Quantifying Metabolic Heterogeneity in Head and Neck Tumors in Real Time: 2-DG Uptake Is Highest in Hypoxic Tumor Regions
Identifieur interne : 001849 ( Main/Exploration ); précédent : 001848; suivant : 001850Quantifying Metabolic Heterogeneity in Head and Neck Tumors in Real Time: 2-DG Uptake Is Highest in Hypoxic Tumor Regions
Auteurs : Erica C. Nakajima [États-Unis] ; Charles Laymon [États-Unis] ; Matthew Oborski [États-Unis] ; Weizhou Hou [États-Unis] ; Lin Wang [États-Unis] ; Jennifer R. Grandis [États-Unis] ; Robert L. Ferris [États-Unis] ; James M. Mountz [États-Unis] ; Bennett Van Houten [États-Unis]Source :
- PLoS ONE [ 1932-6203 ] ; 2014.
Descripteurs français
- KwdFr :
- Animaux, Carcinome épidermoïde (métabolisme), Colorants fluorescents (pharmacocinétique), Glucose (métabolisme), Glycolyse, Humains, Hypoxie cellulaire (physiologie), Hétérogreffes, Immunohistochimie, Immunotransfert, Phosphorylation oxydative, Radio-isotopes du fluor (pharmacocinétique), Souris, Souris nude, Tomographie par émission de positons, Tumeurs de la tête et du cou (métabolisme).
- MESH :
- métabolisme : Carcinome épidermoïde, Glucose, Tumeurs de la tête et du cou.
- pharmacocinétique : Colorants fluorescents, Radio-isotopes du fluor.
- physiologie : Hypoxie cellulaire.
- Animaux, Glycolyse, Humains, Hétérogreffes, Immunohistochimie, Immunotransfert, Phosphorylation oxydative, Souris, Souris nude, Tomographie par émission de positons.
English descriptors
- KwdEn :
- Animals, Carcinoma, Squamous Cell (metabolism), Cell Hypoxia (physiology), Fluorescent Dyes (pharmacokinetics), Fluorine Radioisotopes (pharmacokinetics), Glucose (metabolism), Glycolysis, Head and Neck Neoplasms (metabolism), Heterografts, Humans, Immunoblotting, Immunohistochemistry, Mice, Mice, Nude, Oxidative Phosphorylation, Positron-Emission Tomography.
- MESH :
- chemical , metabolism : Glucose.
- chemical , pharmacokinetics : Fluorescent Dyes, Fluorine Radioisotopes.
- metabolism : Carcinoma, Squamous Cell, Head and Neck Neoplasms.
- physiology : Cell Hypoxia.
- Animals, Glycolysis, Heterografts, Humans, Immunoblotting, Immunohistochemistry, Mice, Mice, Nude, Oxidative Phosphorylation, Positron-Emission Tomography.
Abstract
Intratumoral metabolic heterogeneity may increase the likelihood of treatment failure due to the presence of a subset of resistant tumor cells. Using a head and neck squamous cell carcinoma (HNSCC) xenograft model and a real-time fluorescence imaging approach, we tested the hypothesis that tumors are metabolically heterogeneous, and that tumor hypoxia alters patterns of glucose uptake within the tumor.
Cal33 cells were grown as xenograft tumors (n = 16) in nude mice after identification of this cell line's metabolic response to hypoxia. Tumor uptake of fluorescent markers identifying hypoxia, glucose import, or vascularity was imaged simultaneously using fluorescent molecular tomography. The variability of intratumoral 2-deoxyglucose (IR800-2-DG) concentration was used to assess tumor metabolic heterogeneity, which was further investigated using immunohistochemistry for expression of key metabolic enzymes. HNSCC tumors in patients were assessed for intratumoral variability of 18F-fluorodeoxyglucose (18F-FDG) uptake in clinical PET scans.
IR800-2-DG uptake in hypoxic regions of Cal33 tumors was 2.04 times higher compared to the whole tumor (p = 0.0001). IR800-2-DG uptake in tumors containing hypoxic regions was more heterogeneous as compared to tumors lacking a hypoxic signal. Immunohistochemistry staining for HIF-1α, carbonic anhydrase 9, and ATP synthase subunit 5β confirmed xenograft metabolic heterogeneity. We detected heterogeneous 18F-FDG uptake within patient HNSCC tumors, and the degree of heterogeneity varied amongst tumors.
