Catabolism of exogenous lactate reveals it as a legitimate metabolic substrate in breast cancer
Lactate accumulation in tumors has been associated with metastases and poor overall survival in cancer patients. Lactate promotes angiogenesis and metastasis, providing rationale for understanding how it is processed by cells. The concentration of lactate in tumors is a balance between the amount pr...
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| creator | Kennedy, Kelly M Scarbrough, Peter M Ribeiro, Anthony Richardson, Rachel Yuan, Hong Sonveaux, Pierre Landon, Chelsea D Chi, Jen-Tsan Pizzo, Salvatore Schroeder, Thies Dewhirst, Mark W |
| description | Lactate accumulation in tumors has been associated with metastases and poor overall survival in cancer patients. Lactate promotes angiogenesis and metastasis, providing rationale for understanding how it is processed by cells. The concentration of lactate in tumors is a balance between the amount produced, amount carried away by vasculature and if/how it is catabolized by aerobic tumor or stromal cells. We examined lactate metabolism in human normal and breast tumor cell lines and rat breast cancer: 1. at relevant concentrations, 2. under aerobic vs. hypoxic conditions, 3. under conditions of normo vs. hypoglucosis. We also compared the avidity of tumors for lactate vs. glucose and identified key lactate catabolites to reveal how breast cancer cells process it. Lactate was non-toxic at clinically relevant concentrations. It was taken up and catabolized to alanine and glutamate by all cell lines. Kinetic uptake rates of lactate in vivo surpassed that of glucose in R3230Ac mammary carcinomas. The uptake appeared specific to aerobic tumor regions, consistent with the proposed "metabolic symbiont" model; here lactate produced by hypoxic cells is used by aerobic cells. We investigated whether treatment with alpha-cyano-4-hydroxycinnamate (CHC), a MCT1 inhibitor, would kill cells in the presence of high lactate. Both 0.1 mM and 5 mM CHC prevented lactate uptake in R3230Ac cells at lactate concentrations at ≤ 20 mM but not at 40 mM. 0.1 mM CHC was well-tolerated by R3230Ac and MCF7 cells, but 5 mM CHC killed both cell lines ± lactate, indicating off-target effects. This study showed that breast cancer cells tolerate and use lactate at clinically relevant concentrations in vitro (± glucose) and in vivo. We provided additional support for the metabolic symbiont model and discovered that breast cells prevailingly take up and catabolize lactate, providing rationale for future studies on manipulation of lactate catabolism pathways for therapy. |
| doi_str_mv | 10.1371/journal.pone.0075154 |
| format | Article |
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Lactate promotes angiogenesis and metastasis, providing rationale for understanding how it is processed by cells. The concentration of lactate in tumors is a balance between the amount produced, amount carried away by vasculature and if/how it is catabolized by aerobic tumor or stromal cells. We examined lactate metabolism in human normal and breast tumor cell lines and rat breast cancer: 1. at relevant concentrations, 2. under aerobic vs. hypoxic conditions, 3. under conditions of normo vs. hypoglucosis. We also compared the avidity of tumors for lactate vs. glucose and identified key lactate catabolites to reveal how breast cancer cells process it. Lactate was non-toxic at clinically relevant concentrations. It was taken up and catabolized to alanine and glutamate by all cell lines. Kinetic uptake rates of lactate in vivo surpassed that of glucose in R3230Ac mammary carcinomas. The uptake appeared specific to aerobic tumor regions, consistent with the proposed "metabolic symbiont" model; here lactate produced by hypoxic cells is used by aerobic cells. We investigated whether treatment with alpha-cyano-4-hydroxycinnamate (CHC), a MCT1 inhibitor, would kill cells in the presence of high lactate. Both 0.1 mM and 5 mM CHC prevented lactate uptake in R3230Ac cells at lactate concentrations at ≤ 20 mM but not at 40 mM. 0.1 mM CHC was well-tolerated by R3230Ac and MCF7 cells, but 5 mM CHC killed both cell lines ± lactate, indicating off-target effects. This study showed that breast cancer cells tolerate and use lactate at clinically relevant concentrations in vitro (± glucose) and in vivo. We provided additional support for the metabolic symbiont model and discovered that breast cells prevailingly take up and catabolize lactate, providing rationale for future studies on manipulation of lactate catabolism pathways for therapy.