Sonja Schelhaas1, Lydia Wachsmuth2, Thomas Viel1, Davina J Honess3, Kathrin Heinzmann3, Donna-Michelle Smith3, Sven Hermann1, Stefan Wagner4, Michael T Kuhlmann1, Carsten Müller-Tidow5, Klaus Kopka4, Otmar Schober6, Michael Schäfers6, Richard Schneider7, Eric O Aboagye8, John Griffiths3, Cornelius Faber2, Andreas H Jacobs9. 1. European Institute for Molecular Imaging (EIMI), Westfälische Wilhelms-Universität (WWU) Münster, Münster, Germany. 2. Department of Clinical Radiology, University Hospital of Münster, Münster, Germany. 3. Cancer Research United Kingdom Cambridge Institute, Cambridge, United Kingdom. 4. Department of Nuclear Medicine, University Hospital of Münster, Münster, Germany. 5. Department of Hematology and Oncology, University Hospital of Münster, Münster, Germany. 6. European Institute for Molecular Imaging (EIMI), Westfälische Wilhelms-Universität (WWU) Münster, Münster, Germany Department of Nuclear Medicine, University Hospital of Münster, Münster, Germany. 7. Merck Serono, Darmstadt, Germany. 8. Comprehensive Cancer Imaging Centre, Imperial College London, London, United Kingdom; and. 9. European Institute for Molecular Imaging (EIMI), Westfälische Wilhelms-Universität (WWU) Münster, Münster, Germany Department of Geriatric Medicine, Johanniter Hospital, Bonn, Germany ahjacobs@uni-muenster.de.
Abstract
UNLABELLED: Molecular imaging allows the noninvasive assessment of cancer progression and response to therapy. The aim of this study was to investigate molecular and cellular determinants of 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET and diffusion-weighted (DW) MR imaging in lung carcinoma xenografts. METHODS: Four lung cancer cell lines (A549, HTB56, EBC1, and H1975) were subcutaneously implanted in nude mice, and growth was followed by caliper measurements. Glucose uptake and tumor proliferation were determined by (18)F-FDG and (18)F-FLT PET, respectively. T2-weighted MR imaging was performed, and the apparent diffusion coefficient (ADC) was determined by DW MR imaging as an indicator of cell death. Imaging findings were correlated to histology with markers for tumor proliferation (Ki67, 5-bromo-2'-deoxyuridine [BrdU]) and cell death (caspase-3, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling). The expression of human equilibrative nucleoside transporter 1 (hENT1), thymidine kinase 1 (TK1), thymidylate synthase, and thymidine phosphorylase (TP) were analyzed by Western blot and immunohistochemistry. Thymidine levels were determined by liquid chromatography-mass spectrometry. RESULTS: Xenografts varied with respect to in vivo growth rates. MR imaging and PET revealed intratumoral heterogeneities, which were confirmed by histology. (18)F-FLT uptake differed significantly between tumor lines, with A549 and H1975 demonstrating the highest radiotracer accumulation (A549, 8.5 ± 3.2; HTB56, 4.4 ± 0.7; EBC1, 4.4 ± 1.2; and H1975, 12.1 ± 3.5 maximal percentage injected dose per milliliter). In contrast, differences in (18)F-FDG uptake were only marginal. No clear relationship between (18)F-FLT accumulation and immunohistochemical markers for tumor proliferation (Ki67, BrdU) as well as hENT1, TK1, or TS expression was detected. However, TP was highly expressed in A549 and H1975 xenografts, which was accompanied by low tumor thymidine concentrations, suggesting that tumor thymidine levels influence (18)F-FLT uptake in the tumor models investigated. MR imaging revealed higher ADC values within proliferative regions of H1975 and A549 tumors than in HTB56 and EBC1. These ADC values were negatively correlated with cell density but not directly related to cell death. CONCLUSION: A direct relationship of (18)F-FLT with proliferation or ADC with cell death might be complicated by the interplay of multiple processes at the cellular and physiologic levels in untreated tumors. This issue must be considered when using these imaging modalities in preclinical or clinical settings.
