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European Journal of Nuclear Medicine and Molecular Imaging

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01-12-2007 | Original article

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

Authors: Uwe Haberkorn, Johannes Hoffend, Kerstin Schmidt, Annette Altmann, Gabriel A. Bonaterra, Antonia Dimitrakopoulou-Strauss, Ludwig G. Strauss, Michael Eisenhut, Ralf Kinscherf

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 12/2007

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.

Laird AD, Vajkoczy P, Shawver LK, Thurnher A, Liang C, Mohammadi M, et al. SU6668 is a potent antiangiogenic and antitumour agent that induces regression of established tumours. Cancer Res 2000;60:4152–60.PubMed

Herbst RS, Hess KR, Tran HT, Tseng JE, Mullani NA, Charnsangavej C, et al. Phase I study of recombinant human endostatin in patients with advanced solid tumours. J Clin Oncol 2002;20:3792–803.PubMedCrossRef

Kerr C. Bevacizumab and chemotherapy improves survival in NSCLC. Lancet Oncol 2005;6:266.PubMedCrossRef

Schmidt K, Hoffend J, Altmann A, Strauss LG, Dimitrakopoulou-Strauss A, Engelhardt B, et al. Transfer of the sFLT-1 gene in Morris hepatoma results in decreased growth and perfusion and induction of genes associated with stress response. Clin Cancer Res 2005;11:2132–40.PubMedCrossRef

Schmidt K, Hoffend J, Altmann A, Kiessling F, Strauss LG, Koczan D, et al. Troponin I overexpression inhibits tumour growth, perfusion and vascularization of Morris hepatoma. J Nucl Med 2006;47:1506–14.PubMed

Schmidt K, Hoffend J, Altmann A, Strauss LG, Dimitrakopoulou-Strauss A, Engelhardt B, et al. Angiostatin overexpression in Morris hepatoma results in decreased tumour growth but increased perfusion and vascularization. J Nucl Med 2006;47:543–51.PubMed

Bassa P, Kim EE, Inoue T, Wong FC, Korkmaz M, Yang DJ, et al. Evaluation of preoperative chemotherapy using PET with fluorine-18-fluorodeoxyglucose in breast cancer. J Nucl Med 1996;37:931–8.PubMed

Haberkorn U, Bellemann ME, Gerlach L, Morr I, Trojan H, Brix G, et al. Uncoupling of 2-fluoro-2-deoxyglucose transport and phosphorylation in rat hepatoma during gene therapy with HSV thymidine kinase. Gene Ther 1998;5:880–7.PubMedCrossRef

Haberkorn U, Bellemann ME, Altmann A, Gerlach L, Morr I, Oberdorfer F, et al. PET 2-fluoro-2-deoxyglucose uptake in rat prostate adenocarcinoma during chemotherapy with gemcitabine. J Nucl Med 1997;38:1215–21.PubMed

10.

Haberkorn U, Strauss LG, Dimitrakopoulou A, Engenhart R, Oberdorfer F, Ostertag H, et al. PET studies of fluorodeoxyglucose metabolism in patients with recurrent colorectal tumours receiving radiotherapy. J Nucl Med 1991;32:1485–90.PubMed

11.

Lin WY, Tsai SC, Hung GU. Value of delayed 18F-FDG-PET imaging in the detection of hepatocellular carcinoma. Nucl Med Commun 2005;26:315–21.PubMedCrossRef

12.

Rozental JM, Levine RL, Nickles RJ, Dobkin JA. Glucose uptake by gliomas after treatment. A positron emission tomographic study. Arch Neurol 1989;46:1302–7.PubMed

13.

Goel A, Mathupala SP, Pedersen PL. Glucose metabolism in cancer. Evidence that demethylation events play a role in activating type II hexokinase gene expression. J Biol Chem 2003;278:15333–40.PubMedCrossRef

14.

Tian M, Zhang H, Nakasone Y, Mogi K, Endo K. Expression of Glut-1 and Glut-3 in untreated oral squamous cell carcinoma compared with FDG accumulation in a PET study. Eur J Nucl Med Mol Imaging 2004;31:5–12.PubMedCrossRef

15.

Haberkorn U, Ziegler SI, Oberdorfer F, Trojan H, Haag D, Peschke P, et al. FDG uptake, tumour proliferation and expression of glycolysis associated genes in animal tumour models. Nucl Med Biol 1994;21:827–34.PubMedCrossRef

16.

