Metabolic Alterations During the Growth of Tumour Spheroids

Cell Biochemistry and Biophysics

Volumn 68, Issue 3, 2014, Pages 615-628

  Bloch, Katarzyna ^a   Smith, Hannah ^b   van Hamel Parsons, Victoria ^b   Gavaghan, David ^a   Kelly, Catherine ^a,b   Fletcher, Alexander ^a   Maini, Philip ^a   Callaghan, Richard ^b,c  

^a UNIVERSITY OF OXFORD   (United Kingdom)

^b UNIVERSITY OF OXFORD   (United Kingdom)

^c AUSTRALIAN NATIONAL UNIVERSITY   (Australia)

Author keywords

Glycolytic metabolism; Metabolic adaptation; Solid tumour models; Tumour acidification; Tumour growth; Tumour metabolism; Warburg hypothesis

Indexed keywords

GLUCOSE;

ARTICLE; BIOLOGICAL MODEL; CELL HYPOXIA; CELL PROLIFERATION; ENERGY METABOLISM; ENZYMOLOGY; GENE EXPRESSION REGULATION; GLYCOLYSIS; HUMAN; METABOLISM; MULTICELLULAR SPHEROID; NEOPLASM; PATHOLOGY; PENTOSE PHOSPHATE CYCLE; PH; TUMOR CELL LINE; TUMOR MICROENVIRONMENT;

CELL HYPOXIA; CELL LINE, TUMOR; CELL PROLIFERATION; ENERGY METABOLISM; GENE EXPRESSION REGULATION, NEOPLASTIC; GLUCOSE; GLYCOLYSIS; HUMANS; HYDROGEN-ION CONCENTRATION; MODELS, BIOLOGICAL; NEOPLASMS; PENTOSE PHOSPHATE PATHWAY; SPHEROIDS, CELLULAR; TUMOR MICROENVIRONMENT;

EID: 84896041477     PISSN: 10859195     EISSN: None     Source Type: Journal    
DOI: 10.1007/s12013-013-9757-7     Document Type: Article

References (73)