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0075154</identifier><identifier>PMID: 24069390</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adult ; Aged ; Alanine ; Alanine - biosynthesis ; Alzheimer's disease ; Angiogenesis ; Animals ; Avidity ; Biocompatibility ; Biotechnology ; Breast cancer ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Cancer ; Catabolism ; Catabolites ; Cell cycle ; Cell death ; Cell Death - drug effects ; Cell Hypoxia ; Cell Line, Tumor ; Comparative analysis ; Coumaric Acids - pharmacology ; Dextrose ; Disease Models, Animal ; Feasibility studies ; Female ; Fibroblasts ; Gene expression ; Glucose ; Glucose - metabolism ; Glutamate ; Glutamic Acid - biosynthesis ; Humans ; Hypoxia ; Kinetics ; Lactic acid ; Lactic Acid - metabolism ; Mammary gland ; Medical prognosis ; Metabolic Networks and Pathways - drug effects ; Metabolism ; Metabolomics ; Metastases ; Metastasis ; Middle Aged ; Neoplasm Staging ; Oncology ; Oxidative stress ; Pathology ; Prostate ; Rats ; Respiration ; Stromal cells ; Substrates ; Tumor cell lines ; Tumors</subject><ispartof>PloS one, 2013-09, Vol.8 (9), p.e75154</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Kennedy et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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Lactate promotes angiogenesis and metastasis, providing rationale for understanding how it is processed by cells. The concentration of lactate in tumors is a balance between the amount produced, amount carried away by vasculature and if/how it is catabolized by aerobic tumor or stromal cells. We examined lactate metabolism in human normal and breast tumor cell lines and rat breast cancer: 1. at relevant concentrations, 2. under aerobic vs. hypoxic conditions, 3. under conditions of normo vs. hypoglucosis. We also compared the avidity of tumors for lactate vs. glucose and identified key lactate catabolites to reveal how breast cancer cells process it. Lactate was non-toxic at clinically relevant concentrations. It was taken up and catabolized to alanine and glutamate by all cell lines. Kinetic uptake rates of lactate in vivo surpassed that of glucose in R3230Ac mammary carcinomas. 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Lactate promotes angiogenesis and metastasis, providing rationale for understanding how it is processed by cells. The concentration of lactate in tumors is a balance between the amount produced, amount carried away by vasculature and if/how it is catabolized by aerobic tumor or stromal cells. We examined lactate metabolism in human normal and breast tumor cell lines and rat breast cancer: 1. at relevant concentrations, 2. under aerobic vs. hypoxic conditions, 3. under conditions of normo vs. hypoglucosis. We also compared the avidity of tumors for lactate vs. glucose and identified key lactate catabolites to reveal how breast cancer cells process it. Lactate was non-toxic at clinically relevant concentrations. It was taken up and catabolized to alanine and glutamate by all cell lines. Kinetic uptake rates of lactate in vivo surpassed that of glucose in R3230Ac mammary carcinomas. The uptake appeared specific to aerobic tumor regions, consistent with the proposed "metabolic symbiont" model; here lactate produced by hypoxic cells is used by aerobic cells. We investigated whether treatment with alpha-cyano-4-hydroxycinnamate (CHC), a MCT1 inhibitor, would kill cells in the presence of high lactate. Both 0.1 mM and 5 mM CHC prevented lactate uptake in R3230Ac cells at lactate concentrations at ≤ 20 mM but not at 40 mM. 0.1 mM CHC was well-tolerated by R3230Ac and MCF7 cells, but 5 mM CHC killed both cell lines ± lactate, indicating off-target effects. This study showed that breast cancer cells tolerate and use lactate at clinically relevant concentrations in vitro (± glucose) and in vivo. We provided additional support for the metabolic symbiont model and discovered that breast cells prevailingly take up and catabolize lactate, providing rationale for future studies on manipulation of lactate catabolism pathways for therapy.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24069390</pmid><doi>10.1371/journal.pone.0075154</doi><tpages>e75154</tpages><oa>free_for_read</oa></addata></record> |
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| language | eng |
| recordid | cdi_plos_journals_1432136254 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adult Aged Alanine Alanine - biosynthesis Alzheimer's disease Angiogenesis Animals Avidity Biocompatibility Biotechnology Breast cancer Breast Neoplasms - metabolism Breast Neoplasms - pathology Cancer Catabolism Catabolites Cell cycle Cell death Cell Death - drug effects Cell Hypoxia Cell Line, Tumor Comparative analysis Coumaric Acids - pharmacology Dextrose Disease Models, Animal Feasibility studies Female Fibroblasts Gene expression Glucose Glucose - metabolism Glutamate Glutamic Acid - biosynthesis Humans Hypoxia Kinetics Lactic acid Lactic Acid - metabolism Mammary gland Medical prognosis Metabolic Networks and Pathways - drug effects Metabolism Metabolomics Metastases Metastasis Middle Aged Neoplasm Staging Oncology Oxidative stress Pathology Prostate Rats Respiration Stromal cells Substrates Tumor cell lines Tumors |
| title | Catabolism of exogenous lactate reveals it as a legitimate metabolic substrate in breast cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-19T13%3A37%3A43IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Catabolism%20of%20exogenous%20lactate%20reveals%20it%20as%20a%20legitimate%20metabolic%20substrate%20in%20breast%20cancer&rft.jtitle=PloS%20one&rft.au=Kennedy,%20Kelly%20M&rft.date=2013-09-12&rft.volume=8&rft.issue=9&rft.spage=e75154&rft.pages=e75154-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0075154&rft_dat=%3Cgale_plos_%3EA478300735%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1432136254&rft_id=info:pmid/24069390&rft_galeid=A478300735&rft_doaj_id=oai_doaj_org_article_c3ea2512ce0d4f7aa2fbd10e99779c70&rfr_iscdi=true |