Brown RS, Wahl RL. Overexpression of Glut-1 glucose transporter in human breast cancer. An immunohistochemical study. Cancer 1993;72:2979–85.PubMedCrossRef

17.

Haberkorn U, Altmann A, Kamencic H, Morr I, Traut U, Henze M, et al. Glucose transport and apoptosis after gene therapy with HSV thymidine kinase. Eur J Nucl Med 2001;28:1690–6.PubMedCrossRef

18.

Sharp PE, LaRegina MC. The laboratory rat. Boca Raton: CRC; 1998.

19.

Burger C, Buck A. Requirements and implementation of a flexible kinetic modeling tool. J Nucl Med 1997;38:1818–23.PubMed

20.

Bos R, van Der Hoeven JJ, van Der Wall E, van der Groep P, van Diest PJ, Comans EFI, et al. Biologic correlates of (18)fluorodeoxyglucose uptake in human breast cancer measured by positron emission tomography. J Clin Oncol 2002;20:379–87.PubMedCrossRef

21.

Higashi K, Clavo AC, Wahl RL. In vitro assessment of 2-fluoro-2-deoxy-D-glucose, L-methionine and thymidine as agents to monitor the early response of a human adenocarcinoma cell line to radiotherapy. J Nucl Med 1993;34:773–9.PubMed

22.

Hayes N, Biswas C, Strout HV, Berger J. Activation by protein synthesis inhibitors of glucose transport into L6 muscle cells. Biochem Biophys Res Commun 1993;190:881–7.PubMedCrossRef

23.

Shawver LK, Olson SA, White MK, Weber MJ. Degradation and biosynthesis of the glucose transporter protein in chicken embryo fibroblasts transformed by the src oncogene. Mol Cell Biol 1987;7:2112–8.PubMed

24.

Widnell CC, Baldwin SA, Davies A, Martin S, Pasternak CA. Cellular stress induces a redistribution of the glucose transporter. FASEB J 1990;4:1634–7.PubMed

25.

Flier JS, Mueckler MM, Usher P, Lodish HF. Elevated levels of glucose transport and transporter messenger RNA are induced by ras or src oncogenes. Science 1987;235:1492–5.PubMedCrossRef

26.

Wertheimer E, Sasson S, Cerasi E, Ben-Neriah Y. The ubiquitous glucose transporter GLUT-1 belongs to the glucose-regulated protein family of stress-inducible proteins. Proc Natl Acad Sci U S A 1991;88:2525–9.PubMedCrossRef

27.

Hughes CS, Shen JW, Subjeck JR. Resistance to etoposide induced by three glucose-regulated stresses in Chinese hamster ovary cells. Cancer Res 1989;49:4452–4.PubMed

28.

Haberkorn U, Bellemann ME, Brix G, Kamencic H, Morr I, Traut U, et al. Apoptosis and changes in glucose transport early after treatment of Morris hepatoma with gemcitabine. Eur J Nucl Med 2001;28:418–25.PubMedCrossRef

29.

Haberkorn U, Reinhardt M, Strauss LG, Oberdorfer F, Berger MR, Altmann A, et al. Metabolic design of combination therapy: use of enhanced fluorodeoxyglucose uptake caused by chemotherapy. J Nucl Med 1992;33:1981–7.PubMed

30.

Singh D, Banerji AK, Dwarakanath BS, Tripathi RP, Gupta JP, Mathew TL, et al. Optimizing cancer radiotherapy with 2-deoxy-d-glucose dose escalation studies in patients with glioblastoma multiforme. Strahlenther Onkol 2005;181:507–14.PubMedCrossRef

31.

Zhao W, Liu H, Liu W, Wu Y, Chen W, Jiang B, et al. Abnormal activation of the synuclein-gamma gene in hepatocellular carcinomas by epigenetic alteration. Int J Cancer 2006;118:1081–8.

32.

Yao M, Zhou DP, Jiang SM, Wang QH, Zhou XD, Tang ZY, et al. Elevated activity of N-acetylglucosaminyltransferase V in human hepatocellular carcinoma. J Cancer Res Clin Oncol 1998;124:27–30.PubMedCrossRef

33.

Verma A, Matta A, Shukla NK, Deo SV, Gupta SD, Ralhan R. Clinical significance of mannose-binding lectin-associated serine protease-2 expression in esophageal squamous cell carcinoma. Int J Cancer 2006;118:2930–5.PubMedCrossRef

34.

Xu RH, Pelicano H, Zhou Y, Carew JS, Feng L, Bhalla KN, et al. Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. Cancer Res 2005;65:613–21.PubMedCrossRef

35.

