Skip to main content
SpringerLink
Log in

[(Methyl)1-11C]-Acetate Metabolism in Hepatocellular Carcinoma

  • Research Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

Abstract

Purpose

Studies have established the value of [(methyl)1-11C]-acetate ([11C]Act) combined with 2-deoxy-2[18F]fluoro-d-glucose (FDG) for detecting hepatocellular carcinoma (HCC) using positron emission tomography (PET). In this study, the metabolic fate of [11C]Act in HCC was characterized.

Methods

Experiments with acetic acid [1-14C] sodium salt ([14C]Act) were carried out on WCH-17 cells and freshly derived rat hepatocytes. PET scans with [11C]Act were also carried out on woodchucks with HCC before injection of [14C]Act. The radioactivity levels in different metabolites were quantified with thin-layer chromatography.

Results

In WCH-17 cells, the predominant metabolite was phosphatidylcholine (PC). Regions of HCCs with the highest [11C]Act uptake had higher radioactivity accumulation in lipid-soluble compounds than surrounding hepatic tissues. In those regions, PC and triacylglycerol (TG) accumulated more radioactivity than in surrounding hepatic tissues.

Conclusions

High [11C]Act uptake in HCC is associated with increased de novo lipogenesis. PC and TG are the main metabolites into which the radioactive label from [11C]Act is incorporated in HCC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Ferlay J, Bray F, Pisani P et al (2004) GLOBOCAN 2: cancer incidence, mortality and prevalence worldwide. IARC, Lyon

    Google Scholar 

  2. Theakston F (ed) (2008) World Health Statistics 2008. World Health Organization, Geneva, p 112

  3. El-Serag HB, Mason AC (1999) Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 340(10):745–750

    Article  CAS  PubMed  Google Scholar 

  4. El-Serag HB, Mason AC (2000) Risk factors for the rising rates of primary liver cancer in the United States. Arch Intern Med 160(21):3227–3230

    Article  CAS  PubMed  Google Scholar 

  5. El-Serag HB, Mason AC, Key C (2001) Trends in survival of patients with hepatocellular carcinoma between 1977 and 1996 in the United States. Hepatology 33(1):62–65

    Article  CAS  PubMed  Google Scholar 

  6. Previsani N, Lavanchy D (2002) Hepatitis B. World Health Organization—Department of Communicable Diseases Surveillance and Response, Geneva, p 76

    Google Scholar 

  7. Shin JA, Park JW, An M et al (2006) Diagnostic accuracy of 18F-FDG positron emission tomography for evaluation of hepatocellular carcinoma. Korean J Hepatol 12(4):546–552

    PubMed  Google Scholar 

  8. Yamamoto Y, Nishiyama Y, Kameyama R et al (2008) Detection of hepatocellular carcinoma using 11C-choline PET: comparison with 18F-FDG PET. J Nucl Med 49(8):1245–1248

    Article  PubMed  Google Scholar 

  9. Lin WY, Tsai SC, Hung GU (2005) Value of delayed 18F-FDG-PET imaging in the detection of hepatocellular carcinoma. Nucl Med Commun 26(4):315–321

    Article  PubMed  Google Scholar 

  10. Wudel LJ Jr, Delbeke D, Morris D et al (2003) The role of [18F]fluorodeoxyglucose positron emission tomography imaging in the evaluation of hepatocellular carcinoma. Am Surg 69(2):117–124; discussion 124–116

    PubMed  Google Scholar 

  11. Trojan J, Schroeder O, Raedle J et al (1999) Fluorine-18 FDG positron emission tomography for imaging of hepatocellular carcinoma. Am J Gastroenterol 94(11):3314–3319

    Article  CAS  PubMed  Google Scholar 

  12. Delbeke D, Martin WH, Sandler MP et al (1998) Evaluation of benign vs malignant hepatic lesions with positron emission tomography. Arch Surg 133(5):510–515; discussion 515–516

