title: Biological significance of 18F-FDG uptake on PET in patients with non-small-cell lung cancer.
abstract: BACKGROUND
  The aim of this study is to investigate the underlying biologic mechanisms of 2-[18F]-fluoro-2-deoxy-d-glucose (18F-FDG) uptake on positron emission tomography (PET) in non-small cell lung cancer (NSCLC).
  
  
  METHODS
  One-hundred forty patients with NSCLC who underwent 18F-FDG PET were included in the study. Tumor sections were stained by immunohistochemistry for glucose transporter 1 (GLUT1), GLUT3, hypoxia-inducible factor-1 alpha (HIF-1α), hexokinase I, vascular endothelial growth factor (VEGF), microvessels (CD34), epidermal growth factor receptor (EGFR), and molecules relevant to PI3K/Akt/mTOR signaling pathway (PTEN, p-Akt, p-mTOR and p-S6). We also conducted in vitro studies of 18F-FDG uptake and mTOR inhibition in NSCLC cells.
  
  
  RESULTS
  High 18F-FDG uptake was significantly associated with poor prognosis in NSCLC patients. 18F-FDG uptake was significantly correlated with GLUT1, hexokinase I, HIF-1α, VEGF, CD34, p-Akt, p-mTOR and EGFR. PTEN expression showed inverse correlation with 18F-FDG uptake. In in vitro study, 18F-FDG uptake was markedly decreased by the inhibition of GLUT1 and GLUT1 upregulation by the induction of HIF-1α increased the 18F-FDG uptake. Inhibition of both mTOR complex1 (mTORC1) and mTORC2 suppressed cell growth, but activity of mTORC1 regulated the 18F-FDG uptake. NCI-H1650 cells with PTEN loss showed the highest 18F-FDG uptake and the least sensitivity to mTOR inhibitors.
  
  
  CONCLUSIONS
  The amount of 18F-FDG accumulation is associated with molecules relevant to glucose metabolism, hypoxia, angiogenesis and mTOR signaling pathway. Especially, PTEN status may affect not only 18F-FDG uptake but also effect of mTOR inhibitors on the growth of NSCLC.
authors.affiliation: Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan. Electronic address: kkaira1970@yahoo.co.jp.
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Kaira
authors.affiliation: Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan.
authors.forename: Masakuni
authors.initials: M
authors.lastname: Serizawa
authors.affiliation: Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan. Electronic address: y.koh@scchr.jp.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Koh
authors.affiliation: Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Bioimaging Information Analysis, Gunma University Graduate School of Medicine, Showa-machi, Maebashi, Gunma 371-8511, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Yamaguchi
authors.affiliation: Department of Bioimaging Information Analysis, Gunma University Graduate School of Medicine, Showa-machi, Maebashi, Gunma 371-8511, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hanaoka
authors.affiliation: Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Showa-machi, Maebashi, Gunma 371-8511, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Oriuchi
authors.affiliation: Division of Diagnostic Radiology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Endo
authors.affiliation: Division of Thoracic Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan.
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Ohde
authors.affiliation: Division of Pathology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakajima
authors.affiliation: Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yamamoto
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis*; D066246:ErbB Receptors / Q000378:metabolism; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051274:Glucose Transporter Type 3 / Q000378:metabolism; D006593:Hexokinase / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008175:Lung Neoplasms / Q000175:diagnosis*; D009389:Neovascularization, Pathologic; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011379:Prognosis; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; D051272:Glucose Transporter Type 1; D051274:Glucose Transporter Type 3; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D019788:Fluorodeoxyglucose F18; D006593:Hexokinase; C512478:EGFR protein, human; D066246:ErbB Receptors; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; D005947:Glucose
keywords: (18)F-FDG PET; GLUT1; Hypoxia; NSCLC; PTEN; mTOR