The genomic analysis of lactic acidosis and acidosis response in human cancers.
The genomic analysis of lactic acidosis and acidosis response in human cancers.
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DOI：
10.1371/journal.pgen.1000293
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发表时间：
2008-12
期刊：
影响因子：
4.5
通讯作者：
Chi JT
中科院分区：
文献类型：
--
作者：
Chen JL;Lucas JE;Schroeder T;Mori S;Wu J;Nevins J;Dewhirst M;West M;Chi JT
肿瘤微环境对肿瘤的发展有重要影响。在这种环境中，两个重要的决定因素是缺氧和乳酸酸中毒。虽然乳酸酸中毒长期以来被认为是癌症的一个重要因素，但对细胞如何对乳酸酸中毒做出反应以及这种反应如何与癌症表型相关知之甚少。我们开发基因组规模的基因表达研究，解剖原代人乳腺上皮细胞在体外乳酸酸中毒和缺氧的转录反应，并探讨它们如何与体内临床肿瘤表型。在一组异质的乳腺癌数据集中评价对乳酸酸中毒和缺氧的反应的实验签名。一个强乳酸酸中毒反应的签名确定了一个亚组的低风险乳腺癌患者有不同的代谢概况，提示偏好有氧呼吸。乳酸酸中毒反应与良好生存结局的相关性可能与乳酸酸中毒通过抑制糖酵解将能量产生导向有氧呼吸和利用其他能量来源的作用有关。肿瘤中的这种“糖酵解抑制”表型可能是由糖酵解基因表达的抑制和Akt抑制引起的。我们的研究提出了一个基因组评估的预后信息的乳酸酸中毒反应独立的缺氧反应。我们的研究结果确定了乳酸酸中毒在代谢重编程中的因果作用，以及乳酸酸中毒途径活性对细胞反应和肿瘤发展的直接功能后果。该研究还证明了基因组分析的实用性，该基因组分析将体外实验中基于表达的发现映射到人类样本，以评估与体内临床表型的联系。众所周知，肿瘤微环境在调节人类癌症中的肿瘤进展中起重要作用。虽然以前的研究已经强调了缺氧的重要性，但对肿瘤微环境中其他成分的影响了解有限。因此，我们使用基因表达来比较和分析细胞如何对乳酸，酸度和缺氧做出反应，以及如何利用这些反应来预测乳腺癌患者的临床结果。我们发现了一个意想不到的关联与乳腺癌中的强乳酸酸中毒和酸中毒反应的更好的临床结果，因为它们能够抑制糖酵解和有利于氧化磷酸化产生能量。这种作用不仅是由于糖酵解基因的基因表达受到抑制，而且也是由于暴露于乳酸酸中毒和酸中毒的细胞的Akt活化受到抑制。总之，我们建议乳酸酸中毒和酸中毒被认为是人类癌症的独立预后因素。
The tumor microenvironment has a significant impact on tumor development. Two important determinants in this environment are hypoxia and lactic acidosis. Although lactic acidosis has long been recognized as an important factor in cancer, relatively little is known about how cells respond to lactic acidosis and how that response relates to cancer phenotypes. We develop genome-scale gene expression studies to dissect transcriptional responses of primary human mammary epithelial cells to lactic acidosis and hypoxia in vitro and to explore how they are linked to clinical tumor phenotypes in vivo. The resulting experimental signatures of responses to lactic acidosis and hypoxia are evaluated in a heterogeneous set of breast cancer datasets. A strong lactic acidosis response signature identifies a subgroup of low-risk breast cancer patients having distinct metabolic profiles suggestive of a preference for aerobic respiration. The association of lactic acidosis response with good survival outcomes may relate to the role of lactic acidosis in directing energy generation toward aerobic respiration and utilization of other energy sources via inhibition of glycolysis. This “inhibition of glycolysis” phenotype in tumors is likely caused by the repression of glycolysis gene expression and Akt inhibition. Our study presents a genomic evaluation of the prognostic information of a lactic acidosis response independent of the hypoxic response. Our results identify causal roles of lactic acidosis in metabolic reprogramming, and the direct functional consequence of lactic acidosis pathway activity on cellular responses and tumor development. The study also demonstrates the utility of genomic analysis that maps expression-based findings from in vitro experiments to human samples to assess links to in vivo clinical phenotypes. It is well recognized that tumor microenvironments play an important role in modulating tumor progression in human cancers. Although previous studies have highlighted the importance of hypoxia, there is limited knowledge on the effects of other components in tumor microenvironments. Therefore, we use gene expression to compare and analyze how cells respond to lactate, acidity, and hypoxia, as well as how these responses can be utilized to predict the clinical outcomes of patients with breast cancers. We uncover an unexpected association with better clinical outcome of the strong lactic acidosis and acidosis response in breast cancers as a result of their abilities to inhibit glycolysis and favor oxidative phosphorylation for energy generation. This effect is caused by not only the repression of the gene expression of glycolysis genes but also the inhibition of Akt activation of cells exposed to lactic acidosis and acidosis. In conclusion, we propose that lactic acidosis and acidosis to be considered as independent prognostic factors for human cancers.
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DOI：
10.1016/s0360-3016(01)01630-3
发表时间：
2001-10-01
影响因子：
7
作者：
Brizel, DM;Schroeder, T;Mueller-Klieser, W
通讯作者：
Mueller-Klieser, W
影响因子：
8
作者：
Buzzai, M;Bauer, DE;Thompson, CB
通讯作者：
Thompson, CB
影响因子：
9.8
作者：
Chang HY;Sneddon JB;Alizadeh AA;Sood R;West RB;Montgomery K;Chi JT;van de Rijn M;Botstein D;Brown PO
通讯作者：
Brown PO
影响因子：
5.8
作者：
Chang, Jeffrey T.;Nevins, Joseph R.
通讯作者：
Nevins, Joseph R.
影响因子：
82.9
作者：
Helmlinger, G;Yuan, F;Jain, RK
通讯作者：
Jain, RK