Tumor Cell Metabolism Imaging
The best-known alteration of energy metabolism in cancer cells is increased glycolysis. In normal mammalian cells, glycolysis is inhibited by the presence of oxygen, which allows mitochondria to oxidize pyruvate to CO2 and H2O. This inhibition of glycolysis is termed the Pasteur effect, after Louis Pasteur, who first demonstrated that glucose flux was reduced by the presence of oxygen (12).
In addition to these experimental data, 18F-FDG PET of millions of oncology patients has unequivocally shown that most primary and metastatic human cancers show significantly increased glucose use.
~Roles of facilitative glucose transporter GLUT1 in [18F]FDG positron
emission tomography (PET) imaging of human diseases
Journal of Diagnostic Imaging in Therapy
J. Diagn. Imaging Ther. 2015; 2(1): 30-102.
The facilitative glucose transport protein GLUT1 has important roles in positron emission tomography (PET) imaging of human diseases. GLUT1 has widespread expression and catalyses the energy-independent facilitated diffusion of glucose down its concentration gradient across red blood cell membranes, blood-brain and blood-tissue barriers and membranes of some oragnelles. Import is usually the prevailing direction of transport for providing metabolic fuel, especially in proliferating cells. PET imaging using 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) measures the uptake of [18F]FDG into cells and tissues as a marker of glucose transport and glycolytic activity. Diseases can alter glycolytic activity in localised regions of tissues or organs, which can be visualised using [18F]FDG PET. Expression and/or activity levels of GLUT1 contribute to the pattern and intensity of [18F]FDG. [18F]FDG PET imaging is used in diagnosing and monitoring a range of human diseases and in analysing their response to treatments. Proliferating cancer cells display overexpression of GLUT1 and a vastly higher rate of glycolysis for satisfying their increased nutrient demands. Tumours therefore have significantly enhanced [18F]FDG uptake compared with normal cells, so [18F]FDG PET is routinely used in diagnosing and monitoring cancers. [18F]FDG PET imaging of the brain allows identification of distinct patterns of hypometabolism and/or hypermetabolism associated with neurological disorders including Alzheimer¨s disease, Parkinson¨s disease, epilespsy, schizophrenia, multiple sclerosis and cerebral ischemia. Cardiovascular diseases, along with underlying conditions such as inflammation, sarcoidosis, atherosclerosis, and infections of implants and prosthetics are routinely assessed using [18F]FDG PET. Diabetes alters the distribution of [18F]FDG, which can affect diagnosis of other diseases. The effects of anti-diabetic drugs on glucose metabolism and activation of brown adipose tissue as a preventative measure or treatment for obesity and diabetes have been investigated using [18F]FDG PET. GLUT1 itself is a potential therapeutic target for treatment of some diseases, which has also been investigated using [18F]FDG PET.
Keywords: cancer; cardiovascular disease; diabetes; FDG-PET imaging; glucose metabolism; GLUT1; neurological disorders; positron emission tomography; radiochemistry; transport protein
Roles of facilitative glucose transporter GLUT1 in [18F]FDG positron emission tomography (PET) imaging of human diseases | Open Medscience
Tumor Cell Metabolism Imaging
1Department of Nuclear Medicine, University of Freiburg, Freiburg, Germany; and 2Department of Radiology, German Cancer Research Center, Heidelberg, Germany
Molecular imaging of tumor metabolism has gained considerable interest, since preclinical studies have indicated a close relationship between the activation of various oncogenes and alterations of cellular metabolism. Furthermore, several clinical trials have shown that metabolic imaging can significantly impact patient management by improving tumor staging, restaging, radiation treatment planning, and monitoring of tumor response to therapy. In this review, we summarize recent data on the molecular mechanisms underlying the increased metabolic activity of cancer cells and discuss imaging techniques for studies of tumor glucose, lipid, and amino acid metabolism.
TUMOR GLUCOSE METABOLISM
Molecular Mechanisms Underlying Increased Glucose Use of Cancer Cells
The best-known alteration of energy metabolism in cancer cells is increased glycolysis. In normal mammalian cells, glycolysis is inhibited by the presence of oxygen, which allows mitochondria to oxidize pyruvate to CO2 and H2O. This inhibition of glycolysis is termed the Pasteur effect, after Louis Pasteur, who first demonstrated that glucose flux was reduced by the presence of oxygen (12). Conversion of glucose to lactic acid in the presence of oxygen is known as aerobic glycolysis and was reported by Otto Warburg at the beginning of the 20th century as a specific metabolic abnormality of cancer cells (13). Warburg even hypothesized that cancer results from a defect of mitochondrial metabolism that leads to aerobic glycolysis (13). In some tumor cell lines, however, the total contribution of glycolysis to ATP production reaches only about 15% (14). Furthermore, human and rodent glioma cells have been shown to exhibit high or moderate susceptibility to inhibitors of oxidative phosphorylation (15), and glioma cells with a glycolytic phenotype oxidize pyruvate and glutamine when glucose levels are low (15). These experimental data show that a mitochondrial defect is not a necessary prerequisite for cancer development and in a strict sense disprove Warburg's hypothesis.
18F-FDG PET is by far the most commonly used imaging technique to study glucose metabolism of cancer cells in-vivo. After intravenous injection, 18F-FDG is transported across the cell membrane by sodium-independent, facilitative glucose transporters (Gluts) (Fig. 1). These transporters allow energy-independent transport of glucose across the cell membrane down a concentration gradient (16). Thirteen members of the mammalian facilitative glucose transporter family have been identified. The genes belong to the solute carrier 2A family (SLC2A) (16). In malignant tumors Glut-1 is frequently overexpressed, but expression of Glut-3 and more recently Glut-12 has also been reported in some tumors types (16).
Simplified overview of metabolic processes targeted by PET and MRI. AA pool = amino acid pool; ChoK = choline kinase; FAS = fatty acid synthase; FR-1,6-BP = fructose-1,6-bisphosphate; G-6-P = glucose-6-phosphate; LAT = L-type amino acid transporter; LDH = lactate dehydrogenase; P-choline = phosphocholine; Ribose 5P = ribose-5-phosphate.
Tumor Cell Metabolism Imaging