J Korean Med Assoc.  2009 Feb;52(2):113-120. 10.5124/jkma.2009.52.2.113.

Imaging of Cancer Metabolism using Positron Emission Tomography

• Yun MJ
• Lee JD

• KMID: 1469545
• DOI: http://doi.org/10.5124/jkma.2009.52.2.113

Abstract

In the 1920's, Warburg reported an observation that cancer cells depend on glycolysis even in the presence of available oxygen likely due to impaired function of mitochondria. Since then, this Warburg s effect has been the most important hypothesis in cancer metabolism and is considered as a seventh hallmark of many human cancers. Aerobic glycolysis was originally attributable to increased bioenergetic needs in rapidly proliferating cancer cells. Recently, biosynthetic aspects of aerobic glycolysis, which reprograms cancer metabolism to synthesize macromolecules such as nucleotides, fatty acids, amino acids, etc., are under active investigation. Introduction of positron emission tomography (PET) and metabolic radiotracers including F-18 flurorodeoxyglucose (FDG) and C-11 acetate made it possible to image cancer metabolism in vivo and to renew the interests on this issue. Studies have found that cancer cells with highly glycolysis features are associated with resistance to many chemotherapeutic regimens and radiation treatment. Therefore, development of glycolytic inhibitors can have an incremental effect to conventional treatments. In addition, functional imaging with metabolic radiotracers will continuously play important roles in detecting cancers and monitoring therapeutic responses to novel anti-metabolic approaches to cancer cells.

Keyword

Cancer metabolism; PET; Glycolysis

MeSH Terms

Amino Acids
Electrons
Energy Metabolism
Fatty Acids
Glycolysis
Humans
Mitochondria
Nucleotides
Oxygen
Positron-Emission Tomography
Amino Acids
Fatty Acids
Nucleotides
Oxygen

Reference

1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000. 100:57–70.

2. Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol. 1926. 8:519.

3. Kinahan PE, Townsend DW, Beyer T, Sashin D. Attenuation correction for a combined 3D PET/CT scanner. Med Phys. 1998. 25:2046–2053.

4. Deberardinis RJ, Sayed N, Ditsworth D, Thompson CB. Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev. 2008. 18:54–61.

5. Ramos-Montoya A, Lee WN, Bassilian S, Lim S, Trebukhina RV, Kazhyna MV, Ciudad CJ, Noe V, Centelles JJ, Cascante M. Pentose phosphate cycle oxidative and nonoxidative balance: A new vulnerable target for overcoming drug resistance in cancer. Int J Cancer. 2006. 119:2733–2741.

6. Ortega AD, Sanchez-Arago M, Giner-Sanchez D, Sanchez-Cenizo L, Willers I, Cuezva JM. Glucose avidity of carcinomas. Cancer Lett. 2008. (in press).

7. Angbein S, Zerilli M, Zur Hausen A, Staiger W, Rensch-Boschert K, Lukan N, Popa J, Ternullo MP, Steidler A, Weiss C, Grobholz R, Willeke F, Alken P, Stassi G, Schubert P, Coy JF. Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted. Br J Cancer. 2006. 94:578–585.

8. Hatzivassiliou G, Zhao F, Bauer DE, Andreadis C, Shaw AN, Dhanak D, Hingorani SR, Tuveson DA, Thompson CB. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell. 2005. 8:311–321.

9. Baron A, Migita T, Tang D, Loda M. Fatty acid synthase: a metabolic oncogene in prostate cancer? J Cell Biochem. 2004. 91:47–53.

10. Coleman PS. Membrane cholesterol and tumor bioenergetics. Ann N Y Acad Sci. 1986. 488:451–467.

11. Baggetto LG. Deviant energetic metabolism of glycolytic cancer cells. Biochimie. 1992. 74:959–974.

12. Chang LO, Morris HP. Enzymatic and immunological studies on pyruvate carboxylase in livers and liver tumors. Cancer Res. 1973. 33:2034–2041.

13. Brand A, Engelmann J, Leibfritz D. A 13C NMR study on fluxes into the TCA cycle of neuronal and glial tumor cell lines and primary cells. Biochimie. 1992. 74:941–948.

14. Mazurek S, Boschek CB, Hugo F, Eigenbrodt E. Pyruvate kinase type M2 and its role in tumor growth and spreading. Semin Cancer Biol. 2005. 15:300–308.

15. Forbes NS, Meadows AL, Clark DS, Blanch HW. Estradiol stimulates the biosynthetic pathways of breast cancer cells: detection by metabolic flux analysis. Metab Eng. 2006. 8:639–652.

