Quantifying Metabolic Heterogeneity in Head and Neck Tumors in Real Time: 2-DG Uptake Is Highest in Hypoxic Tumor Regions

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.

Prognostic significance of monocarboxylate transporter expression in oral cavity tumors

“…HNSCC cells also feature high levels of aerobic glycolysis. 10,11 In fact, some reports have already described that lactate, the end product of glycolysis, can be used as a prognostic tool in this type of tumor. Indeed, high levels of tumor lactate concentrations predict an increased metastasis formation 12 and a reduced overall and disease-free patient survival.…”

More challenges ahead—metabolic heterogeneity of pancreatic cancer stem cells

“…Indeed, our data are in line with several recent studies reporting diverse subsets of cancer cells with different metabolic requirements that reside within various tumor entities. 7,8 The co-existence of CSC subsets differing in their oxygen metabolism has also been suggested for established head and neck squamous cell carcinoma cell lines with hypoxia inducible factor 1 a (HIF-1a) as a major determinant. 9 Moreover, metabolically distinct subsets of CSCs have been found in relation to an epithelial-mesenchymal transition (EMT) phenotype.…”

Risk Stratification of Metastatic Neck Nodes by CT and PET in Patients with Head and Neck Cancer Receiving Definitive Radiotherapy

“…Theoretically, the hypodense necrotic zones on CT contrast images imply areas of hypovascularity and might harbor hypoxic cells, which could lead to the negative impact on nodal control as hypoxic cells are less radiosensitive (18). Nakajima et al (21) analyzed tumor cells grown as xenograft in nude mice after the identification of the metabolic response to hypoxia and found 2-deoxyglucose uptake in hypoxic regions of the tumors was approximately 2 times higher than in the whole tumor. They concluded that hypoxia is associated with increased intratumoral metabolic heterogeneities on 18 F-FDG PET.…”