Hyperpolarized [1,3-13C2]ethyl acetoacetate is a novel diagnostic metabolic marker of liver cancer
Hyperpolarized [1,3-13C2]ethyl acetoacetate is a novel diagnostic metabolic marker of liver cancer
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DOI：
10.1002/ijc.29162
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发表时间：
2015-02-15
影响因子：
6.4
通讯作者：
Lerche, Mathilde H.
中科院分区：
文献类型：
--
作者：
Jensen, Pernille R.;Serra, Sonia Colombo;Lerche, Mathilde H.
肝病如丙型肝炎和非酒精性脂肪肝的患病率增加导致最常见的肝癌形式肝细胞癌（HCC）的发病率增加。HCC最常见于肝硬化，因此在诊断HCC时仅依赖解剖信息可能具有挑战性。由于新兴的磁共振（MR）技术，使用C-13标记的超极化分子，可以获得高灵敏度的特定细胞代谢的有价值的信息。我们的兴趣是探索潜在的新的高对比度的肝癌代谢标志物，使用超极化C-13-MR。这项工作导致一类底物，低分子量乙基酯的鉴定，表现出高特异性的羧基酯酶，并证明在许多情况下，具有良好的信号增强性能。特别是，超极化的[1，3-C-13（2）]乙酰乙酸乙酯（EAA）显示出提供HCC的代谢指纹。使用这种基质，由于代谢基质与产物的比率比周围健康组织高约4倍，因此诊断出植入大鼠体内的肝癌（p=0.009）。EAA的不受调节的细胞摄取以及共底物独立的酶促转化使得该底物作为超极化C-13-MR标记物非常有用。这可以通过从EAA获得的信噪比（SNR）来理解，其与使用最先进的超极化底物[1-C-13]丙酮酸的文献肝癌研究中报告的SNR相当。此外，与使用[1-C-13]丙酮酸报告的等效图像中的CNR相比，基于EAA的代谢比图像中的对比度噪声（CNR）得到了显著改善。一种新兴的癌症代谢成像方法是基于C-13超极化磁共振（MR）光谱。但是，必须确定特定于癌症的代谢标志物才能实现其承诺。在这里，超极化酯的代谢转化被探索作为检测肝细胞癌（HCC）的潜在手段。发现超极化的[1，3-C-13（2）]乙酰乙酸乙酯（EAA）是羧基酯酶-1的特别好的底物，羧基酯酶-1的浓度和活性在癌细胞中改变。EAA作为C-13-超极化MR的底物的代谢转化显著增强了大鼠植入性肝癌的检测。
An increased prevalence of liver diseases such as hepatitis C and nonalcoholic fatty liver results in an augmented incidence of the most common form of liver cancer, hepatocellular carcinoma (HCC). HCC is most often found in the cirrhotic liver and it can therefore be challenging to rely on anatomical information alone when diagnosing HCC. Valuable information on specific cellular metabolism can be obtained with high sensitivity thanks to an emerging magnetic resonance (MR) technique that uses C-13 labeled hyperpolarized molecules. Our interest was to explore potential new high contrast metabolic markers of HCC using hyperpolarized C-13-MR. This work led to the identification of a class of substrates, low molecular weight ethyl-esters, which showed high specificity for carboxyl esterases and proved in many cases to possess good properties for signal enhancement. In particular, hyperpolarized [1,3-C-13(2)]ethyl acetoacetate (EAA) was shown to provide a metabolic fingerprint of HCC. Using this substrate a liver cancer implanted in rats was diagnosed as a consequence of an approximate to 4 times higher metabolic substrate-to-product ratio than in the surrounding healthy tissue, (p=0.009). Unregulated cellular uptake as well as cosubstrate independent enzymatic conversion of EAA, made this substrate highly useful as a hyperpolarized C-13-MR marker. This could be appreciated by the signal-to-noise (SNR) obtained from EAA, which was comparable to the SNR reported in a literature liver cancer study with state-of-the-art hyperpolarized substrate, [1-C-13]pyruvate. Also, the contrast-to-noise (CNR) in the EAA based metabolic ratio images was significantly improved compared with the CNR in equivalent images reported using [1-C-13]pyruvate.What's New? An emerging approach to metabolic imaging in cancer is based on C-13-hyperpolarized magnetic resonance (MR) spectroscopy. But metabolic markers specific to cancer must be identified to realize its promise. Here, metabolic conversion of hyperpolarized esters was explored as a potential means of detecting hepatocellular carcinoma (HCC). Hyperpolarized [1,3-C-13(2)]ethyl acetoacetate (EAA) was found to be an exceptionally good substrate for carboxyl esterase-1, concentrations and activities of which are altered in cancer cells. Metabolic conversion of EAA as a substrate for C-13-hyperpolarized MR significantly enhanced the detection of implanted liver cancer in rats.