The genomic analysis of lactic acidosis and acidosis response in human cancers.
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 a...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2008-12-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC2585811?pdf=render |
| _version_ | 1818545020033040384 |
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| author | Julia Ling-Yu Chen Joseph E Lucas Thies Schroeder Seiichi Mori Jianli Wu Joseph Nevins Mark Dewhirst Mike West Jen-Tsan Chi |
| author_facet | Julia Ling-Yu Chen Joseph E Lucas Thies Schroeder Seiichi Mori Jianli Wu Joseph Nevins Mark Dewhirst Mike West Jen-Tsan Chi |
| author_sort | Julia Ling-Yu Chen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T22:56:04Z |
| format | Article |
| id | doaj.art-23fd5bbd06b848649aaed526c6b8b8ae |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-11T22:56:04Z |
| publishDate | 2008-12-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-23fd5bbd06b848649aaed526c6b8b8ae2022-12-22T00:47:14ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042008-12-01412e100029310.1371/journal.pgen.1000293The genomic analysis of lactic acidosis and acidosis response in human cancers.Julia Ling-Yu ChenJoseph E LucasThies SchroederSeiichi MoriJianli WuJoseph NevinsMark DewhirstMike WestJen-Tsan ChiThe 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.http://europepmc.org/articles/PMC2585811?pdf=render |
| spellingShingle | Julia Ling-Yu Chen Joseph E Lucas Thies Schroeder Seiichi Mori Jianli Wu Joseph Nevins Mark Dewhirst Mike West Jen-Tsan Chi The genomic analysis of lactic acidosis and acidosis response in human cancers. PLoS Genetics |
| title | The genomic analysis of lactic acidosis and acidosis response in human cancers. |
| title_full | The genomic analysis of lactic acidosis and acidosis response in human cancers. |
| title_fullStr | The genomic analysis of lactic acidosis and acidosis response in human cancers. |
| title_full_unstemmed | The genomic analysis of lactic acidosis and acidosis response in human cancers. |
| title_short | The genomic analysis of lactic acidosis and acidosis response in human cancers. |
| title_sort | genomic analysis of lactic acidosis and acidosis response in human cancers |
| url | http://europepmc.org/articles/PMC2585811?pdf=render |
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