Fanciulli M, Valentini A, Bruno T, Citro G, Zupi G, Floridi A. Effect of the antitumour drug lonidamine on glucose metabolism of adriamycin-sensitive and -resistant human breast cancer cells. Oncol Res 1996;8:111–20.PubMed

36.

Coppola T, Perret-Menoud V, Gattesco S, Magnin S, Pombo I, Blank U, et al. The death domain of Rab3 guanine nucleotide exchange protein in GDP/GTP exchange activity in living cells. Biochem J 2002;362:273–9.PubMedCrossRef

37.

Al-Zoubi AM, Efimova EV, Kaithamana S, Martinez O, El-Idrissi ME, Dogan RE, et al. Contrasting effects of IG20 and its splice isoforms, MADD and DENN-SV, on tumour necrosis factor alpha-induced apoptosis and activation of caspase-8 and -3. J Biol Chem 2001;276:47202–11.PubMedCrossRef

38.

Tomiyoshi G, Horita Y, Nishita M, Ohashi K, Mizuno K. Caspase-mediated cleavage and activation of LIM-kinase 1 and its role in apoptotic membrane blebbing. Genes Cells 2004;9:591–600.PubMedCrossRef

39.

Cataldegirmen G, Zeng S, Feirt N, Ippagunta N, Dun H, Qu W, et al. RAGE limits regeneration after massive liver injury by coordinated suppression of TNF-alpha and NF-kappaB. J Exp Med 2005;201:473–84.PubMedCrossRef

40.

Yasuda S, Arii S, Mori A, Isobe N, Yang W, Oe H, et al. Hexokinase II and VEGF expression in liver tumours: correlation with hypoxia-inducible factor 1 alpha and its significance. J Hepatol 2004;40:117–23.PubMedCrossRef

41.

Hatzivassiliou G, Zhao F, Bauer DE, Andreadis C, Shaw A, Dhanak D, et al. ATP citrate lyase inhibition can suppress tumour cell growth. Cancer Cell 2005;8:311–21.PubMedCrossRef

42.

Yamauchi J, Kaziro Y, Itoh H. C-terminal mutation of G protein beta subunit affects differentially extracellular signal-regulated kinase and c-Jun N-terminal kinase pathways in human embryonal kidney 293 cells. J Biol Chem 1997;272:7602–7.PubMedCrossRef

43.

Qin Z, Itoh S, Jeney V, Ushio-Fukai M, Fukai T. Essential role for the Menkes ATPase in activation of extracellular superoxide dismutase: implication for vascular oxidative stress. FASEB J 2006;20:334–6.PubMedCrossRef

44.

Cai W, Gao QD, Zhu L, Peppa M, He C, Vlassara H. Oxidative stress-inducing carbonyl compounds from common foods: novel mediators of cellular dysfunction. Mol Med 2002;8:337–46.PubMed

45.

Simm A, Bartling B, Silber RE. RAGE: a new pleiotropic antagonistic gene? Ann N Y Acad Sci 2004;1019:228–31.PubMedCrossRef

46.

Baumann H, Morella KK, Wong GH. TNF-alpha, IL-1 beta, and hepatocyte growth factor cooperate in stimulating specific acute phase plasma protein genes in rat hepatoma cells. J Immunol 1993;151:4248–57.PubMed

47.

Nakamura H, Fujii Y, Inoki I, Sugimoto K, Tanzawa K, Matsuki H, et al. Brevican is degraded by matrix metalloproteinases and aggrecanase-1 (ADAMTS4) at different sites. J Biol Chem 2000;275:38885–90.PubMedCrossRef

48.

Koli K, Hyytiainen M, Ryynanen MJ, Keski-Oja J. Sequential deposition of latent TGF-beta binding proteins (LTBPs) during formation of the extracellular matrix in human lung fibroblasts. Exp Cell Res 2005;310:370–82.PubMedCrossRef

Title: Changes in glucose metabolism and gene expression after transfer of anti-angiogenic genes in rat hepatoma
Authors: Uwe Haberkorn
Johannes Hoffend
Kerstin Schmidt
Annette Altmann
Gabriel A. Bonaterra
Antonia Dimitrakopoulou-Strauss
Ludwig G. Strauss
Michael Eisenhut
Ralf Kinscherf
Publication date: 01-12-2007
Publisher: Springer-Verlag
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 12/2007
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-007-0520-4

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Purpose

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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