Rapid uptake of glucose and lactate, and not hypoxia, induces apoptosis in three-dimensional tumor tissue culture.
Rapid uptake of glucose and lactate, and not hypoxia, induces apoptosis in three-dimensional tumor tissue culture.
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DOI：
10.1039/c4ib00001c
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发表时间：
2014-04
期刊：
影响因子：
--
通讯作者：
Forbes NS
中科院分区：
文献类型：
--
作者：
Kasinskas RW;Venkatasubramanian R;Forbes NS
肿瘤组织中细胞代谢的空间排列严重影响癌症的治疗。然而，很少有人知道如何扩散和细胞摄取涉及到细胞内代谢和细胞死亡的三维。为了量化这些机制，使用荧光显微镜和多细胞肿瘤圆柱体来测量pH和氧分布，并量化活细胞、凋亡细胞和坏死细胞的分布。球体解离，酶分析和质谱法用于测量葡萄糖，乳酸盐和谷氨酰胺的浓度分布。使用数学模型来整合这些测量值并计算代谢率参数。结果发现，直径大于500μm的大圆柱体含有凋亡和坏死细胞，而小圆柱体含有凋亡但不含坏死细胞。圆柱体的中心被发现是酸性的，但不缺氧。葡萄糖、乳酸和谷氨酰胺的浓度从边缘到中心迅速下降。在整个细胞群中，乳酸被消耗而不产生。这些测量结果表明，细胞凋亡是细胞死亡的主要机制;酸性不是由乳酸引起的;细胞死亡是由碳源耗尽而不是缺氧引起的。数学模型表明，葡萄糖和乳酸的转运酶是不饱和的，氧摄取是有限的细胞内代谢，和氧摄取不受膜运输或扩散。不饱和的跨膜摄取可能是癌症中增殖和凋亡机制的原因。这些结果表明，转运蛋白酶是治疗氧合良好的肿瘤的极好靶点。
The spatial arrangement of cellular metabolism in tumor tissue critically affects the treatment of cancer. However, little is known about how diffusion and cellular uptake relate to intracellular metabolism and cell death in three-dimensions. To quantify these mechanisms, fluorescent microscopy and multicellular tumor cylindroids were used to measure pH and oxygen profiles, and quantify the distribution of viable, apoptotic and necrotic cells. Spheroid dissociation, enzymatic analysis, and mass spectrometry were used to measure concentration profiles of glucose, lactate and glutamine. A mathematical model was used to integrate these measurements and calculate metabolic rate parameters. It was found that large cylindroids, >500μm in diameter, contained apoptotic and necrotic cells, whereas small cylindroids contained apoptotic but not necrotic cells. The center of cylindroids was found to be acidic but not hypoxic. From the edge to the center, concentrations of glucose, lactate and glutamine decreased rapidly. Throughout the cell masses lactate was consumed and not produced. These measurements indicate that apoptosis was the primary mechanism of cell death; acidity was not caused by lactic acid; and cell death was caused by depletion of carbon sources and not hypoxia. The mathematical model showed that the transporter enzymes for glucose and lactate were not saturated; oxygen uptake was limited by intracellular metabolism; and oxygen uptake was not limited by membrane-transport or diffusion. Unsaturated transmembrane uptake may be the cause of both proliferative and apoptotic regimes in cancer. These results suggest that transporter enzymes are excellent targets for treating well oxygenated tumors.
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影响因子：
9
作者：
通讯作者：
--
肿瘤微环境产生的酸度驱动局部侵袭。
影响因子：
11.2
作者：
Estrella V;Chen T;Lloyd M;Wojtkowiak J;Cornnell HH;Ibrahim-Hashim A;Bailey K;Balagurunathan Y;Rothberg JM;Sloane BF;Johnson J;Gatenby RA;Gillies RJ
通讯作者：
Gillies RJ
影响因子：
82.9
作者：
Helmlinger, G;Yuan, F;Jain, RK
通讯作者：
Jain, RK
影响因子：
50.3
作者：
Jeong SM;Xiao C;Finley LW;Lahusen T;Souza AL;Pierce K;Li YH;Wang X;Laurent G;German NJ;Xu X;Li C;Wang RH;Lee J;Csibi A;Cerione R;Blenis J;Clish CB;Kimmelman A;Deng CX;Haigis MC
通讯作者：
Haigis MC
影响因子：
8.5
作者：
CASCIARI, JJ;SOTIRCHOS, SV;SUTHERLAND, RM
通讯作者：
SUTHERLAND, RM