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A novel radiotracer to image glycogen metabolism in tumors by positron emission tomography.

ABSTRACT: The high rate of glucose uptake to fuel the bioenergetic and anabolic demands of proliferating cancer cells is well recognized and is exploited with (18)F-2-fluoro-2-deoxy-d-glucose positron emission tomography ((18)F-FDG-PET) to image tumors clinically. In contrast, enhanced glucose storage as glycogen (glycogenesis) in cancer is less well understood and the availability of a noninvasive method to image glycogen in vivo could provide important biologic insights. Here, we demonstrate that (18)F-N-(methyl-(2-fluoroethyl)-1H-[1,2,3]triazole-4-yl)glucosamine ((18)F-NFTG) annotates glycogenesis in cancer cells and tumors in vivo, measured by PET. Specificity of glycogen labeling was demonstrated by isolating (18)F-NFTG-associated glycogen and with stable knockdown of glycogen synthase 1, which inhibited (18)F-NFTG uptake, whereas oncogene (Rab25) activation-associated glycogen synthesis led to increased uptake. We further show that the rate of glycogenesis is cell-cycle regulated, enhanced during the nonproliferative state of cancer cells. We demonstrate that glycogen levels, (18)F-NFTG, but not (18)F-FDG uptake, increase proportionally with cell density and G1-G0 arrest, with potential application in the assessment of activation of oncogenic pathways related to glycogenesis and the detection of posttreatment tumor quiescence.

SUBMITTER: Witney TH

PROVIDER: S-EPMC3966281 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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A novel radiotracer to image glycogen metabolism in tumors by positron emission tomography.

Witney Timothy H TH Carroll Laurence L Alam Israt S IS Chandrashekran Anil A Nguyen Quang-Dé QD Sala Roberta R Harris Robert R DeBerardinis Ralph J RJ Agarwal Roshan R Aboagye Eric O EO

Cancer research 20140301 5

The high rate of glucose uptake to fuel the bioenergetic and anabolic demands of proliferating cancer cells is well recognized and is exploited with (18)F-2-fluoro-2-deoxy-d-glucose positron emission tomography ((18)F-FDG-PET) to image tumors clinically. In contrast, enhanced glucose storage as glycogen (glycogenesis) in cancer is less well understood and the availability of a noninvasive method to image glycogen in vivo could provide important biologic insights. Here, we demonstrate that (18)F- ...[more]

PMID: 24590807

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Project description:Fluorine-18-fluoro-2-deoxy-D-glucose (FDG) is widely used as positron-emission-tomography (PET) radiotracer for the detection and staging of human cancer. Tumor uptake of FDG varies substantially between different cancer types and between patients with the same tumor type. The molecular basis for this heterogeneity is unknown. Using cancer cell lines and primary human tumors of distinct histologic origins, we here show that increased FDG uptake is universally associated with coordinate upregulation of genes within the glycolysis, pentose-phosphate, and other related metabolic pathways. In primary human breast cancers, this FDG signature shows significant overlap with established breast cancer signatures for the “basal-like” disease subtype and “poor prognosis”. FDG high breast cancer showed significantly more gene copy number alterations genome wide than FDG low cancers. About 50 % of primary breast cancers with high FDG uptake and FDG gene expression signature show DNA copy gain encompassing the c-myc gene locus and express gene sets regulated by the transcription factor MYC. Our data shows that FDG-PET marks a distinct subset of “basal-like” human breast cancer which is characterized by MYC and prognostically unfavorable gene expression signatures, suggesting that FDG-PET imaging may be useful to risk-stratify patients with locally advanced breast cancer. Our general strategy to identify molecular determinants of FDG-retention through a genome-wide approach consisted of FDG uptake measurements in cancer cell lines and primary human tumors, the selection of samples with particularly high versus low FDG-retention, and subsequent pathway-based analysis of RNA expression data collected from these samples. Cell line RNA was extracted from a 10 cm plate seeded simultaneously and at the same density as the wells for FDG-uptake assays. For primary human tumor samples, RNA was extracted from macrodissected frozen tumor tissue. All cell line RNA samples and the astrocytoma RNA aliquots were hybridized to Affymetrix U133 Plus 2.0 arrays. All primary breast cancer RNA samples were hybridized to Affymetrix U133A arrays.

Dataset Information

A novel radiotracer to image glycogen metabolism in tumors by positron emission tomography.

Publications

A novel radiotracer to image glycogen metabolism in tumors by positron emission tomography.

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