1. Warburg, O. (1956). On the origin of cancer cells. Science, 123, 309-314.
2. Ward, P. S., & Thompson, C. B. (2012). Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell, 21, 297-308.
3. DeBerardinis, R. J., Mancuso, A., Daikhin, E., Nissim, I., Yudkoff, M., Wehrli, S., et al. (2007). Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proceedings of the National Academy of Sciences of the United States of America, 104, 19345-19350.
4. Fantin, V. R., & Leder, P. (2006). Mitochondriotoxic compounds for cancer therapy. Oncogene, 25, 4787-4797.
5. Moreno-Sanchez, R., Rodriguez-Enriquez, S., Marin-Hernandez, A., & Saavedra, E. (2007). Energy metabolism in tumor cells. FEBS Journal, 274, 1393-1418.
6. Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009). Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science, 324, 1029-1033.
7. Weinhouse, S. (1976). The Warburg hypothesis fifty years later. Journal of Cancer Research and Clinical Oncology. Cancer Research and Clinical Oncology, 87, 115-126.
8. Gottschalk, S., Anderson, N., Hainz, C., Eckhardt, S. G., & Serkova, N. J. (2004). Imatinib (STI571)-mediated changes in glucose metabolism in human leukemia BCR-ABL-positive cells. Clinical Cancer Research, 10, 6661-6668.
9. Nolop, K. B., Rhodes, C. G., Brudin, L. H., Beaney, R. P., Krausz, T., Jones, T., et al. (1987). Glucose utilization in vivo by human pulmonary neoplasms. Cancer, 60, 2682-2689.
10. Chen, J. Q., & Russo, J. (2012). Dysregulation of glucose transport, glycolysis, TCA cycle and glutaminolysis by oncogenes and tumor suppressors in cancer cells. Biochimica et Biophysica Acta, 1826, 370-384.
11. Israel, M., & Schwartz, L. (2011). The metabolic advantage of tumor cells. Molecular Cancer, 10, 70.
12. Dang, C. V., Le, A., & Gao, P. (2009). MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clinical Cancer Research, 15, 6479-6483.
13. Li, F., Wang, Y., Zeller, K. I., Potter, J. J., Wonsey, D. R., O'Donnell, K. A., et al. (2005). Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Molecular and Cellular Biology, 25, 6225-6234.
14. Talks, K. L., Turley, H., Gatter, K. C., Maxwell, P. H., Pugh, C. W., Ratcliffe, P. J., et al. (2000). The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. American Journal of Pathology, 157, 411-421.
15. Dang, C. V. (2010). Glutaminolysis: supplying carbon or nitrogen or both for cancer cells? Cell Cycle, 9, 3884-3886.
16. Semenza, G. L. (2009). Regulation of cancer cell metabolism by hypoxia-inducible factor 1. Seminars in Cancer Biology, 19, 12-16.
17. Semenza, G. L., Roth, P. H., Fang, H. M., & Wang, G. L. (1994). Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. Journal of Biological Chemistry, 269, 23757-23763.
18. Bensaad, K., Tsuruta, A., Selak, M. A., Vidal, M. N., Nakano, K., Bartrons, R., et al. (2006). TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell, 126, 107-120.
19. Contractor, T., & Harris, C. R. (2012). p53 negatively regulates transcription of the pyruvate dehydrogenase kinase Pdk2. Cancer Research, 72, 560-567.
20. Hu, W., Zhang, C., Wu, R., Sun, Y., Levine, A., & Feng, Z. (2010). Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proceedings of the National Academy of Sciences of the United States of America, 107, 7455-7460.
21. Primeau, A. J., Rendon, A., Hedley, D., Lilge, L., & Tannock, I. F. (2005). The distribution of the anticancer drug Doxorubicin in relation to blood vessels in solid tumors. Clinical Cancer Research, 11, 8782-8788.
22. Swietach, P., Patiar, S., Supuran, C. T., Harris, A. L., & Vaughan-Jones, R. D. (2009). The role of carbonic anhydrase 9 in regulating extracellular and intracellular ph in three-dimensional tumor cell growths. Journal of Biological Chemistry, 284, 20299-20310.
23. Wykoff, C. C., Beasley, N. J., Watson, P. H., Turner, K. J., Pastorek, J., Sibtain, A., et al. (2000). Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Research, 60, 7075-7083.
24. Modok, S., Hyde, P., Mellor, H. R., Roose, T., & Callaghan, R. (2006). Diffusivity and distribution of vinblastine in three-dimensional tumour tissue: Experimental and mathematical modelling. European Journal of Cancer, 42, 2404-2413.
25. Tong, R. T., Boucher, Y., Kozin, S. V., Winkler, F., Hicklin, D. J., & Jain, R. K. (2004). Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Research, 64, 3731-3736.
26. Hall, M. D., Martin, C., Ferguson, D. J. P., Phillips, R. M., Hambley, T. W., & Callaghan, R. (2004). Comparative efficacy of novel platinum(IV) compounds with established chemotherapeutic drugs in solid tumour models. Biochemical Pharmacology, 67, 17-30.
27. Mellor, H. R., Ferguson, D. J., & Callaghan, R. (2005). A model of quiescent tumour microregions for evaluating multicellular resistance to chemotherapeutic drugs. British Journal of Cancer, 93, 302-309.