Hypoxia is associated with increased intratumoral metabolic heterogeneity. 18F-FDG PET scans may be used to stratify patients according to the metabolic heterogeneity within their tumors, which could be an indicator of prognosis.
Url:
DOI: 10.1371/journal.pone.0102452
PubMed: 25127378
PubMed Central: 4134191
Affiliations:
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Ferris</name><affiliation wicri:level="2"><nlm:aff id="aff7"><addr-line>Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Mountz, James M" sort="Mountz, James M" uniqKey="Mountz J" first="James M." last="Mountz">James M. Mountz</name><affiliation wicri:level="2"><nlm:aff id="aff4"><addr-line>Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Van Houten, Bennett" sort="Van Houten, Bennett" uniqKey="Van Houten B" first="Bennett" last="Van Houten">Bennett Van Houten</name><affiliation wicri:level="4"><nlm:aff id="aff3"><addr-line>Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea><placeName><region type="state">Pennsylvanie</region><settlement type="city">Pittsburgh</settlement></placeName><orgName type="university">Université de Pittsburgh</orgName></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Carcinoma, Squamous Cell (metabolism)</term><term>Cell Hypoxia (physiology)</term><term>Fluorescent Dyes (pharmacokinetics)</term><term>Fluorine Radioisotopes (pharmacokinetics)</term><term>Glucose (metabolism)</term><term>Glycolysis</term><term>Head and Neck Neoplasms (metabolism)</term><term>Heterografts</term><term>Humans</term><term>Immunoblotting</term><term>Immunohistochemistry</term><term>Mice</term><term>Mice, Nude</term><term>Oxidative Phosphorylation</term><term>Positron-Emission Tomography</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Carcinome épidermoïde (métabolisme)</term><term>Colorants fluorescents (pharmacocinétique)</term><term>Glucose (métabolisme)</term><term>Glycolyse</term><term>Humains</term><term>Hypoxie cellulaire (physiologie)</term><term>Hétérogreffes</term><term>Immunohistochimie</term><term>Immunotransfert</term><term>Phosphorylation oxydative</term><term>Radio-isotopes du fluor (pharmacocinétique)</term><term>Souris</term><term>Souris nude</term><term>Tomographie par émission de positons</term><term>Tumeurs de la tête et du cou (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Glucose</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacokinetics" xml:lang="en"><term>Fluorescent Dyes</term><term>Fluorine Radioisotopes</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Carcinoma, Squamous Cell</term><term>Head and Neck Neoplasms</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Carcinome épidermoïde</term><term>Glucose</term><term>Tumeurs de la tête et du cou</term></keywords><keywords scheme="MESH" qualifier="pharmacocinétique" xml:lang="fr"><term>Colorants fluorescents</term><term>Radio-isotopes du fluor</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Hypoxie cellulaire</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Cell Hypoxia</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Glycolysis</term><term>Heterografts</term><term>Humans</term><term>Immunoblotting</term><term>Immunohistochemistry</term><term>Mice</term><term>Mice, Nude</term><term>Oxidative Phosphorylation</term><term>Positron-Emission Tomography</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Glycolyse</term><term>Humains</term><term>Hétérogreffes</term><term>Immunohistochimie</term><term>Immunotransfert</term><term>Phosphorylation oxydative</term><term>Souris</term><term>Souris nude</term><term>Tomographie par émission de positons</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Purpose</title><p>Intratumoral metabolic heterogeneity may increase the likelihood of treatment failure due to the presence of a subset of resistant tumor cells. Using a head and neck squamous cell carcinoma (HNSCC) xenograft model and a real-time fluorescence imaging approach, we tested the hypothesis that tumors are metabolically heterogeneous, and that tumor hypoxia alters patterns of glucose uptake within the tumor.