Changes in glucose metabolism and gene expression after transfer of anti-angiogenic genes in rat hepatoma.
OBJECTIVE
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 (18)F-fluorodeoxyglucose ((18)FDG) 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
(18)FDG 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.


CONCLUSIONS
TROP-, sFLT- or ASTAT-expressing MH3924A tumours show enhanced influx of (18)FDG, 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.
Haberkorn
Uwe
U
Department of Nuclear Medicine, University of Heidelberg, Heidelberg, Germany. Uwe_Haberkorn@med.uni-heidelberg.de
Hoffend
Johannes
J
Schmidt
Kerstin
K
Altmann
Annette
A
Bonaterra
Gabriel A
GA
Dimitrakopoulou-Strauss
Antonia
A
Strauss
Ludwig G
LG
Eisenhut
Michael
M
Kinscherf
Ralf
R
D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000000981:diagnostic imaging / Q000378:metabolism*; D045744:Cell Line, Tumor; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000378:metabolism*; D008113:Liver Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D019275:Radiopharmaceuticals; D011994:Recombinant Proteins; D019788:Fluorodeoxyglucose F18; D005947:Glucose
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