定（尽管有再氧合期），并有利于 COX-2 的诱导，这通过使用埃可霉素和 HIF-1alpha 靶向小干扰 RNA 得到验证。使用特异性 COX-2 抑制剂和专门的 COX-2 靶向小干扰 RNA，我们记录到 COX-2 解释了由周期性缺氧赋予的更高的内皮细胞存活和血管生成潜力。周期性缺氧还导致肿瘤细胞中 COX-2 的优先诱导，并且与持续缺氧相反，促进了预先挑战的肿瘤细胞更高的转移率。
我们的研究表明，PTGS2/COX-2 是周期性缺氧基因特征的一部分，在很大程度上解释了暴露于 pO2 波动的内皮细胞和肿瘤细胞的独特表型，从而为表达 COX-2 与其他周期性缺氧反应基因的肿瘤聚类提供了新的视角。
