Oncogene pathway activation in mammary tumors dictates FDG-PET uptake.
Oncogene pathway activation in mammary tumors dictates FDG-PET uptake.
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DOI：
10.1158/0008-5472.can-14-1235
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发表时间：
2014-12-15
期刊：
影响因子：
11.2
通讯作者：
Chodosh LA
中科院分区：
文献类型：
--
作者：
Alvarez JV;Belka GK;Pan TC;Chen CC;Blankemeyer E;Alavi A;Karp JS;Chodosh LA
葡萄糖利用增加是人类癌症的一个标志，临床上用于对肿瘤进行成像。在这一广泛使用的应用中，肿瘤的葡萄糖摄取是通过标记葡萄糖类似物F-18-2-氟-2-脱氧葡萄糖(18F-FDG)的正电子发射断层扫描(PET)来监测的。尽管FDG被广泛应用于临床，但决定FDG摄取的细胞和分子机制--一种可以监测肿瘤异质性的工具--仍然知之甚少。在这项研究中，我们比较了基因工程小鼠中Akt1、c-myc、HER2/neu、WNT1或H-RAS癌基因驱动的乳腺肿瘤对FDG的摄取，并将其与肿瘤生长、细胞增殖和糖酵解代谢关键步骤相关的基因表达水平进行了关联。我们发现肿瘤摄取FDG主要由致癌基因决定，与肿瘤生长或细胞增殖无关。无论基线摄取水平如何，癌基因下调都会导致FDG摄取的快速下降，进而影响肿瘤的消退。FDG摄取与己糖激酶-2和缺氧诱导因子-1α的表达呈正相关，与PFK-2b和p-AMPK的表达呈负相关。HK2和FDG摄取的相关性独立于所有被测试的变量，包括启动癌基因，这表明HK2是FDG摄取的独立预测因子。相反，只有在Akt或HER2/neu驱动的肿瘤中，Glut1的表达与FDG摄取相关。总之，这些结果表明，肿瘤内激活的致癌途径是其FDG摄取的主要决定因素，由关键的糖酵解酶介导，这些酶提供了一个框架来解释临床成像中这一关键参数的影响。
Increased glucose utilization is a hallmark of human cancer that is used to image tumors clinically. In this widely used application, glucose uptake by tumors is monitored by positron emission tomography (PET) of the labeled glucose analog F-18-2-fluoro-2-deoxyglucose (18F-FDG). Despite its widespread clinical use, the cellular and molecular mechanisms that determine FDG uptake - a tool that can monitor tumor heterogeneity - remain poorly understood. In this study, we compared FDG uptake in mammary tumors driven by the Akt1, c-MYC, HER2/neu, Wnt1 or H-Ras oncogenes in genetically engineered mice, correlating it to tumor growth, cell proliferation and levels of gene expression involved in key steps of glycolytic metabolism. We found that FDG uptake by tumors was dictated principally by the driver oncogene and was not independently associated with tumor growth or cellular proliferation. Oncogene downregulation resulted in a rapid decrease in FDG uptake, preceding effects on tumor regression, irrespective of the baseline level of uptake. FDG uptake correlated positively with expression of hexokinase-2 (HK2) and HIF-1α and associated negatively with PFK-2b expression and p-AMPK. The correlation of HK2 and FDG uptake was independent of all variables tested, including the initiating oncogene, suggesting that HK2 is an independent predictor of FDG uptake. In contrast, expression of Glut1 was correlated with FDG uptake only in tumors driven by Akt or HER2/neu. Together, these results showed that the oncogenic pathway activated within a tumor is a primary determinant of its FDG uptake, mediated by key glycolytic enzymes that provide a framework to interpret effects on this key parameter in clinical imaging.