Spatial heterogeneity and oxygen dependence of glucose consumption in R3230Ac and fibrosarcomas of the Fischer 344 rat
Spatial heterogeneity and oxygen dependence of glucose consumption in R3230Ac and fibrosarcomas of the Fischer 344 rat
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DOI：
10.1158/0008-5472.can-04-3900
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发表时间：
2005-06-15
期刊：
影响因子：
11.2
通讯作者：
Dewhirst, MW
中科院分区：
文献类型：
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作者：
Schroeder, T;Yuan, H;Dewhirst, MW
为了检查实体瘤中葡萄糖消耗的氧依赖性，我们监测了 Fischer 344 大鼠中生长的 R3230Ac 和 FSA 肿瘤中的葡萄糖、乳酸和缺氧梯度。在连续肿瘤切片中进行生物发光成像、Hoechst 33342 检测以及缺氧标记物 EF5 [2-8-N-(2,2,3,3,3-五氟丙基)乙酰胺]的免疫染色。还测定了肝脏和血液中的葡萄糖和乳酸水平。进一步测试细胞的体外葡萄糖消耗和乳酸产生。在两种肿瘤类型中，EF5 染色显示相似的最大缺氧水平；最强烈的染色发生在坏死周围区域。肝脏中的葡萄糖浓度最高，从血液到肿瘤边缘下降，进一步进入重要的肿瘤区域，并且在接近坏死时最低。 FSA 中的葡萄糖显着低于 R3230Ac 肿瘤中的葡萄糖。 R3230Ac 肿瘤中的葡萄糖浓度在非缺氧区域始终高于缺氧区域，最大值等于全身血液水平。无论是否存在缺氧，FSA 肿瘤中的葡萄糖都接近于零。不同肿瘤类型之间的乳酸没有显着差异。与 R3230Ac 相比，培养中的 FSA 细胞显示出有氧葡萄糖消耗更高的趋势。在缺氧条件下，两种细胞系的乳酸产量都增加到相似的水平。我们得出的结论是，R3230Ac 和 FSA 肿瘤都保留了巴斯德效应，即缺氧触发糖酵解增加。然而，我们的结果表明，有氧葡萄糖利用率的增加会导致 FSA 中的葡萄糖水平较低，并且出现供应限制摄取的情况。这解释了反复观察到的肿瘤血流量与 F-18-脱氧葡萄糖摄取之间的相关性。
To examine the oxygen-dependence of glucose consumption in solid tumors, we monitored gradients of glucose, lactate, and hypoxia in R3230Ac and FSA tumors growing in Fischer 344 rats. Bioluminescence imaging, detection of Hoechst 33342, and immunostaining of the hypoxia marker EF5 [2-8-N-(2,2,3,3,3-pentafluoropropyl)acetamide] were done in serial tumor slices. Glucose and lactate levels were also determined in liver and blood. Cells were further tested for glucose consumption and lactate production in vitro. In both tumor types, EF5 staining indicated similar maximum levels of hypoxia; the most intense staining occurred in perinecrotic regions. Glucose concentrations were highest in liver, declined from blood to tumor edge, further into vital tumor regions, and were lowest close to necrosis. Glucose was significantly lower in FSA than in R3230Ac tumors. Glucose concentrations in R3230Ac tumors were consistently higher in nonhypoxic than in hypoxic areas, with maximum values equal to systemic blood levels. Glucose in FSA tumors was close to zero, regardless of the presence or absence of hypoxia. Lactate did not differ significantly between the tumor types. FSA cells in culture showed a trend towards higher aerobic glucose consumption versus R3230Ac. Both cell lines increased their lactate production to similar levels under hypoxia. We conclude that both R3230Ac and FSA tumors retain the Pasteur effect, i.e., hypoxia triggers increased glycolysis. However, our results imply that increased aerobic glucose utilization leads to low glucose levels in FSA and a situation where supply limits uptake. This explains the repeatedly observed correlation between tumor blood flow and F-18-deoxyglucose uptake.