GLUT1 expression in tissue and (18)F-FDG uptake.

For staging of cancer patients, 18FFDG PET imaging has been applied for about a decade. It is generally accepted that imaging the metabolic activity of tumor tissue provides more sensitive and more specific information about the extent of disease than morphologic or anatomic imaging alone. The metabolic activity offers additional information about cancer biology and can be used to determine tumor aggressiveness and also help to assess response to treatment (1,2). In contrast, the rate-limiting step for the cellular accumulation of 18F-FDG in different tissues is still not fully understood. The uptake mechanism and biochemical pathway of 18F-FDG has been extensively studied in vitro and in vivo, and the transport through the cell membrane via glucose transport proteins (GLUTs) and the intracellular phosphorylation by hexokinase (HK) have been identified as key steps for subsequent tissue accumulation. As FDG-6-phosphate is not a suitable substrate for glucose-6-phosphate isomerase, and the enzyme level of glucose6-phosphatase is generally low in tumors, FDG-6-phosphate accumulates in cells and is visualized by PET. 18F-FDG uptake in tissue, however, is not tumor specific and little is known about the underlying cellular mechanisms of 18F-FDG accumulation in inflammatory tissue. Therefore, the study by Chung et al. on pages 999–1003 in this issue of The Journal of Nuclear Medicine (3) addresses an important issue of exploring in more detail falsepositive and false-negative PET results on a cellular level. 18F-FDG PET imaging of 62 patients with non-small cell lung cancer (NSCLC) was compared with histology and immunohistochemistry of mediastinal lymph nodes obtained from surgery or mediastinoscopy. The GLUT1 expression in metastatic tumors was higher in true-positive lymph nodes than that in false-negative lymph nodes, and metastatic squamous cell carcinoma showed stronger GLUT1 expression than metastatic adenocarcinomas. A higher grade of follicular hyperplasia was found in false-positive compared with true-negative lymph nodes, and the lymphoid follicular cells were strongly positive for the expression of GLUT1. The authors concluded that lymphoid follicular hyperplasia with GLUT1 overexpression may be related to false-positive results in PET imaging, and the weak expression of GLUT1 in adenocarcinomas might be responsible for false-negative results in mediastinal staging. These conclusions are based on 2 hypotheses: (a) Cellular 18F-FDG uptake is predominantly related to expression of GLUT1, and (b) overexpression of GLUT1 in tissue results in increased 18F-FDG uptake. Therefore, false-negative 18F-FDG PET imaging may be explained by weak GLUT1 expression, and nonmalignant tissue expressing GLUT1 will cause subsequent false-positive 18F-FDG uptake. Glucose is the major substrate for energy supply of mammalian cells and is a precursor of glycoproteins, triglycerides, glycogen, as well as riboses necessary for RNA and DNA synthesis. Because of its hydrophilic character, specific transport proteins are required for glucose to cross the cell membrane. They are present in all cell types and provide a central pore for the transmembrane passage of glucose. The number of known mammalian glucose transporters (GLUTs) has expanded over the past several years and 2 different families have been identified: sodium glucose cotransporters (SGLTs) and facilitative GLUTs (4). SGLTs consist of 14 transmembrane domains, and 6 subtypes (SGLT1– SGLT6) have been identified (5). They couple the movement of sodium down a gradient with the transport of glucose up a gradient. Little is known about the expression of SGLTs in tumors; however, SGLT2 has been recently suggested to play a role in glucose uptake of lung cancer metastases (6). Thirteen members of the family of facilitative GLUTs (GLUT1–GLUT13) are known (4). These various transporters consist of 12 transmembrane domains and are only capable of carrying glucose and other sugars down a gradient. They exhibit different substrate specificities, kinetic properties, and expression in tissue depending on the cellular demand and regulation. GLUT1, which is almost ubiquitously expressed in all cell types, mediates glucose transport into erythrocytes and through the blood–brain barrier, and its expression is also upregulated in many tumors (5). GLUT2 is found in the liver, pancreatic -cells, and other tissues. Its affinity for glucose is lower than that of GLUT1, but it has broader substrate specificity and also transports other sugars such as fructose and glucosamine. GLUT3 has the highest affinity for glucose and is the major form found in neurons. GLUT4 is the insulin-sensitive transporter and is found, for example, in muscle tissue. The presence of several different transporters in certain tissues and cells indicates that glucose delivery into cells is a process of considerable complexity. Although different types of tumors demonstrate overexpression of Received Feb. 16, 2004; revision accepted Feb. 23, 2004. For correspondence or reprints contact: Norbert Avril, MD, University of Pittsburgh Medical Center, 200 Lothrop St., Pittsburgh, PA 15213. E-mail: avrilne@msx.upmc. edu