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Quantifying metabolic heterogeneity in head and neck tumors in real time: 2-DG uptake is highest in hypoxic tumor regions

Nakajima, EC and Laymon, C and Oborski, M and Hou, W and Wang, L and Grandis, JR and Ferris, RL and Mountz, JM and Van Houten, B (2014) Quantifying metabolic heterogeneity in head and neck tumors in real time: 2-DG uptake is highest in hypoxic tumor regions. PLoS ONE, 9 (8).

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Purpose: 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. Experimental Design: 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. Results: 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. Conclusion: 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. © 2014 Nakajima et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Nakajima, ECecn8@pitt.eduECN8
Laymon, Ccml14@pitt.eduCML14
Oborski, Mmjo29@pitt.eduMJO29
Hou, Wweh29@pitt.eduWEH29
Wang, L
Grandis, JRjgrandis@pitt.eduJGRANDIS
Ferris, RLrlf1@pitt.eduRLF1
Mountz, JMjmm92@pitt.eduJMM92
Van Houten, Bbev15@pitt.eduBEV15
ContributionContributors NameEmailPitt UsernameORCID
Date: 15 August 2014
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 9
Number: 8
DOI or Unique Handle: 10.1371/journal.pone.0102452
Schools and Programs: School of Medicine > Immunology
School of Medicine > Otolaryngology
School of Medicine > Pathology
School of Medicine > Pharmacology and Chemical Biology
School of Medicine > Radiology
Refereed: Yes
Date Deposited: 23 Sep 2014 16:17
Last Modified: 02 Feb 2019 16:58


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