</p></sec><sec><title>Experimental Design</title><p>Cal33 cells were grown as xenograft tumors (n = 16) in nude mice after identification of this cell line's metabolic response to hypoxia. Tumor uptake of fluorescent markers identifying hypoxia, glucose import, or vascularity was imaged simultaneously using fluorescent molecular tomography. The variability of intratumoral 2-deoxyglucose (IR800-2-DG) concentration was used to assess tumor metabolic heterogeneity, which was further investigated using immunohistochemistry for expression of key metabolic enzymes. HNSCC tumors in patients were assessed for intratumoral variability of <sup>18</sup>F-fluorodeoxyglucose (<sup>18</sup>F-FDG) uptake in clinical PET scans.</p></sec><sec><title>Results</title><p>IR800-2-DG uptake in hypoxic regions of Cal33 tumors was 2.04 times higher compared to the whole tumor (p = 0.0001). IR800-2-DG uptake in tumors containing hypoxic regions was more heterogeneous as compared to tumors lacking a hypoxic signal. Immunohistochemistry staining for HIF-1α, carbonic anhydrase 9, and ATP synthase subunit 5β confirmed xenograft metabolic heterogeneity. We detected heterogeneous <sup>18</sup>F-FDG uptake within patient HNSCC tumors, and the degree of heterogeneity varied amongst tumors.</p></sec><sec><title>Conclusion</title><p>Hypoxia is associated with increased intratumoral metabolic heterogeneity. <sup>18</sup>F-FDG PET scans may be used to stratify patients according to the metabolic heterogeneity within their tumors, which could be an indicator of prognosis.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Yushkevich, Pa" uniqKey="Yushkevich P">PA Yushkevich</name></author><author><name sortKey="Piven, J" uniqKey="Piven J">J Piven</name></author><author><name sortKey="Hazlett, Hc" uniqKey="Hazlett H">HC Hazlett</name></author><author><name sortKey="Smith, Rg" uniqKey="Smith R">RG Smith</name></author><author><name sortKey="Ho, S" uniqKey="Ho S">S Ho</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Marusyk, A" uniqKey="Marusyk A">A 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Kang</name></author><author><name sortKey="Livesey, Km" uniqKey="Livesey K">KM Livesey</name></author><author><name sortKey="Kroemer, G" uniqKey="Kroemer G">G Kroemer</name></author><author><name sortKey="Billiar, Tr" uniqKey="Billiar T">TR Billiar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Van Velden, Fhp" uniqKey="Van Velden F">FHP van Velden</name></author><author><name sortKey="Cheebsumon, P" uniqKey="Cheebsumon P">P Cheebsumon</name></author><author><name sortKey="Yaqub, M" uniqKey="Yaqub M">M Yaqub</name></author><author><name sortKey="Smit, Ef" uniqKey="Smit E">EF Smit</name></author><author><name sortKey="Hoekstra, Os" uniqKey="Hoekstra O">OS Hoekstra</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Maryland</li><li>Pennsylvanie</li></region><settlement><li>Pittsburgh</li></settlement><orgName><li>Université de Pittsburgh</li></orgName></list><tree><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Nakajima, Erica C" sort="Nakajima, Erica C" uniqKey="Nakajima E" first="Erica C." last="Nakajima">Erica C. Nakajima</name></region><name sortKey="Ferris, Robert L" sort="Ferris, Robert L" uniqKey="Ferris R" first="Robert L." last="Ferris">Robert L. Ferris</name><name sortKey="Grandis, Jennifer R" sort="Grandis, Jennifer R" uniqKey="Grandis J" first="Jennifer R." last="Grandis">Jennifer R. Grandis</name><name sortKey="Hou, Weizhou" sort="Hou, Weizhou" uniqKey="Hou W" first="Weizhou" last="Hou">Weizhou Hou</name><name sortKey="Laymon, Charles" sort="Laymon, Charles" uniqKey="Laymon C" first="Charles" last="Laymon">Charles Laymon</name><name sortKey="Mountz, James M" sort="Mountz, James M" uniqKey="Mountz J" first="James M." last="Mountz">James M. Mountz</name><name sortKey="Nakajima, Erica C" sort="Nakajima, Erica C" uniqKey="Nakajima E" first="Erica C." last="Nakajima">Erica C. Nakajima</name><name sortKey="Nakajima, Erica C" sort="Nakajima, Erica C" uniqKey="Nakajima E" first="Erica C." last="Nakajima">Erica C. Nakajima</name><name sortKey="Oborski, Matthew" sort="Oborski, Matthew" uniqKey="Oborski M" first="Matthew" last="Oborski">Matthew Oborski</name><name sortKey="Van Houten, Bennett" sort="Van Houten, Bennett" uniqKey="Van Houten B" first="Bennett" last="Van Houten">Bennett Van Houten</name><name sortKey="Wang, Lin" sort="Wang, Lin" uniqKey="Wang L" first="Lin" last="Wang">Lin Wang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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