Schroeder Thies, Yuan Hong, Viglianti Benjamin L, Peltz Cathryn, Asopa Shubha, Vujaskovic Zeljko, Dewhirst Mark W
Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Cancer Res. 2005 Jun 15;65(12):5163-71. doi: 10.1158/0008-5472.CAN-04-3900.
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 18F-deoxyglucose uptake.
为了研究实体瘤中葡萄糖消耗对氧的依赖性，我们监测了在Fischer 344大鼠体内生长的R3230Ac和FSA肿瘤中葡萄糖、乳酸和缺氧的梯度变化。在连续的肿瘤切片中进行生物发光成像、Hoechst 33342检测以及缺氧标志物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。进一步在体外测试细胞的葡萄糖消耗和乳酸生成情况。在两种肿瘤类型中，EF5染色显示缺氧的最大水平相似；最强烈的染色出现在坏死周边区域。葡萄糖浓度在肝脏中最高，从血液到肿瘤边缘逐渐下降，进入肿瘤活性区域后进一步降低，在接近坏死处最低。FSA肿瘤中的葡萄糖显著低于R3230Ac肿瘤。R3230Ac肿瘤中非缺氧区域的葡萄糖浓度始终高于缺氧区域，最大值等于全身血液水平。FSA肿瘤中的葡萄糖接近零，无论有无缺氧情况。两种肿瘤类型之间的乳酸没有显著差异。培养的FSA细胞与R3230Ac相比，显示出有氧葡萄糖消耗更高的趋势。在缺氧条件下，两种细胞系的乳酸生成均增加到相似水平。我们得出结论，R3230Ac和FSA肿瘤均保留巴斯德效应，即缺氧触发糖酵解增加。然而，我们的结果表明，有氧葡萄糖利用增加导致FSA中葡萄糖水平降低，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与18F-脱氧葡萄糖摄取之间的相关性。
