Moeller Benjamin J, Dreher Matthew R, Rabbani Zahid N, Schroeder Thies, Cao Yiting, Li Chuan Y, Dewhirst Mark W
Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Cancer Cell. 2005 Aug;8(2):99-110. doi: 10.1016/j.ccr.2005.06.016.
We have previously shown that radiation increases HIF-1 activity in tumors, causing significant radioprotection of the tumor vasculature. The impact that HIF-1 activation has on overall tumor radiosensitivity, however, is unknown. We reveal here that HIF-1 plays an important role in determining tumor radioresponsiveness through regulating four distinct processes. By promoting ATP metabolism, proliferation, and p53 activation, HIF-1 has a radiosensitizing effect on tumors. Through stimulating endothelial cell survival, HIF-1 promotes tumor radioresistance. As a result, the net effect of HIF-1 blockade on tumor radioresponsiveness is highly dependent on treatment sequencing, with "radiation first" strategies being significantly more effective than the alternative. These data provide a strong rationale for pursuing sequence-specific combinations of HIF-1 blockade and conventional therapeutics.
我们之前已经表明，辐射会增加肿瘤中HIF-1的活性，从而对肿瘤血管系统产生显著的辐射防护作用。然而，HIF-1激活对肿瘤总体放射敏感性的影响尚不清楚。我们在此揭示，HIF-1通过调节四个不同的过程在决定肿瘤放射反应性方面发挥重要作用。通过促进ATP代谢、增殖和p53激活，HIF-1对肿瘤具有放射增敏作用。通过刺激内皮细胞存活，HIF-1促进肿瘤放射抗性。因此，HIF-1阻断对肿瘤放射反应性的净效应高度依赖于治疗顺序，“先放疗”策略比其他策略显著更有效。这些数据为采用HIF-1阻断与传统疗法的顺序特异性联合方案提供了有力的理论依据。
