Division of Nephrology, Department of Internal Medicine, University of California, Davis, CA 95616, USA.
Int J Cancer. 2012 Jun 15;130(12):2791-800. doi: 10.1002/ijc.26274. Epub 2011 Sep 14.
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 is 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.
肾癌通常在治疗选择受到严重限制的晚期才被诊断出来。因此，需要更深入地了解肿瘤代谢，最终为诊断提供新的方法。我们的实验室一直利用代谢组学来评估出现在肾癌患者生物流体中的化合物，这些化合物的浓度与对照患者不同。在这里，我们收集了肾癌患者的尿液样本，并通过与质谱联用的色谱法进行了分析。在将其标准化以控制尿液浓度后，由两个独立的实验室进行分析。经过技术验证，我们现在显示出几种酰基辅酶 A 的尿浓度差异，这是癌症状态和肾癌分级的函数，大多数酰基辅酶 A 在癌症患者和癌症分级较高的患者的尿液中增加。这一发现在人肾癌的异种移植小鼠模型中得到了验证。生物学验证表明，酰基辅酶 A 的碳链长度依赖性对体外细胞毒性的影响，以及更高链长的酰基辅酶 A 对 NF-κB 激活的抑制作用，表明这些化合物具有免疫调节作用。因此，肾癌尿液中的酰基辅酶 A 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化疗耐药性。这项研究首次表明，一类新的代谢物具有潜在的价值，可能为癌症提供新的治疗方法，并可能在癌症生物标志物研究中证明有用。此外，这些发现为研究肾癌的代谢基础开辟了一个新的研究领域。
