PDF(Pubmed)
Abstract：
Telomere maintenance is a hallmark of cancer. Most tumors maintain telomere length via reactivation of telomerase reverse transcriptase (TERT) expression. Identifying clinically translatable imaging biomarkers of TERT can enable noninvasive assessment of tumor proliferation and response to therapy.
We used RNAi, doxycycline-inducible expression systems, and pharmacologic inhibitors to mechanistically delineate the association between TERT and metabolism in preclinical patient-derived tumor models. Deuterium magnetic resonance spectroscopy (2H-MRS), which is a novel, translational metabolic imaging modality, was used for imaging TERT in cells and tumor-bearing mice in vivo.
Our results indicate that TERT expression is associated with elevated NADH in multiple cancers, including glioblastoma, oligodendroglioma, melanoma, neuroblastoma, and hepatocellular carcinoma. Mechanistically, TERT acts via the metabolic regulator FOXO1 to upregulate nicotinamide phosphoribosyl transferase, which is the key enzyme for NAD+ biosynthesis, and the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase, which converts NAD+ to NADH. Because NADH is essential for pyruvate flux to lactate, we show that 2H-MRS-based assessment of lactate production from [U-2H]-pyruvate reports on TERT expression in preclinical tumor models in vivo, including at clinical field strength (3T). Importantly, [U-2H]-pyruvate reports on early response to therapy in mice bearing orthotopic patient-derived gliomas at early timepoints before radiographic alterations can be visualized by MRI.
Elevated NADH is a metabolic consequence of TERT expression in cancer. Importantly, [U-2H]-pyruvate reports on early response to therapy, prior to anatomic alterations, thereby providing clinicians with a novel tool for assessment of tumor burden and treatment response in cancer.
We used RNAi, doxycycline-inducible expression systems, and pharmacologic inhibitors to mechanistically delineate the association between TERT and metabolism in preclinical patient-derived tumor models. Deuterium magnetic resonance spectroscopy (2H-MRS), which is a novel, translational metabolic imaging modality, was used for imaging TERT in cells and tumor-bearing mice in vivo.
Our results indicate that TERT expression is associated with elevated NADH in multiple cancers, including glioblastoma, oligodendroglioma, melanoma, neuroblastoma, and hepatocellular carcinoma. Mechanistically, TERT acts via the metabolic regulator FOXO1 to upregulate nicotinamide phosphoribosyl transferase, which is the key enzyme for NAD+ biosynthesis, and the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase, which converts NAD+ to NADH. Because NADH is essential for pyruvate flux to lactate, we show that 2H-MRS-based assessment of lactate production from [U-2H]-pyruvate reports on TERT expression in preclinical tumor models in vivo, including at clinical field strength (3T). Importantly, [U-2H]-pyruvate reports on early response to therapy in mice bearing orthotopic patient-derived gliomas at early timepoints before radiographic alterations can be visualized by MRI.
Elevated NADH is a metabolic consequence of TERT expression in cancer. Importantly, [U-2H]-pyruvate reports on early response to therapy, prior to anatomic alterations, thereby providing clinicians with a novel tool for assessment of tumor burden and treatment response in cancer.
摘要：
端粒维持是癌症的标志。大多数肿瘤通过端粒酶逆转录酶（TERT）表达的再激活来维持端粒长度。鉴定TERT的临床可翻译的成像生物标志物可以实现对肿瘤增殖和对治疗的反应的非侵入性评估。
我们使用了RNAi,多西环素诱导表达系统，和药物抑制剂在临床前患者来源的肿瘤模型中从机制上描述TERT与代谢之间的关联。氘磁共振波谱(2H-MRS),这是一部小说，平移代谢成像模式，用于体内细胞和荷瘤小鼠中的TERT成像。
我们的结果表明，TERT表达与多种癌症中NADH升高有关，包括胶质母细胞瘤,少突胶质细胞瘤,黑色素瘤，神经母细胞瘤,和肝细胞癌。机械上,TERT通过代谢调节剂FOXO1上调烟酰胺磷酸核糖转移酶，这是NAD+生物合成的关键酶，糖酵解酶甘油醛-3-磷酸脱氢酶,它将NAD+转换为NADH。因为NADH对于丙酮酸流到乳酸来说是必不可少的，我们表明，从[U-2H]-丙酮酸乳酸生产的2H-MRS为基础的评估报告TERT表达在临床前肿瘤模型体内，包括临床场强(3T)。重要的是,[U-2H]-丙酮酸报告了在MRI可以观察到影像学改变之前的早期时间点，患有原位患者衍生的神经胶质瘤的小鼠对治疗的早期反应。
NADH升高是TERT在癌症中表达的代谢结果。重要的是,[U-2H]-丙酮酸对治疗的早期反应报告，在解剖改变之前，从而为临床医生提供了一种评估肿瘤负荷和癌症治疗反应的新工具。
我们使用了RNAi,
我们的结果表明，TERT表达与多种癌症中NADH升高有关，
NADH升高是TERT在癌症中表达的代谢结果。
