Journal List > Int J Thyroidol > v.8(2) > 1094476

Int J Thyroidol. 2015 Nov;8(2):147-152. Korean.
Published online November 30, 2015.
Copyright © 2015. the Korean Thyroid Association. All rights reserved.
Understanding of Cancer Cell Metabolism and Thyroid Cancer
Won Gu Kim and Won Bae Kim
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Correspondence: Won Bae Kim, MD, PhD, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. Tel: 82-2-3010-3913, Fax: 82-2-3010-6962, Email:
Received May 16, 2015; Revised June 26, 2015; Accepted June 26, 2015.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


Metabolic reprogramming of cancer cell is one of essential hallmarks of cancer. Otto Warburg first demonstrated that cancer cells utilized more glucose and enhanced glycolytic pathway in the presence of oxygen in 1926. Scientific observations of basic and clinical research in several decades supported that cancer-specific metabolism can be an emerging target for treatment of cancer. Metabolic reprogramming is regulated by both oncogenic signaling and tumor suppressor genes associated with critical signaling pathways in metabolism. These changes provided energy, substrates for cell growth and proliferation, favoring microenvironment, and important for redox balancing for cancer cells. Recent advance of several tools for evaluation comprehensive metabolic profiles of cancer cells provided us to identification of metabolic Achilles' heel of cancers including thyroid cancer. This approach can be a useful strategy for advance in treatment of cancer patients.

Keywords: Cancer; Metabolism; Metabolome; Warburg effect


Fig. 1
Summary of changes in metabolic characteristics of cancer cells. 3PG: 3-phosphoglycerate, αKG: alphaketoglutarate, AcCoA: Acetyl coenzyme A, FA: fatty acids, G6P: glucose-6-phosphate, Gln: glutamate, Glu: glutamine, PPP: pentose phosphate pathway. Bold arrow indicates increase of metabolic pathways in cancers.
Click for larger image

1. American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009;19(11):1167–1214.
2. Shoup M, Stojadinovic A, Nissan A, Ghossein RA, Freedman S, Brennan MF, et al. Prognostic indicators of outcomes in patients with distant metastases from differentiated thyroid carcinoma. J Am Coll Surg 2003;197(2):191–197.
3. Schlumberger M, Brose M, Elisei R, Leboulleux S, Luster M, Pitoia F, et al. Definition and management of radioactive iodine-refractory differentiated thyroid cancer. Lancet Diabetes Endocrinol 2014;2(5):356–358.
4. Durante C, Haddy N, Baudin E, Leboulleux S, Hartl D, Travagli JP, et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab 2006;91(8):2892–2899.
5. Brose MS, Nutting CM, Jarzab B, Elisei R, Siena S, Bastholt L, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet 2014;384(9940):319–328.
6. Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, et al. Lenvatinib versus placebo in radioiodinerefractory thyroid cancer. N Engl J Med 2015;372(7):621–630.
7. Fojo T, Parkinson DR. Biologically targeted cancer therapy and marginal benefits: are we making too much of too little or are we achieving too little by giving too much? Clin Cancer Res 2010;16(24):5972–5980.
8. Bock C, Lengauer T. Computational epigenetics. Bioinformatics 2008;24(1):1–10.
9. Gillies RJ, Verduzco D, Gatenby RA. Evolutionary dynamics of carcinogenesis and why targeted therapy does not work. Nat Rev Cancer 2012;12(7):487–493.
10. Stincone A, Prigione A, Cramer T, Wamelink MM, Campbell K, Cheung E, et al. The return of metabolism: biochemistry and physiology of the pentose phosphate pathway. Biol Rev Camb Philos Soc. 2014
[Epub ahead of print].
11. Vander Heiden MG. Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov 2011;10(9):671–684.
12. Sborov DW, Haverkos BM, Harris PJ. Investigational cancer drugs targeting cell metabolism in clinical development. Expert Opin Investig Drugs 2015;24(1):79–94.
13. Warburg O, Wind F, Negelein E. The Metabolism of Tumors in the Body. J Gen Physiol 1927;8(6):519–530.
14. Warburg O. On the origin of cancer cells. Science 1956;123(3191):309–314.
15. Warburg O. On respiratory impairment in cancer cells. Science 1956;124(3215):269–270.
16. Mankoff DA, Eary JF, Link JM, Muzi M, Rajendran JG, Spence AM, et al. Tumor-specific positron emission tomography imaging in patients: [18F] fluorodeoxyglucose and beyond. Clin Cancer Res 2007;13(12):3460–3469.
17. Weinhouse S. The Warburg hypothesis fifty years later. Z Krebsforsch Klin Onkol Cancer Res Clin Oncol 1976;87(2):115–126.
18. Jang M, Kim SS, Lee J. Cancer cell metabolism: implications for therapeutic targets. Exp Mol Med 2013;45:e45
19. Kroemer G, Pouyssegur J. Tumor cell metabolism: cancer's Achilles' heel. Cancer Cell 2008;13(6):472–482.
20. Pouyssegur J, Dayan F, Mazure NM. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 2006;441(7092):437–443.
21. Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis. Nat Rev Cancer 2004;4(11):891–899.
22. Koukourakis MI, Giatromanolaki A, Harris AL, Sivridis E. Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas: a metabolic survival role for tumor-associated stroma. Cancer Res 2006;66(2):632–637.
23. Swietach P, Vaughan-Jones RD, Harris AL. Regulation of tumor pH and the role of carbonic anhydrase 9. Cancer Metastasis Rev 2007;26(2):299–310.
24. Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 2007;109(9):3812–3819.
25. Hensley CT, Wasti AT, DeBerardinis RJ. Glutamine and cancer: cell biology, physiology, and clinical opportunities. J Clin Invest 2013;123(9):3678–3684.
26. Reitzer LJ, Wice BM, Kennell D. Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells. J Biol Chem 1979;254(8):2669–2676.
27. DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci U S A 2007;104(49):19345–19350.
28. Schulze A, Harris AL. How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature 2012;491(7424):364–373.
29. Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer 2011;11(2):85–95.
30. Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci U S A 2008;105(48):18782–18787.
31. David CJ, Chen M, Assanah M, Canoll P, Manley JL. HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 2010;463(7279):364–368.
32. Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, et al. p53 regulates mitochondrial respiration. Science 2006;312(5780):1650–1653.
33. Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R, et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 2006;126(1):107–120.
34. Li T, Kon N, Jiang L, Tan M, Ludwig T, Zhao Y, et al. Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence. Cell 2012;149(6):1269–1283.
35. Munoz-Pinedo C, El Mjiyad N, Ricci JE. Cancer metabolism: current perspectives and future directions. Cell Death Dis 2012;3:e248.
36. Vicha A, Taieb D, Pacak K. Current views on cell metabolism in SDHx-related pheochromocytoma and paraganglioma. Endocr Relat Cancer 2014;21(3):R261–R277.
37. Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 2002;30(4):406–410.
38. Dunn WB. Current trends and future requirements for the mass spectrometric investigation of microbial, mammalian and plant metabolomes. Phys Biol 2008;5(1):011001.
39. Armitage EG, Barbas C. Metabolomics in cancer biomarker discovery: current trends and future perspectives. J Pharm Biomed Anal 2014;87:1–11.
40. Patti GJ, Yanes O, Siuzdak G. Innovation: Metabolomics: the apogee of the omics trilogy. Nat Rev Mol Cell Biol 2012;13(4):263–269.
41. You L, Zhang B, Tang YJ. Application of stable isotope-assisted metabolomics for cell metabolism studies. Metabolites 2014;4(2):142–165.
42. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 2013;499(7457):214–218.