    Article  CAS  PubMed  Google Scholar 

  13. Bruix J, Sherman M (2005) Management of hepatocellular carcinoma. Hepatology 42(5):1208–1236

    Article  PubMed  Google Scholar 

  14. Llovet JM, Bruix J (2008) Novel advancements in the management of hepatocellular carcinoma in 2008. J Hepatol 48(Suppl 1):S20–S37

    Article  CAS  PubMed  Google Scholar 

  15. Ho CL, Yu SC, Yeung DW (2003) 11C-Acetate PET imaging in hepatocellular carcinoma and other liver masses. J Nucl Med 44(2):213–221

    PubMed  Google Scholar 

  16. Li S, Beheshti M, Peck-Radosavljevic M et al (2006) Comparison of (11)C-acetate positron emission tomography and (67)Gallium citrate scintigraphy in patients with hepatocellular carcinoma. Liver Int 26(8):920–927

    Article  CAS  PubMed  Google Scholar 

  17. Park JW, Kim JH, Kim SK et al (2008) A prospective evaluation of 18F-FDG and 11C-acetate PET/CT for detection of primary and metastatic hepatocellular carcinoma. J Nucl Med 49(12):1912–1921

    Article  PubMed  Google Scholar 

  18. Hwang KH, Choi DJ, Lee SY et al (2009) Evaluation of patients with hepatocellular carcinomas using [(11)C]acetate and [(18)F]FDG PET/CT: a preliminary study. Appl Radiat Isot 67:1195–1198

    Article  CAS  PubMed  Google Scholar 

  19. Yu MC, Yuan JM, Govindarajan S et al (2000) Epidemiology of hepatocellular carcinoma. Can J Gastroenterol 14(8):703–709

    CAS  PubMed  Google Scholar 

  20. Tennant BC, Toshkov IA, Peek SF et al (2004) Hepatocellular carcinoma in the woodchuck model of hepatitis B virus infection. Gastroenterology 127(5 Suppl 1):S283–S293

    Article  PubMed  Google Scholar 

  21. Abe K, Kurata T, Shikata T et al (1988) Enzyme-altered liver cell foci in woodchucks infected with woodchuck hepatitis virus. Jpn J Cancer Res 79(4):466–472

    CAS  PubMed  Google Scholar 

  22. Aldrich CE, Coates L, Wu TT et al (1989) In vitro infection of woodchuck hepatocytes with woodchuck hepatitis virus and ground squirrel hepatitis virus. Virology 172(1):247–252

    Article  CAS  PubMed  Google Scholar 

  23. Chen HS, Kaneko S, Girones R et al (1993) The woodchuck hepatitis virus X gene is important for establishment of virus infection in woodchucks. J Virol 67(3):1218–1226

    CAS  PubMed  Google Scholar 

  24. Cote PJ, Korba BE, Steinberg H et al (1991) Cyclosporin A modulates the course of woodchuck hepatitis virus infection and induces chronicity. J Immunol 146(9):3138–3144

    CAS  PubMed  Google Scholar 

  25. Korba BE, Cote PJ, Wells FV et al (1989) Natural history of woodchuck hepatitis virus infections during the course of experimental viral infection: molecular virologic features of the liver and lymphoid tissues. J Virol 63(3):1360–1370

    CAS  PubMed  Google Scholar 

  26. Popper H, Roth L, Purcell RH et al (1987) Hepatocarcinogenicity of the woodchuck hepatitis virus. Proc Natl Acad Sci U S A 84(3):866–870

    Article  CAS  PubMed  Google Scholar 

  27. Chu CK, Boudinot FD, Peek SF et al (1998) Preclinical investigation of L-FMAU as an anti-hepatitis B virus agent. Antivir Ther 3(Suppl 3):113–121

    CAS  PubMed  Google Scholar 

  28. Luxembourg A, Hannaman D, Wills K et al (2008) Immunogenicity in mice and rabbits of DNA vaccines expressing woodchuck hepatitis virus antigens. Vaccine 26(32):4025–4033