28. Mellor, H. R., Snelling, S., Hall, M. D., Modok, S., Jaffar, M., Hambley, T. W., et al. (2005). The influence of tumour microenvironmental factors on the efficacy of cisplatin and novel platinum(IV) complexes. Biochemical Pharmacology, 70, 1137-1146.
29. Hirschhaeuser, F., Menne, H., Dittfeld, C., West, J., Mueller-Klieser, W., & Kunz-Schughart, L. A. (2010). Multicellular tumor spheroids: an underestimated tool is catching up again. Journal of Biotechnology, 148, 3-15.
30. Hanahan, D., & Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100, 57-70.
31. Casciari, J. J., Sotirchos, S. V., & Sutherland, R. M. (1992). Variations in tumor cell growth rates and metabolism with oxygen concentration, glucose concentration, and extracellular pH. Journal of Cellular Physiology, 151, 386-394.
32. Vaupel, P., Fortmeyer, H. P., Runkel, S., & Kallinowski, F. (1987). Blood flow, oxygen consumption, and tissue oxygenation of human breast cancer xenografts in nude rats. Cancer Research, 47, 3496-3503.
33. Vaupel, P. W., Frinak, S., & Bicher, H. I. (1981). Heterogeneous oxygen partial pressure and pH distribution in C3H mouse mammary adenocarcinoma. Cancer Research, 41, 2008-2013.
34. Wilson, J. E. (2003). Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function. Journal of Experimental Biology, 206, 2049-2057.
35. Pastorino, J. G., & Hoek, J. B. (2008). Regulation of hexokinase binding to VDAC. Journal of Bioenergetics and Biomembranes, 40, 171-182.
36. Pedersen, P. L., Mathupala, S., Rempel, A., Geschwind, J. F., & Ko, Y. H. (2002). Mitochondrial bound type II hexokinase: a key player in the growth and survival of many cancers and an ideal prospect for therapeutic intervention. Biochimica et Biophysica Acta, 1555, 14-20.
37. Bustamante, E., Morris, H. P., & Pedersen, P. L. (1981). Energy metabolism of tumor cells. Requirement for a form of hexokinase with a propensity for mitochondrial binding. Journal of Biological Chemistry, 256, 8699-8704.
38. Linden, M., Gellerfors, P., & Nelson, B. D. (1982). Pore protein and the hexokinase-binding protein from the outer membrane of rat liver mitochondria are identical. FEBS Letters, 141, 189-192.
39. Pastorino, J. G., Hoek, J. B., & Shulga, N. (2005). Activation of glycogen synthase kinase 3beta disrupts the binding of hexokinase II to mitochondria by phosphorylating voltage-dependent anion channel and potentiates chemotherapy-induced cytotoxicity. Cancer Research, 65, 10545-10554.
40. Baggetto, L. G., Clottes, E., & Vial, C. (1992). Low mitochondrial proton leak due to high membrane cholesterol content and cytosolic creatine kinase as two features of the deviant bioenergetics of Ehrlich and AS30-D tumor cells. Cancer Research, 52, 4935-4941.
41. Yalcin, A., Telang, S., Clem, B., & Chesney, J. (2009). Regulation of glucose metabolism by 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatases in cancer. Experimental and Molecular Pathology, 86, 174-179.
42. Jenkins, C. M., Yang, J., Sims, H. F., & Gross, R. W. (2011). Reversible high affinity inhibition of phosphofructokinase-1 by acyl-CoA: a mechanism integrating glycolytic flux with lipid metabolism. Journal of Biological Chemistry, 286, 11937-11950.
43. Hers, H. G., & van Schaftingen, E. (1982). Fructose 2, 6-bisphosphate 2 years after its discovery. Biochemistry Journal, 206, 1-12.
44. Okar, D. A., Manzano, A., Navarro-Sabate, A., Riera, L., Bartrons, R., & Lange, A. J. (2001). PFK-2/FBPase-2: maker and breaker of the essential biofactor fructose-2, 6-bisphosphate. Trends in Biochemical Sciences, 26, 30-35.
45. Rider, M. H., Bertrand, L., Vertommen, D., Michels, P. A., Rousseau, G. G., & Hue, L. (2004). 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase: head-to-head with a bifunctional enzyme that controls glycolysis. Biochemistry Journal, 381, 561-579.
46. Chesney, J., Mitchell, R., Benigni, F., Bacher, M., Spiegel, L., Al-Abed, Y., et al. (1999). An inducible gene product for 6-phosphofructo-2-kinase with an AU-rich instability element: role in tumor cell glycolysis and the Warburg effect. Proceedings of the National Academy of Sciences of the United States of America, 96, 3047-3052.
47. Mor, I., Cheung, E. C., & Vousden, K. H. (2011). Control of glycolysis through regulation of PFK1: old friends and recent additions. Cold Spring Harbor Symposia on Quantitative Biology, 76, 211-216.
48. Tudzarova, S., Colombo, S. L., Stoeber, K., Carcamo, S., Williams, G. H., & Moncada, S. (2011). Two ubiquitin ligases, APC/C-Cdh1 and SKP1-CUL1-F (SCF)-beta-TrCP, sequentially regulate glycolysis during the cell cycle. Proceedings of the National Academy of Sciences of the United States of America, 108, 5278-5283.
49. Marsin, A. S., Bouzin, C., Bertrand, L., & Hue, L. (2002). The stimulation of glycolysis by hypoxia in activated monocytes is mediated by AMP-activated protein kinase and inducible 6-phosphofructo-2-kinase. Journal of Biological Chemistry, 277, 30778-30783.