UNLABELLED: Molecular imaging allows the noninvasive assessment of cancer progression and response to therapy. The aim of this study was to investigate molecular and cellular determinants of 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET and diffusion-weighted (DW) MR imaging in lung carcinoma xenografts. METHODS: Four lung cancer cell lines (A549, HTB56, EBC1, and H1975) were subcutaneously implanted in nude mice, and growth was followed by caliper measurements. Glucose uptake and tumor proliferation were determined by (18)F-FDG and (18)F-FLT PET, respectively. T2-weighted MR imaging was performed, and the apparent diffusion coefficient (ADC) was determined by DW MR imaging as an indicator of cell death. Imaging findings were correlated to histology with markers for tumor proliferation (Ki67, 5-bromo-2'-deoxyuridine [BrdU]) and cell death (caspase-3, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling). The expression of humanequilibrative nucleoside transporter 1 (hENT1), thymidine kinase 1 (TK1), thymidylate synthase, and thymidine phosphorylase (TP) were analyzed by Western blot and immunohistochemistry. Thymidine levels were determined by liquid chromatography-mass spectrometry. RESULTS: Xenografts varied with respect to in vivo growth rates. MR imaging and PET revealed intratumoral heterogeneities, which were confirmed by histology. (18)F-FLT uptake differed significantly between tumor lines, with A549 and H1975 demonstrating the highest radiotracer accumulation (A549, 8.5 ± 3.2; HTB56, 4.4 ± 0.7; EBC1, 4.4 ± 1.2; and H1975, 12.1 ± 3.5 maximal percentage injected dose per milliliter). In contrast, differences in (18)F-FDG uptake were only marginal. No clear relationship between (18)F-FLT accumulation and immunohistochemical markers for tumor proliferation (Ki67, BrdU) as well as hENT1, TK1, or TS expression was detected. However, TP was highly expressed in A549 and H1975 xenografts, which was accompanied by low tumorthymidine concentrations, suggesting that tumorthymidine levels influence (18)F-FLT uptake in the tumor models investigated. MR imaging revealed higher ADC values within proliferative regions of H1975 and A549 tumors than in HTB56 and EBC1. These ADC values were negatively correlated with cell density but not directly related to cell death. CONCLUSION: A direct relationship of (18)F-FLT with proliferation or ADC with cell death might be complicated by the interplay of multiple processes at the cellular and physiologic levels in untreated tumors. This issue must be considered when using these imaging modalities in preclinical or clinical settings.
Authors: Sabrina Doblas; Gilberto S Almeida; François-Xavier Blé; Philippe Garteiser; Benjamin A Hoff; Dominick J O McIntyre; Lydia Wachsmuth; Thomas L Chenevert; Cornelius Faber; John R Griffiths; Andreas H Jacobs; David M Morris; James P B O'Connor; Simon P Robinson; Bernard E Van Beers; John C Waterton Journal: J Magn Reson Imaging Date: 2015-05-26 Impact factor: 4.813
Authors: Sandra Heskamp; Linda Heijmen; Danny Gerrits; Janneke D M Molkenboer-Kuenen; Edwin G W Ter Voert; Kathrin Heinzmann; Davina J Honess; Donna-Michelle Smith; John R Griffiths; Sabrina Doblas; Ralph Sinkus; Peter Laverman; Wim J G Oyen; Arend Heerschap; Otto C Boerman Journal: Mol Imaging Biol Date: 2017-08 Impact factor: 3.488
Authors: Kathrin Heinzmann; Davina Jean Honess; David Yestin Lewis; Donna-Michelle Smith; Christopher Cawthorne; Heather Keen; Sandra Heskamp; Sonja Schelhaas; Timothy Howard Witney; Dmitry Soloviev; Kaye Janine Williams; Andreas Hans Jacobs; Eric Ofori Aboagye; John Richard Griffiths; Kevin Michael Brindle Journal: EJNMMI Res Date: 2016-08-11 Impact factor: 3.138
Authors: Dominic Carlin; Alexander Weller; Gem Kramer; Yan Liu; John C Waterton; Arturo Chiti; Martina Sollini; A Joop de Langen; Mary E R O'Brien; Maria Urbanowicz; Bart Km Jacobs; Nandita deSouza Journal: BJR Open Date: 2019-07-20