16. Bi X, Lin Q, Foo TW, Joshi S, You T, Shen HM, Ong CN, Cheah PY, Eu KW, Hew CL. Proteomic analysis of colorectal cancer reveals alterations in metabolic pathways: mechanism of tumorigenesis. Mol Cell Proteomics. 2006. 5:1119–1130.

17. Gillies RJ, Robey I, Gatenby RA. Causes and consequences of increased glucose metabolism of cancers. J Nucl Med. 2008. 49:S2. 24S–42S.

18. Rofstad EK, Mathiesen B, Kindem K, Galappathi K. Acidic extracellular pH promotes experimental metastasis of human melanoma cells in athymic nude mice. Cancer Res. 2006. 66:6699–6707.

19. Su J, Chen X, Kanekura T. A CD147-targeting siRNA inhibits the proliferation, invasiveness, and VEGF production of human malignant melanoma cells by down-regulating glycolysis. Cancer Lett. 2009. 273:140–147.

20. Le Mellay V, Troppmair J, Benz R, Rapp UR. Negative regulation of mitochondrial VDAC channels by C-Raf kinase. BMC Cell Biol. 2002. 3:14.

21. Kostakoglu L, Goldsmith S. Fluorine-18 fluorodeoxyglucose positron emission tomography in the staging and follow-up of lymphoma: is it time to shift gears? Eur J Nucl Med. 2000. 27:1564–1578.

22. Mac Manus M, Hicks R, Ball D, Kalff V, Matthews JP, Salminen E, Khaw P, Wirth A, Rischin D, McKenzie A. F-18 fluorodeoxyglucose positron emission tomography staging in radical radiotherapy candidates with nonsmall cell lung carcinoma: powerful correlation with survival and high impact on treatment. Cancer. 2001. 92:886–895.

23. Hung G, Shiau Y, Tsai S, Chao T, Ho Y, Kao C. Value of 18F-fluoro-2-deoxyglucose positron emission tomography in the evaluation of recurrent colorectal cancer. Anticancer Res. 2001. 21(2B):1375–1378.

24. Isidoro A, Casado E, Redondo A, Acebo P, Espinosa E, Alonso AM, Cejas P, Hardisson D, Fresno Vara JA, Belda-Iniesta C, Gonzalez-Baron M, Cuezva JM. Breast carcinomas fulfill the Warburg hypothesis and provide metabolic markers of cancer prognosis. Carcinogenesis. 2005. 26:2095–2104.

25. Lopez-Rios F, Sanchez-Arago M, Garcia-Garcia E, Ortega AD, Berrendero JR, Pozo-Rodriguez F, Lopez-Encuentra A, Ballestin C, Cuezva JM. Loss of the mitochondrial bioenergetic capacity underlies the glucose avidity of carcinomas. Cancer Res. 2007. 67:9013–9017.

26. Lee JD, Yang WI, Park YN, Kim KS, Choi JS, Yun M, Ko D, Kim TS, Cho AE, Kim HM, Han KH, Im SS, Ahn YH, Choi CW, Park JH. Different glucose uptake and glycolytic mechanisms between hepatocellular carcinoma and intrahepatic mass-forming cholangiocarcinoma with increased (18)F-FDG uptake. J Nucl Med. 2005. 46:1753–1759.

27. Trojan J, Schroeder O, Raedle J, Baum RP, Herrmann G, Jacobi V, Zeuzem S. Fluorine-18 FDG positron emission tomography for imaging of hepatocellular carcinoma. Am J Gastroenterol. 1999. 94:3314–3319.

28. Kong YH, Han CJ, Lee SD, Sohn WS, Kim MJ, Ki SS, Kim J, Jeong SH, Kim YC, Lee JO, Cheon GJ, Choi CW, Lim SM. Positron emission tomography with fluorine-18-fluorode-oxyglucose is useful for predicting the prognosis of patients with hepatocellular carcinoma. Korean J Hepatol. 2004. 10:279–287.

29. Hatano E, Ikai I, Higashi T, Teramukai S, Torizuka T, Saga T, Fujii H, Shimahara Y. Preoperative positron emission tomography with fluorine-18-fluorodeoxyglucose is predictive of prognosis in patients with hepatocellular carcinoma after resection. World J Surg. 2006. 30:1736–1741.

30. Yang SH, Suh KS, Lee HW, Cho EH, Cho JY, Cho YB, Yi NJ, Lee KU. The role of (18) F-FDG-PET imaging for the selection of liver transplantation candidates among hepatocellular carcinoma patients. Liver Transpl. 2006. 12:1655–1660.

