Abstract
PurposeIntratumoral 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 DesignCal33 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.ResultsIR800-2-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.ConclusionHypoxia 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.
Highlights
Intratumoral heterogeneity is gaining attention as a contributor to tumor recurrence and incomplete response to therapy [1,2,3,4]
Immunohistochemistry staining for hypoxia inducible factor-1a (HIF-1a), carbonic anhydrase 9, and ATP synthase subunit 5b confirmed xenograft metabolic heterogeneity
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
Summary
Intratumoral heterogeneity is gaining attention as a contributor to tumor recurrence and incomplete response to therapy [1,2,3,4]. A tumor’s response to variable oxygen levels can lead to metabolic flexibility and type of intratumoral symbiosis, in which lactate produced by hypoxic, glycolytic cells provides a fuel source for oxygenated cells performing oxidative phosphorylation (OXPHOS) [7,17,19,20]. While the elevated glycolytic activity of malignant cells has long dominated the study of cancer metabolism [1,3,21], increasing evidence demonstrates tumors can consume a variety of metabolites such as lactate, glutamine, and fatty acids [5,7,9,11,13,22]. We believe metabolically flexible malignant cells are more likely to form aggressive tumors due to their ability to adapt to environmental pressures
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