    Article  CAS  PubMed  Google Scholar 

  29. Menne S, Butler SD, George AL et al (2008) Antiviral effect of lamivudine, emtricitabine, adefovir dipivoxil, and tenofovir disoproxil fumarate, administered orally alone and in combination, to woodchucks with chronic woodchuck hepatitis virus infection. Antimicrob Agents Chemother 52: 3617–3632

    Article  CAS  PubMed  Google Scholar 

  30. Menne S, Cote PJ, Korba BE et al (2005) Antiviral effect of oral administration of tenofovir disoproxil fumarate in woodchucks with chronic woodchuck hepatitis virus infection. Antimicrob Agents Chemother 49(7):2720–2728

    Article  CAS  PubMed  Google Scholar 

  31. Menne S, Tennant BC, Gerin JL et al (2007) Chemoimmunotherapy of chronic hepatitis B virus infection in the woodchuck model overcomes immunologic tolerance and restores T-cell responses to pre-S and S regions of the viral envelope protein. J Virol 81(19):10614–10624

    Article  CAS  PubMed  Google Scholar 

  32. Torizuka T, Tamaki N, Inokuma T et al (1995) In vivo assessment of glucose metabolism in hepatocellular carcinoma with FDG-PET. J Nucl Med 36(10):1811–1817

    CAS  PubMed  Google Scholar 

  33. Salem N, MacLennan GT, Kuang Y et al (2007) Quantitative evaluation of 2-deoxy-2[F-18]fluoro-D-glucose-positron emission tomography imaging on the woodchuck model of hepatocellular carcinoma with histological correlation. Mol Imaging Biol 9(3):135–143

    Article  PubMed  Google Scholar 

  34. Salem N, Kuang Y, Wang F et al (2009) PET imaging of hepatocellular carcinoma with 2-deoxy-2[18F]fluoro-D-glucose, 6-deoxy-6[18F] fluoro-D-glucose, [1-11C]-acetate and [N-methyl-11C]-choline. Q J Nucl Med Mol Imaging 53(2):144–156

    CAS  PubMed  Google Scholar 

  35. Berry MN, Friend DS (1969) High-yield preparation of isolated rat liver parenchymal cells: a biochemical and fine structural study. J Cell Biol 43(3):506–520

    Article  CAS  PubMed  Google Scholar 

  36. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  37. Bligh EG, Dyer WJ (1959) A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37(8):911–917

    CAS  PubMed  Google Scholar 

  38. Smillie RM, Krotkov G (1960) The estimation of nucleic acids in some algae and higher plants. Can J Bot 38:31–49

    Article  CAS  Google Scholar 

  39. Yoshimoto M, Waki A, Yonekura Y et al (2001) Characterization of acetate metabolism in tumor cells in relation to cell proliferation: acetate metabolism in tumor cells. Nucl Med Biol 28(2):117–122

    Article  CAS  PubMed  Google Scholar 

  40. Norfolk E, Khan SH, Fried B et al (1994) Comparison of amino acid separations on high performance silica gel, cellulose, and C-18 reversed phase layers and application of HPTLC to the determination of amino acids in Biomphalaria glabrata snails. J Liq Chromatogr Relat Technol 17(6):1317–1326

    Article  CAS  Google Scholar 

  41. Kupke IR, Zeugner S (1978) Quantitative high-performance thin-layer chromatography of lipids in plasma and liver homogenates after direct application of 0.5-microliter samples to the silica-gel layer. J Chromatogr 146(2):261–271

    Article  CAS  PubMed  Google Scholar 

  42. Kihlberg T, Valind S, Langstrom B (1994) Synthesis of [1-11C], [2-11C], [1-11C](2H3) and [2-11C](2H3)acetate for in vivo studies of myocardium using PET. Nucl Med Biol 21(8):1067–1072