31. Gayed I, Vu T, Iyer R, Johnson M, Macapinlac H, Swanston N, Podoloff D. The role of 18F-FDG PET in staging and early prediction of response to therapy of recurrent gastrointestinal stromal tumors. J Nucl Med. 2004. 45:17–21.

32. Xu RH, Pelicano H, Zhou Y, Carew JS, Feng L, Bhalla KN, Keating MJ, Huang P. Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. Cancer Res. 2005. 65:613–621.

33. Pelicano H, Martin DS, Xu RH, Huang P. Glycolysis inhibition for anticancer treatment. Oncogene. 2006. 25:4633–4646.

34. Ott K, Fink U, Becker K, Stahl A, Dittler HJ, Busch R, Stein H, Lordick F, Link T, Schwaiger M, Siewert JR, Weber WA. Prediction of response to preoperative chemotherapy in gastric carcinoma by metabolic imaging: results of a prospective trial. J Clin Oncol. 2003. 21:4604–4610.

35. Stahl A, Ott K, Schwaiger M, Weber WA. Comparison of different SUV-based methods for monitoring cytotoxic therapy with FDG PET. Eur J Nucl Med Mol Imaging. 2004. 31:1471–1478.

36. Oyama N, Akino H, Suzuki Y, Kanamaru H, Sadato N, Yonekura Y, Okada K. The increased accumulation of [18F]fluorodeoxyglucose in untreated prostate cancer. Jpn J Clin Oncol. 1999. 29:623–629.

37. Ho C, Yu S, Yeung D. 11C-acetate PET imaging in hepatocellular carcinoma and other liver masses. J Nucl Med. 2003. 44:213–221.

38. Dimitrakopoulou-Strauss A, Strauss LG, Rudi J. PET-FDG as predictor of therapy response in patients with colorectal carcinoma. Q J Nucl Med. 2003. 47:8–13.

39. Kang DE, White RL Jr, Zuger JH, Sasser HC, Teigland CM. Clinical use of fluorodeoxyglucose F 18 positron emission tomography for detection of renal cell carcinoma. J Urol. 2004. 171:1806–1809.

40. Shreve P, Chiao PC, Humes HD, Schwaiger M, Gross MD. Carbon-11-acetate PET imaging in renal disease. J Nucl Med. 1995. 36:1595–1601.

41. Oyama N, Akino H, Kanamaru H, Kanamaru H, Sadato N, Yonekura Y, Okada K. 11C-acetate PET imaging of prostate cancer. J Nucl Med. 2002. 43:181–186.

42. Yoshimoto M, Waki A, Yonekura Y, Sadato N, Murata T, Omata N, Takahashi N, Welch MJ, Fujibayashi Y. Characterization of acetate metabolism in tumor cells in relation to cell proliferation: acetate metabolism in tumor cells. Nucl Med Biol. 2001. 28:117–122.

43. Vavere AL, Kridel SJ, Wheeler FB, Lewis JS. 1-11C-acetate as a PET radiopharmaceutical for imaging fatty acid synthase expression in prostate cancer. J Nucl Med. 2008. 49:327–334.

44. Goldberg RP, Brunengraber H. Contributions of cytosolic and mitochondrial acetyl-CoA syntheses to the activation of lipogenic acetate in rat liver. Adv Exp Med Biol. 1980. 132:413–418.

45. Medes G, Thomas A, Weinhouse S. Metabolism of neoplastic tissue. IV. A study of lipid synthesis in neoplastic tissue slices in vitro. Cancer Res. 1953. 13:27–29.

46. Weiss L, Hoffmann GE, Schreiber R, Andres H, Fuchs E, Korber E, Kolb HJ. Fatty-acid biosynthesis in man, a pathway of minor importance. Purification, optimal assay conditions, and organ distribution of fatty-acid synthase. Biol Chem Hoppe Seyler. 1986. 367:905–912.

47. Howard BV. Acetate as a carbon source for lipid synthesis in cultured cells. Biochim Biophys Acta. 1977. 488:145–151.

48. Seufert CD, Graf M, Janson G, Kuhn A, Soling HD. Formation of free acetate by isolated perfused livers from normal, starved and diabetic rats. Biochem Biophys Res Commun. 1974. 57:901–909.

49. Park JW, Kim JH, Kim SK, Kang KW, Park KW, Choi JI, Lee WJ, Kim CM, Nam BH. A prospective evaluation of 18F-FDG and 11C-acetate PET/CT for detection of primary and metastatic hepatocellular carcinoma. J Nucl Med. 2008. 49:1912–1921.