Acute Tumor Lactate Perturbations as a Biomarker of Genotoxic Stress: Development of a Biochemical Model.
Acute Tumor Lactate Perturbations as a Biomarker of Genotoxic Stress: Development of a Biochemical Model.
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DOI：
10.1158/1535-7163.mct-15-0217
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发表时间：
2015-12
影响因子：
5.7
通讯作者：
Lai SY
中科院分区：
文献类型：
--
作者：
Sandulache VC;Chen Y;Skinner HD;Lu T;Feng L;Court LE;Myers JN;Meyn RE;Fuller CD;Bankson JA;Lai SY
电离辐射是实体瘤的主要非手术治疗方式。其有效性受到时间限制的影响，如分异、缺氧和耐辐射克隆的发育。急性放射反应的生物标志物对于开发更有效的临床算法至关重要。我们假设肿瘤乳酸水平的急性扰动作为辐射反应的替代标志物。体外实验采用经验证的人甲状腺间变性癌（ATC）、头颈部鳞状细胞癌（HNSCC）和甲状腺乳头状癌（PTC） 3种组织学来源的细胞系进行。细胞代谢活性用标准生化测定法测定。使用先前建立的ATC异种移植小鼠模型的正位和侧翼衍生物进行体内验证。细胞和肿瘤的照射触发了乳酸水平的快速、剂量依赖性、短暂性下降，这被自由基清除剂逆转。辐照后急性乳酸扰动可以识别缺氧状态，并与缺氧引起的辐射抵抗相关。突变的TP53细胞和p53活性被剥夺的细胞（shRNA）对辐射表现出钝化的乳酸反应，与辐射抗性表型一致。因此，乳酸测量可以快速检测到诱导（即缺氧）和内在（即mutp53驱动）的辐射抗性。我们得出结论，乳酸是急性遗传毒性应激的定量生物标志物，具有时间分辨率，可以为临床决策提供信息。结合新开发的代谢成像平台的空间分辨率，这种生物标志物可能会导致真正个性化治疗策略的发展。
Ionizing radiation is the primary non-surgical treatment modality for solid tumors. Its effectiveness is impacted by temporal constraints such as fractionation, hypoxia and development of radioresistant clones. Biomarkers of acute radiation response are essential to developing more effective clinical algorithms. We hypothesized that acute perturbations in tumor lactate levels act as a surrogate marker of radiation response. In vitro experiments were carried out using validated human derived cell lines from 3 histologies: anaplastic thyroid carcinoma (ATC), head and neck squamous cell carcinoma (HNSCC) and papillary thyroid carcinoma (PTC). Cellular metabolic activity was measured using standard biochemical assays. In vivo validation was performed using both an orthotopic and a flank derivative of a previously established ATC xenograft murine model. Irradiation of cells and tumors triggered a rapid, dose-dependent, transient decrease in lactate levels which was reversed by free radical scavengers. Acute lactate perturbations following irradiation could identify hypoxic conditions and correlated with hypoxia-induced radioresistance. Mutant TP53 cells and cells in which p53 activity was abrogated (shRNA) demonstrated a blunted lactate response to irradiation, consistent with a radioresistant phenotype. Lactate measurements therefore rapidly detected both induced (i.e. hypoxia) and intrinsic (i.e. mutTP53 driven) radioresistance. We conclude that lactate is a quantitative biomarker of acute genotoxic stress, with a temporal resolution which can inform clinical decision-making. Combined with the spatial resolution of newly developed metabolic imaging platforms, this biomarker could lead to the development of truly individualized treatment strategies.