    Article  CAS  PubMed  Google Scholar 

  43. Folch J, Lees M, Sloane Stanley GH (1957) A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 226(1):497–509

    CAS  PubMed  Google Scholar 

  44. Brown M, Marshall DR, Sobel BE et al (1987) Delineation of myocardial oxygen utilization with carbon-11-labeled acetate. Circulation 76(3):687–696

    CAS  PubMed  Google Scholar 

  45. Blouin A, Bolender RP, Weibel ER (1977) Distribution of organelles and membranes between hepatocytes and nonhepatocytes in the rat liver parenchyma. A stereological study. J Cell Biol 72(2):441–455

    Article  CAS  PubMed  Google Scholar 

  46. Jiang J, Xu N, Zhang X et al (2007) Lipids changes in liver cancer. Journal of Zhejiang University-Science B 8(6):398–409

    Article  CAS  PubMed  Google Scholar 

  47. Yamashita T, Honda M, Takatori H et al (2009) Activation of lipogenic pathway correlates with cell proliferation and poor prognosis in hepatocellular carcinoma. J Hepatol 50(1):100–110

    Article  CAS  PubMed  Google Scholar 

  48. Kawata S, Takaishi K, Nagase T et al (1990) Increase in the active form of 3-hydroxy-3-methylglutaryl coenzyme A reductase in human hepatocellular carcinoma: possible mechanism for alteration of cholesterol biosynthesis. Cancer Res 50(11):3270–3273

    CAS  PubMed  Google Scholar 

  49. Yun M, Bang SH, Kim JW et al (2009) The importance of acetyl coenzyme A synthetase for 11C-acetate uptake and cell survival in hepatocellular carcinoma. J Nucl Med 50(8):1222–1228

    Article  CAS  PubMed  Google Scholar 

  50. Wang F, Anderson PW, Salem N et al (2006) Gene expression studies of hepatitis virus-induced woodchuck hepatocellular carcinoma in correlation with human results. Int J Oncol 30(1):33–44

    Google Scholar 

  51. Yu K, Schomisch SJ, Chandramouli V et al (2006) Hexokinase and glucose-6-phosphatase activity in woodchuck model of hepatitis virus-induced hepatocellular carcinoma. Comp Biochem Physiol C Toxicol Pharmacol 143(2):225–231

    Article  Google Scholar 

Download references

Acknowledgments

We are grateful to Dr. Ann-Marie Broome for her technical assistance in obtaining, preserving, and maintaining the cell lines used in this study. This work was supported in part by NIH/NCI CA095307 (Principal Investigator: Zhenghong Lee), a NIH Interdisciplinary Biomedical Imaging Training Program predoctoral training grant T32EB007509-02 (Principal Investigator: David L. Wilson), and a 2008 Society of Nuclear Medicine fellowship award (recipient: Nicolas Salem). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Authors and Affiliations

  1. Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, 44106, USA

    Nicolas Salem, Yu Kuang, Jeffrey A. Kolthammer, Fangjing Wang, Yanming Wang & Zhenghong Lee

  2. Department of Radiology, University Hospitals Case Medical Center, 11100 Euclid Ave., Bishop Building, Room S-109B, Cleveland, OH, 44106, USA

    David Corn, Bernadette Erokwu, Haibin Tian, Chunying Wu, Yanming Wang & Zhenghong Lee

Authors
  1. Nicolas Salem
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yu Kuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David Corn
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bernadette Erokwu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jeffrey A. Kolthammer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Haibin Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chunying Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Fangjing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yanming Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zhenghong Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhenghong Lee.

Additional information

Nicolas Salem and Yu Kuang equally contributed to the work presented in this manuscript.

This work was supported by NIH/NCI CA095307, NIH T32007509, and a 2008 SNM fellowship award.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Salem, N., Kuang, Y., Corn, D. et al. [(Methyl)1-11C]-Acetate Metabolism in Hepatocellular Carcinoma. Mol Imaging Biol 13, 140–151 (2011). https://doi.org/10.1007/s11307-010-0308-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-010-0308-y

Key words

Search

Navigation