50. Minchenko, O., Opentanova, I., & Caro, J. (2003). Hypoxic regulation of the 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase gene family (PFKFB-1-4) expression in vivo. FEBS Letters, 554, 264-270.
51. Moon, J. S., Jin, W. J., Kwak, J. H., Kim, H. J., Yun, M. J., Kim, J. W., et al. (2011). Androgen stimulates glycolysis for de novo lipid synthesis by increasing the activities of hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 2 in prostate cancer cells. Biochemistry Journal, 433, 225-233.
52. Li, H., & Jogl, G. (2009). Structural and biochemical studies of TIGAR (TP53-induced glycolysis and apoptosis regulator). Journal of Biological Chemistry, 284, 1748-1754.
53. Kimata, M., Matoba, S., Iwai-Kanai, E., Nakamura, H., Hoshino, A., Nakaoka, M., et al. (2010). p53 and TIGAR regulate cardiac myocyte energy homeostasis under hypoxic stress. American Journal of Physiology. Heart and Circulatory Physiology, 299, H1908-H1916.
54. Mazurek, S. (2011). Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells. International Journal of Biochemistry & Cell Biology, 43, 969-980.
55. Tamada, M., Suematsu, M., & Saya, H. (2012). Pyruvate kinase m2: multiple faces for conferring benefits on cancer cells. Clinical Cancer Research, 18, 5554-5561.
56. Christofk, H. R., Vander Heiden, M. G., Harris, M. H., Ramanathan, A., Gerszten, R. E., Wei, R., et al. (2008). The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature, 452, 230-233.
57. Hitosugi, T., Kang, S., Vander Heiden, M. G., Chung, T. W., Elf, S., Lythgoe, K., et al. (2009). Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. Science Signal, 2, ra73.
58. Ashizawa, K., Willingham, M. C., Liang, C. M., & Cheng, S. Y. (1991). In vivo regulation of monomer-tetramer conversion of pyruvate kinase subtype M2 by glucose is mediated via fructose 1, 6-bisphosphate. Journal of Biological Chemistry, 266, 16842-16846.
59. Christofk, H. R., Vander Heiden, M. G., Wu, N., Asara, J. M., & Cantley, L. C. (2008). Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature, 452, 181-186.
60. Dombrauckas, J. D., Santarsiero, B. D., & Mesecar, A. D. (2005). Structural basis for tumor pyruvate kinase M2 allosteric regulation and catalysis. Biochemistry, 44, 9417-9429.
61. Kletzien, R. F., Harris, P. K., & Foellmi, L. A. (1994). Glucose-6-phosphate dehydrogenase: a "housekeeping" enzyme subject to tissue-specific regulation by hormones, nutrients, and oxidant stress. FASEB Journal, 8, 174-181.
62. Wood, T. (1986). Physiological functions of the pentose phosphate pathway. Cell Biochemistry and Function, 4, 241-247.
63. Stanton, R. C. (2012). Glucose-6-phosphate dehydrogenase, NADPH, and cell survival. IUBMB Life, 64, 362-369.
64. Holten, D., Procsal, D., & Chang, H. L. (1976). Regulation of pentose phosphate pathway dehydrogenases by NADP +/NADPH ratios. Biochemical and Biophysical Research Communications, 68, 436-441.
65. Boros, L. G., Brandes, J. L., Yusuf, F. I., Cascante, M., Williams, R. D., & Schirmer, W. J. (1998). Inhibition of the oxidative and nonoxidative pentose phosphate pathways by somatostatin: a possible mechanism of antitumor action. Medical Hypotheses, 50, 501-506.
66. Frederiks, W. M., Bosch, K. S., Hoeben, K. A., van Marle, J., & Langbein, S. (2010). Renal cell carcinoma and oxidative stress: The lack of peroxisomes. Acta Histochemica, 112, 364-371.
67. Cosentino, C., Grieco, D., & Costanzo, V. (2011). ATM activates the pentose phosphate pathway promoting anti-oxidant defence and DNA repair. EMBO Journal, 30, 546-555.
68. Jiang, P., Du, W., Wang, X., Mancuso, A., Gao, X., Wu, M., et al. (2011). p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nature Cell Biology, 13, 310-316.
69. Feron, O. (2009). Pyruvate into lactate and back: from the Warburg effect to symbiotic energy fuel exchange in cancer cells. Radiotherapy and Oncology, 92, 329-333.
70. Yun, H., Lee, M., Kim, S. S., & Ha, J. (2005). Glucose deprivation increases mRNA stability of vascular endothelial growth factor through activation of AMP-activated protein kinase in DU145 prostate carcinoma. Journal of Biological Chemistry, 280, 9963-9972.
71. Friedrich, J., Ebner, R., & Kunz-Schughart, L. A. (2007). Experimental anti-tumor therapy in 3-D: spheroids-old hat or new challenge? International Journal of Radiation Biology, 83, 849-871.
72. Kunz-Schughart, L. A., Groebe, K., & Mueller-Klieser, W. (1996). Three-dimensional cell culture induces novel proliferative and metabolic alterations associated with oncogenic transformation. International Journal of Cancer, 66, 578-586.
73. Rodriguez-Enriquez, S., Gallardo-Perez, J. C., Aviles-Salas, A., Marin-Hernandez, A., Carreno-Fuentes, L., Maldonado-Lagunas, V., et al. (2008). Energy metabolism transition in multi-cellular human tumor spheroids. Journal of Cellular Physiology, 216, 189-197.