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Changes in glucose metabolism and gene expression after transfer of anti-angiogenic genes in rat hepatoma

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Human troponin I (TROP), the soluble receptor for vascular endothelial growth factor (sFLT) and angiostatin (ASTAT) are potent inhibitors of endothelial cell proliferation, angiogenesis and tumour growth in vivo. Transfer of these genes into tumours may induce changes not only in perfusion, but also more general ones such as changes in metabolism. The aim of this study was to assess these reactions using FDG-PET and high-throughput methods such as gene profiling.

Methods

We established Morris hepatoma (MH3924A) cell lines expressing TROP, sFLT or ASTAT and quantified 18F-fluorodeoxyglucose (18FDG) uptake by dynamic positron emission tomography (PET) after tumour inoculation in ACI rats. Furthermore, expression of glucose transporter-1 and -3 (GLUT-1 and GLUT-3) as well as hexokinase-1 and -2 were investigated by RT-PCR and immunohistomorphometry. In addition, gene array analyses were performed.

Results

18FDG uptake, vascular fraction and distribution volume were significantly higher in all genetically modified tumours. Immunohistomorphometry showed an increased percentage of hexokinase-1 and -2 as well as GLUT-1 and -3 immunoreactive (ir) cells. Using gene arrays and comparing all three groups of genetically modified tumours, we found upregulated expression of 36 genes related to apoptosis, signal transduction, stress or metabolism.

Conclusion

TROP-, sFLT- or ASTAT-expressing MH3924A tumours show enhanced influx of 18FDG, which seems to be caused by several factors: enhanced exchange of nutrients between blood and tumour, increased amounts of glucose transporters and hexokinases, and increased expression of genes related to apoptosis, matrix and stress, which induce an increased demand for glucose.

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Acknowledgements

The authors wish to thank Karin Leotta, Silke Vorwald, and Uschi Schierbaum for their help in performing the animal experiments and for technical assistance in histology. Financial support was from the Wilhelm Sander Stiftung (1999.085.1) and the Tumourzentrum Heidelberg/Mannheim, the Bequest of Herbert Dauss as well as the Foundation for Cancer and Scarlatina Research and EMIL.

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Authors and Affiliations

  1. Department of Nuclear Medicine, University of Heidelberg, INF 400, 69120, Heidelberg, Germany

    Uwe Haberkorn, Johannes Hoffend, Kerstin Schmidt & Annette Altmann

  2. Clinical Cooperation Unit Nuclear Medicine, DKFZ and University of Heidelberg, INF 280, 69120, Heidelberg, Germany

    Uwe Haberkorn, Kerstin Schmidt, Annette Altmann, Antonia Dimitrakopoulou-Strauss & Ludwig G. Strauss

  3. Anatomy and Developmental Biology, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer Ufer 1–3, 68167, Mannheim, Germany

    Kerstin Schmidt, Gabriel A. Bonaterra & Ralf Kinscherf

  4. Department of Radiopharmaceutical Chemistry, DKFZ, INF 280, 69120, Heidelberg, Germany

    Michael Eisenhut

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  1. Uwe Haberkorn
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Correspondence to Uwe Haberkorn.

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Haberkorn, U., Hoffend, J., Schmidt, K. et al. Changes in glucose metabolism and gene expression after transfer of anti-angiogenic genes in rat hepatoma. Eur J Nucl Med Mol Imaging 34, 2011–2023 (2007). https://doi.org/10.1007/s00259-007-0520-4

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  • DOI: https://doi.org/10.1007/s00259-007-0520-4

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