Urinary acylcarnitines are altered in human kidney cancer.
Urinary acylcarnitines are altered in human kidney cancer.
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DOI：
10.1002/ijc.26274
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发表时间：
2012-06-15
影响因子：
6.4
通讯作者：
Weiss, Robert H.
中科院分区：
文献类型：
--
作者：
Ganti, Sheila;Taylor, Sandra L.;Kim, Kyoungmi;Hoppel, Charles L.;Guo, Lining;Yang, Joy;Evans, Christopher;Weiss, Robert H.
肾癌通常在治疗选择严重受限的晚期被诊断出来。因此，需要对肿瘤代谢有更深入的了解，最终导致新的诊断方法。我们的实验室一直在利用代谢组学来评估肾癌患者的生物流体中出现的浓度与对照患者不同的化合物。在这里，我们收集了肾癌患者的尿液样本，并通过色谱-质谱联用进行分析。尿浓度标准化至对照后，由两个独立的实验室分析样品。经过技术验证，我们现在显示了几种酰基肉毒碱的不同尿液浓度作为癌症状态和肾癌级别的函数，大多数酰基肉毒碱在癌症患者和高癌症级别患者的尿液中增加。这一发现在人肾癌的小鼠异种移植模型中得到了验证。生物学验证显示，酰基肉毒碱对体外细胞毒性的碳链长度依赖性作用，并且更高链长的酰基肉毒碱对NF-κB活化表现出抑制作用，表明这些化合物具有免疫调节作用。因此，肾癌尿液中的酰基肉毒碱可能反映了代谢，细胞成分合成和/或免疫监视的改变，并可能有助于解释这种癌症的深刻化疗耐药性。这项研究首次显示了一类新的代谢物的价值，这可能会导致新的癌症治疗方法，并可能证明在癌症生物标志物研究中有用。此外，这些发现开辟了肾癌代谢基础的新研究领域。
Kidney cancer often diagnosed at late stages when treatment options are severely limited. Thus, greater understanding of tumor metabolism leading ultimately to novel approaches to diagnosis are needed. Our laboratory has been utilizing metabolomics to evaluate compounds appearing in kidney cancer patients’ biofluids at concentrations different from control patients. Here, we collected urine samples from kidney cancer patients and analyzed them by chromatography coupled to mass spectrometry. Once normalized to control for urinary concentration, samples were analyzed by two independent laboratories. After technical validation, we now show differential urinary concentrations of several acylcarnitines as a function of both cancer status and kidney cancer grade, with most acylcarnitines being increased in the urine of cancer patients and in those patients with high cancer grades. This finding was validated in a mouse xenograft model of human kidney cancer. Biological validation shows carbon chain length-dependent effects of the acylcarnitines on cytotoxicity in vitro, and higher chain length acylcarnitines demonstrated inhibitory effects on NF-κB activation, suggesting an immune modulatory effect of these compounds. Thus, acylcarnitines in the kidney cancer urine may reflect alterations in metabolism, cell component synthesis, and/or immune surveillance, and may help explain the profound chemotherapy resistance seen with this cancer. This study shows for the first time the value of a novel class of metabolites which may lead to new therapeutic approaches for cancer and may prove useful in cancer biomarker studies. Furthermore, these findings open up a new area of investigation into the metabolic basis of kidney cancer.
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影响因子：
7.4
作者：
Minkler, PE;Ingalls, ST;Hoppel, CL
通讯作者：
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11.2
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