Article Figures & Data
Figures
- FIGURE 1.
Model for metabolic trapping of [14C]acetate involves preferential uptake into astrocyte or tumor from extracellular fluid through unidentified isoform of monocarboxylic acid transporter. Stimulation of acetate uptake into cell might be enhanced by high rate of glycolysis and lactate efflux, that is, transacceleration of acetate uptake by lactate export (6). Once in cell, acetate can be converted to acetyl coenzyme A (CoA) and metabolized further by various pathways, including entry into tricarboxylic acid (TCA) cycle, leading to incorporation of 14C into various acidic compounds, including α-ketoglutarate (αKG) and oxalacetate (OAA). Rapid transamination reactions would cause labeling of TCA cycle–derived amino acids, glutamate, glutamine, and aspartate. With longer experimental times, label derived from acetate would also be incorporated into lipid and protein.
- FIGURE 2.
Metabolic labeling of C6 glioma tumors with [14C]acetate is illustrated in tumors grown in rat brain in vivo for 2 (A and B) or 3 (C) wk and assessed by autoradiography (A–C) and histologic staining (A and D). Autoradiographs show heterogeneous metabolic labeling by [14C]deoxyglucose (DG) and [2-14C]acetate in 2-wk-old intracerebral (A1 and A2) and extracerebral (B1–B3) tumors and in 3-wk-old necrotic tumors (C1–C3); different serial sections of same tumor (B2 and B3; C2 and C3) illustrate varied labeling of larger tumors, particularly in necrotic tumor. Thionin staining of sections near those used for autoradiography detects regions of densely packed cells in tumor (A3 and A4; D5–D8) compared with normal tissue. GFAP is marker for reactive astrocytes and also stains portions of C6 glioma tumors and zones surrounding tumors (D1–D4). Stained sections in D correspond to autoradiograph sections taken from same animals (B and C). Note low labeling of white matter (i.e., corpus callosum and subcortical white matter) by deoxyglucose and acetate (A–C), high labeling of lateral ventricle by acetate (B2 and B3), and relatively low labeling by acetate in boundary zone ventral to necrotic tumor (C2), which appears to coincide with GFAP-rich zone in 3-wk-old tumor (D4). Values for glucose use and net acetate uptake are presented in Table 1.
- FIGURE 3.
Representative 20-μm-thick sections of slices of human glioblastoma (1–3) or meningioma (4–6) tumors that were incubated in vitro with [14C]acetate for 10–40 min show heterogeneous labeling. Arrows indicate local areas of more intense uptake of tracer.
Tables
Brain region Glucose use (μmol/100 g/min) Net acetate uptake (mL/100 g/ min) Rat C6 glioma 111.0 ± 34.0* 9.9 ± 2.1† Contralateral brain tissue 81.0 ± 5.0 3.9 ± 1.0 Tumor/contralateral tissue 1.4 ± 0.5 2.3 ± 0.3‡ Human U-373 glioblastoma/astrocytoma 112.0 ± 27.0* 4.2 ± 0.1† Contralateral brain tissue 86.0 ± 11.0 2.8 ± 0.5 Tumor/contralateral tissue 1.3 ± 0.2 1.5 ± 0.2 Rat gray matter§ Frontal cortex Right 82.4 ± 7.4 4.8 ± 0.7 Left 77.3 ± 6.5 6.9 ± 2.0 Sensorimotor cortex Right 84.4 ± 7.8 4.6 ± 1.2 Left 75.4 ± 3.7 4.3 ± 1.4 Caudate nucleus Right 83.6 ± 8.5 3.3 ± 0.4 Left 76.6 ± 9.6 3.7 ± 0.8 Sensory cortex Right 87.6 ± 7.5 4.2 ± 0.8 Left 87.5 ± 7.9 4.1 ± 0.9 Rat white matter§ Forceps minor corpus callosum Right 35.6 ± 2.8 2.2 ± 0.6 Left 35.5 ± 2.3 2.3 ± 0.2 Genu of corpus callosum Right 35.2 ± 2.4 2.5 ± 0.5 Left 32.0 ± 1.2 2.3 ± 0.4 ↵* P < 0.09 vs. contralateral tissue.
↵† P < 0.005 vs. contralateral tissue.
↵‡ P < 0.05 vs. deoxyglucose tumor-to-tissue ratio.
↵§ Data are from rats implanted with C6 tumors.
Data are mean ± SD (C6 tumors: n = 6 for glucose use, n = 7 for acetate uptake; U-373 tumors: n = 4 per group for glucose use and acetate uptake).
Fraction Percentage of total 14C in acid extract (mean ± SD, n = 3) C6 tumor Contralateral cerebral cortex Unmetabolized [14C]acetate 5.0 ± 2.9 5.5 ± 1.9 Acidic + any neutral metabolites 37.0 ± 2.2 29.1 ± 0.8 Amino acids + any basic metabolites 59.6 ± 3.1 68.7 ± 2.9 Total metabolized 96.6 ± 2.6 97.7 ± 2.7 Proportions of labeled compounds recovered in acidic and amino acid fractions were not significantly different in tumor and contralateral tissue (P > 0.08, t test).
Tumor type/sample Acetate uptake (μmol/100 g/min) Whole tumor Hot spots Glioblastoma 1 high grade 1.90 2.60 2 recurrent 0.56 0.93 3 low grade 0.38 0.56 4 recurrent 1.20 1.60 5 recurrent 0.55 0.89 6 unknown grade 0.42 0.80 Mean ± SD (n = 6) 0.84 ± 0.60 1.20 ± 0.76 Meningioma 1 0.77 1.30 2 0.52 0.83 3 0.24 0.42 4 1.60 2.40 Mean ± SD (n = 4) 0.78 ± 0.58 1.20 ± 0.80 Pituitary adenoma 1 0.22 0.36 2 0.27 0.41 Oligodendroglioma 1 0.67 1.00 2 0.27 0.39 Gliotic tissue 0.13 0.23 Data are average uptake into entire slice for all slices at all incubation times for each tumor and average for hot spots in same tumors.
Tumor type Tumor sample Incubation time (min) Percentage of total 14C in acid extract Unmetabolized [14C]acetate Acidic + any neutral metabolites Amino acids + any basic metabolites Glioblastoma 1 10 101 2 3 20 63 12 29 2 10 76 10 16 20 20 25 52 3 10 37 17 51 20 20 17 59 Meningioma 1 10 58 22 24 40 41 26 27 2 10 42 30 29 20 22 35 47 3 10 11 29 60 20 12 30 58 Protein content of acid-extracted slices was 0.06–1.2 mg per sample. Recovery of 14C in fractions of acid extract was 101% ± 4%.
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