Denko Nicholas C, Fontana Lucrezia A, Hudson Karen M, Sutphin Patrick D, Raychaudhuri Soumya, Altman Russ, Giaccia Amato J
Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Oncogene. 2003 Sep 1;22(37):5907-14. doi: 10.1038/sj.onc.1206703.
Clinical evidence shows that tumor hypoxia is an independent prognostic indicator of poor patient outcome. Hypoxic tumors have altered physiologic processes, including increased regions of angiogenesis, increased local invasion, increased distant metastasis and altered apoptotic programs. Since hypoxia is a potent controller of gene expression, identifying hypoxia-regulated genes is a means to investigate the molecular response to hypoxic stress. Traditional experimental approaches have identified physiologic changes in hypoxic cells. Recent studies have identified hypoxia-responsive genes that may define the mechanism(s) underlying these physiologic changes. For example, the regulation of glycolytic genes by hypoxia can explain some characteristics of the Warburg effect. The converse of this logic is also true. By identifying new classes of hypoxia-regulated gene(s), we can infer the physiologic pressures that require the induction of these genes and their protein products. Furthermore, these physiologically driven hypoxic gene expression changes give us insight as to the poor outcome of patients with hypoxic tumors. Approximately 1-1.5% of the genome is transcriptionally responsive to hypoxia. However, there is significant heterogeneity in the transcriptional response to hypoxia between different cell types. Moreover, the coordinated change in the expression of families of genes supports the model of physiologic pressure leading to expression changes. Understanding the evolutionary pressure to develop a 'hypoxic response' provides a framework to investigate the biology of the hypoxic tumor microenvironment.
临床证据表明，肿瘤缺氧是患者预后不良的独立预后指标。缺氧肿瘤具有改变的生理过程，包括血管生成区域增加、局部侵袭增加、远处转移增加以及凋亡程序改变。由于缺氧是基因表达的有效调控因子，鉴定缺氧调节基因是研究对缺氧应激分子反应的一种手段。传统实验方法已确定了缺氧细胞中的生理变化。最近的研究已鉴定出可能定义这些生理变化潜在机制的缺氧反应基因。例如，缺氧对糖酵解基因的调控可以解释瓦伯格效应的一些特征。这种逻辑的反命题也是正确的。通过鉴定新的缺氧调节基因类别，我们可以推断出需要诱导这些基因及其蛋白质产物的生理压力。此外，这些由生理驱动的缺氧基因表达变化让我们了解到缺氧肿瘤患者预后不良的情况。基因组中约1 - 1.5%对缺氧有转录反应。然而，不同细胞类型对缺氧的转录反应存在显著异质性。此外，基因家族表达的协同变化支持了生理压力导致表达变化的模型。理解产生“缺氧反应”的进化压力为研究缺氧肿瘤微环境的生物学提供了一个框架。
