头颈部鳞状细胞癌的肿瘤代谢：TP53 突变的体外研究及其治疗意义。

Tumour metabolism in squamous cell carcinoma of the head and neck: an in-vitro study of the consequences of TP53 mutation and therapeutic implications.

机构信息

Liverpool Cancer Research Centre, University of Liverpool, Liverpool, UK; Department of Otorhinolaryngology - Head & Neck Surgery, University Hospital Aintree, Liverpool, UK.

出版信息

Lancet. 2015 Feb 26;385 Suppl 1:S101. doi: 10.1016/S0140-6736(15)60416-0.

DOI:10.1016/S0140-6736(15)60416-0

PMID:26312831

Abstract

BACKGROUND

Survival for squamous cell carcinoma of the head and neck (SCCHN) has not improved substantially in recent years. Since radiotherapy is a cornerstone of treatment, it is crucial to identify ways to augment its efficacy, for which tumour metabolism is an attractive target. p53 is a metabolic mediator, and TP53 mutations are common in this disorder. We sought to investigate metabolic changes in SCCHN, to elucidate any correlation with TP53 status, and to determine whether targeted metabolic therapy might be used to potentiate the effects of radiation.

METHODS

Extracellular acidification and oxygen consumptions rates, respective measures of glycolytic flux and mitochondrial respiration, were assayed in real time for a panel of wild-type (wt) and mutant (mut) TP53 SCCHN cell lines in an extracellular flux analyser (XF24, Seahorse Bioscience, Billerica, MA, USA) during specifically designed stress tests. Sensitivity to radiation with or without 25mM 2-deoxyglucose (glycolytic inhibitor) was evaluated in clonogenic assays.

FINDINGS

MutTP53 SCCHN cell lines showed a distinct metabolic phenotype from that of wtTP53 cells: wtTP53 cells maintained metabolic diversity, displaying robust mitochondrial and glycolytic reserve capacities, whereas mutTP53 cells displayed glycolytic dependence with markedly reduced mitochondrial and glycolytic reserve, functioning near capacity under basal conditions. This metabolic shift, in turn, correlated with radiation response after administration of 2-deoxyglucose, which significantly (p<0·05) potentiated effects of radiation in mutTP53 but not wtTP53 cells.

INTERPRETATION

TP53 mutation in SCCHN seems to correlate with a metabolic shift away from mitochondrial respiration towards glycolysis, resulting in sensitivity to the potentiating effects of glycolytic inhibition on radiation. Consequently, TP53 status could be applied clinically as a marker of metabolic phenotype in SCCHN, enabling a more tailored therapeutic approach, which would also specifically target the typically treatment-resistant disease associated with TP53 mutation.

FUNDING

Cancer Research UK, Royal College of Surgeons of England.

摘要

背景

近年来，头颈部鳞状细胞癌（SCCHN）的生存率并未显著提高。由于放疗是治疗的基石，因此确定增强其疗效的方法至关重要，而肿瘤代谢是一个有吸引力的目标。p53 是一种代谢调节剂，TP53 突变在这种疾病中很常见。我们试图研究 SCCHN 的代谢变化，阐明其与 TP53 状态的任何相关性，并确定是否可以使用靶向代谢治疗来增强放疗的效果。

方法

在体外通量分析仪（XF24，Seahorse Bioscience，马萨诸塞州比勒里卡）中，对一组野生型（wt）和突变型（mut）TP53 SCCHN 细胞系进行实时测定，以测定细胞外酸化率和耗氧量，分别为糖酵解通量和线粒体呼吸的指标。在特定的应激测试中，在克隆形成测定中评估了有或没有 25mM 2-脱氧葡萄糖（糖酵解抑制剂）的辐射敏感性。

结果

MutTP53 SCCHN 细胞系表现出与 wtTP53 细胞不同的代谢表型：wtTP53 细胞保持代谢多样性，表现出强大的线粒体和糖酵解储备能力，而 mutTP53 细胞表现出糖酵解依赖性，线粒体和糖酵解储备明显减少，在基础条件下接近容量。这种代谢转变反过来又与 2-脱氧葡萄糖给药后的辐射反应相关，2-脱氧葡萄糖显著（p<0·05）增强了 mutTP53 但不是 wtTP53 细胞的辐射效应。