Systemic oxygenation weakens the hypoxia and hypoxia inducible factor 1α-dependent and extracellular adenosine-mediated tumor protection.
Systemic oxygenation weakens the hypoxia and hypoxia inducible factor 1α-dependent and extracellular adenosine-mediated tumor protection.
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DOI：
10.1007/s00109-014-1189-3
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发表时间：
2014-12
影响因子：
4.7
通讯作者：
Sitkovsky, Michail
中科院分区：
文献类型：
--
作者：
Hatfield, Stephen M.;Kjaergaard, Jorgen;Lukashev, Dmitriy;Belikoff, Bryan;Schreiber, Taylor H.;Sethumadhavan, Shalini;Abbott, Robert;Philbrook, Phaethon;Thayer, Molly;Shujia, Dai;Rodig, Scott;Kutok, Jeffrey L.;Ren, Jin;Ohta, Akio;Podack, Eckhard R.;Karger, Barry;Jackson, Edwin K.;Sitkovsky, Michail
肿瘤内缺氧和缺氧诱导因子-1α (HIF-1α)依赖的CD39/CD73外酶可能控制肿瘤微环境（TME）中保护肿瘤的细胞外腺苷的积累和通过A2A腺苷受体（A2AR）的信号传导。在这里，我们探索了使用补充氧气作为抑制缺氧/HIF-1α-CD39/ cd73驱动的细胞外腺苷在TME中的积累以削弱肿瘤保护的概念上的新动机。我们报道，根据小鼠蛋白质组学研究，高氧呼吸（60% O2）降低了TME缺氧，以及TME中HIF-1α和HIF-1α下游靶蛋白的水平。重要的是，氧合还下调了TME中腺苷生成外酶的表达，并显著降低了肿瘤保护细胞外腺苷的水平。使用补充氧作为TME研究的工具，我们还发现FHL-1是将低氧TME转化为常氧TME的潜在有用标记。高氧呼吸导致肿瘤细胞上抗原呈递mhc - I类分子的上调，肿瘤反应性细胞毒性T细胞更好地识别和增加对杀伤的易感性。治疗性呼吸60%的氧气导致明显抑制已建立的B16的生长。F10黑色素瘤和延长小鼠存活。综上所述，本文提供的数据为全身氧合的治疗潜力提供了原理证明，将缺氧、富含腺苷和保护肿瘤的TME转化为缺氧、细胞外缺乏腺苷的TME，进而可能促进肿瘤消退。我们建议探索补充氧与现有癌症免疫疗法的结合。
Intratumoral hypoxia and Hypoxia Inducible Factor-1α (HIF-1α)-dependent CD39/CD73 ecto-enzymes may govern the accumulation of tumor-protecting extracellular adenosine and signaling through the A2A adenosine receptors (A2AR) in tumor microenvironments (TME). Here, we explored the conceptually novel motivation to use supplemental oxygen as a treatment to inhibit the hypoxia/HIF-1α-CD39/CD73-driven accumulation of extracellular adenosine in the TME in order to weaken the tumor protection. We report that hyperoxic breathing (60% O2) decreased the TME hypoxia, as well as levels of HIF-1α and downstream target proteins of HIF-1α in the TME according to proteomics studies in mice. Importantly, oxygenation also down-regulated the expression of adenosine-generating ecto-enzymes and significantly lowered levels of tumor-protecting extracellular adenosine in the TME. Using supplemental oxygen as a tool in studies of the TME, we also identified FHL-1 as a potentially useful marker for the conversion of hypoxic into normoxic TME. Hyperoxic breathing resulted in the up-regulation of antigen-presenting MHC-class I molecules on tumor cells and in the better recognition and increased susceptibility to killing by tumor-reactive cytotoxic T cells. Therapeutic breathing of 60% oxygen resulted in the significant inhibition of growth of established B16.F10 melanoma tumors and prolonged survival of mice. Taken together, the data presented here provide proof-of principle for the therapeutic potential of systemic oxygenation to convert the hypoxic, adenosine-rich and tumor-protecting TME into a normoxic and extracellular adenosine-poor TME that, in turn, may facilitate tumor regression. We propose to explore the combination of supplemental oxygen with existing immunotherapies of cancer.
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影响因子：
20.3
作者：
Manalo, DJ;Rowan, A;Semenza, GL
通讯作者：
Semenza, GL
DOI：
10.1073/pnas.0605251103
发表时间：
2006-08-29
影响因子：
11.1
作者：
Ohta, Akio;Gorelik, Elieser;Sitkovsky, Michail
通讯作者：
Sitkovsky, Michail
影响因子：
4.7
作者：
Longhi, Maria Serena;Robson, Simon C.;Bernstein, Steven H.;Serra, Sara;Deaglio, Silvia
通讯作者：
Deaglio, Silvia
DOI：
10.1073/pnas.0812801106
发表时间：
2009-02-17
影响因子：
11.1
作者：
Lee, KangAe;Qian, David Z.;Semenza, Gregg L.
通讯作者：
Semenza, Gregg L.
影响因子：
11.5
作者：
Sitkovsky, Michail V.;Kjaergaard, Jorgen;Ohta, Akio
通讯作者：
Ohta, Akio