Bindra Ranjit S, Crosby Meredith E, Glazer Peter M
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520-8040, USA.
Cancer Metastasis Rev. 2007 Jun;26(2):249-60. doi: 10.1007/s10555-007-9061-3.
Emerging evidence indicates that the tumor microenvironmental stress of hypoxia can induce genetic instability in cancer cells. We and others have found that the expression levels of key genes within the DNA mismatch repair (MMR) and homologous recombination (HR) pathways are coordinately repressed by hypoxia. These decreases are associated with functional impairments in both MMR and HR repair under hypoxic conditions, and thus they represent a possible mechanistic explanation for the observed phenomenon of hypoxia-induced genetic instability. In parallel, studies also indicate that several DNA damage response factors are activated in response to hypoxia and subsequent reoxygenation, including ATM/ATR, Chkl/Chk2 and BRCA1. Taken together, these findings reveal that hypoxia induces a unique cellular stress response involving an initial, acute DNA damage response to hypoxia and reoxygenation, followed by a chronic response to prolonged hypoxia in which selected DNA repair pathways are coordinately suppressed. In this review, we discuss these pathways and the possible mechanisms involved, as well as the consequences for genetic instability and tumor progression within the tumor microenvironment.
新出现的证据表明，缺氧的肿瘤微环境应激可诱导癌细胞中的基因不稳定。我们和其他人发现，DNA错配修复（MMR）和同源重组（HR）途径中的关键基因表达水平会被缺氧协同抑制。这些降低与缺氧条件下MMR和HR修复的功能受损有关，因此它们代表了对观察到的缺氧诱导基因不稳定现象的一种可能的机制解释。同时，研究还表明，几种DNA损伤反应因子会在缺氧及随后的复氧过程中被激活，包括ATM/ATR、Chk1/Chk2和BRCA1。综上所述，这些发现揭示了缺氧诱导一种独特的细胞应激反应，包括对缺氧和复氧的初始急性DNA损伤反应，随后是对长期缺氧的慢性反应，其中特定的DNA修复途径被协同抑制。在这篇综述中，我们讨论了这些途径和可能涉及的机制，以及肿瘤微环境中基因不稳定和肿瘤进展的后果。
