In vivo pH in metabolic-defective Ras-transformed fibroblast tumors: Key role of the monocarboxylate transporter, MCT4, for inducing an alkaline intracellular pH
In vivo pH in metabolic-defective Ras-transformed fibroblast tumors: Key role of the monocarboxylate transporter, MCT4, for inducing an alkaline intracellular pH
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DOI：
10.1002/ijc.26125
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发表时间：
2012-04-01
影响因子：
6.4
通讯作者：
Lutz, Norbert W.
中科院分区：
文献类型：
--
作者：
Chiche, Johanna;Le Fur, Yann;Lutz, Norbert W.
我们介绍了一项关于肿瘤pH调节的研究，旨在支持我们先前提出的一种新的抗癌治疗概念。我们的研究使用了ras转化的仓鼠成纤维细胞CCL39的肿瘤模型，该细胞移植到裸鼠的大腿上。我们首次证明，质子产生和/或质子运输的特定机制的遗传修改导致细胞内和细胞外肿瘤pH的明显、可重复的变化，这些变化可以在体内无创地检测和量化，同时在同一实验中确定肿瘤的能量状态和坏死。使用的CCL39变种缺乏钠/质子交换器NHE-1和/或单羧酸转运体MCT4；此外，变种缺乏糖酵解或呼吸作用。与不表达MCT4的CCL39野生型肿瘤相比，MCT4的表达显著增加了细胞内和细胞外的pH梯度，从0.14增加到0.43。所研究的其他基因修改产生了细胞内较小但显著的增加和细胞外pH的下降。总体而言，pH梯度的增加与肿瘤生长性能的增加和坏死区的减少是平行的，CCL39变体中50%既不表达MCT4也不表达NHE-1，但具有完全的糖酵解和氧化磷酸化的遗传能力，在达到1厘米直径之前进行了回归。除CCL39野生型肿瘤外，未检测到HIF-1a的显著表达。我们在体内的结果支持了一种多管齐下的治疗肿瘤的方法，该方法基于通过靶向几个质子产生和质子运输过程来最小化细胞内的pH，其中非常有效的MCT4质子/乳酸联合运输值得特别关注。
We present an investigation of tumor pH regulation, designed to support a new anticancer therapy concept that we had previously proposed. Our study uses a tumor model of ras-transformed hamster fibroblasts, CCL39, xenografted in the thighs of nude mice. We demonstrate, for the first time, that genetic modifications of specific mechanisms of proton production and/or proton transport result in distinct, reproducible changes in intracellular and extracellular tumor pH that can be detected and quantified noninvasively in vivo, simultaneously with determinations of tumor energetic status and necrosis in the same experiment. The CCL39 variants used were deficient in the sodium/proton exchanger, NHE-1, and/or in the monocarboxylate transporter, MCT4; further, variants were deficient in glycolysis or respiration. MCT4 expression markedly increased the gradient between intracellular and extracellular pH from 0.14 to 0.43 when compared to CCL39 wild-type tumors not expressing MCT4. The other genetic modifications studied produced smaller but significant increases in intracellular and decreases in extracellular pH. In general, increased pH gradients were paralleled by increased tumor growth performance and diminished necrotic regions, and 50% of the CCL39 variant expressing neither MCT4 nor NHE-1, but possessing full genetic capacity for glycolysis and oxidative phosphorylation, underwent regression before reaching a 1-cm diameter. Except for CCL39 wild-type tumors, no significant HIF-1a expression was detected. Our in vivo results support a multipronged approach to tumor treatment based on minimizing intracellular pH by targeting several proton production and proton transport processes, among which the very efficient MCT4 proton/lactate co-transport deserves particular attention.