Journal of Bioenergetics and Biomembranes

, Volume 44, Issue 6, pp 645–653 | Cite as

Imaging mitochondrial redox potential and its possible link to tumor metastatic potential



Cellular redox states can regulate cell metabolism, growth, differentiation, motility, apoptosis, signaling pathways, and gene expressions etc. A growing body of literature suggest the importance of redox status for cancer progression. While most studies on redox state were done on cells and tissue lysates, it is important to understand the role of redox state in a tissue in vivo/ex vivo and image its heterogeneity. Redox scanning is a clinical-translatable method for imaging tissue mitochondrial redox potential with a submillimeter resolution. Redox scanning data in mouse models of human cancers demonstrate a correlation between mitochondrial redox state and tumor metastatic potential. I will discuss the significance of this correlation and possible directions for future research.


Cancer aggressiveness Fluorescence Redox scanning NADH FAD or flavoprotein 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adler V, Yin ZM, Tew KD, Ronai Z (1999) Role of redox potential and reactive oxygen species in stress signaling. Oncogene 18(45):6104–6111CrossRefGoogle Scholar
  2. Agarwal AK, Auchus RJ (2005) Minireview: cellular redox state regulates hydroxysteroid dehydrogenase activity and intracellular hormone potency. Endocrinology 146(6):2531–2538CrossRefGoogle Scholar
  3. Amaravadi RK, Yu D, Lum JJ, Bui T, Christophorou MA, Evan GI, Thomas-Tikhonenko A, Thompson CB (2007) Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest 117(2):326–336CrossRefGoogle Scholar
  4. Banerjee R (2008) Redox biochemistry. John Wiley & Sons, HobokenGoogle Scholar
  5. Barlow CH, Harden WR 3rd, Harken AH, Simson MB, Haselgrove JC, Chance B, O’Connor M, Austin G (1979) Fluorescence mapping of mitochrondrial redox changes in heart and brain. Crit Care Med 7(9):402–406CrossRefGoogle Scholar
  6. Becker DF, Zhu W, Moxley MA (2011) Flavin redox switching of protein functions. Antioxid Redox Signal 14(6):1079–1091CrossRefGoogle Scholar
  7. Blinova K, Levine RL, Boja ES, Griffiths GL, Shi ZD, Ruddy B, Balaban RS (2008) Mitochondrial NADH fluorescence is enhanced by Complex I binding. Biochemistry 47(36):9636–9645CrossRefGoogle Scholar
  8. Bohndiek SE, Kettunen MI, Hu D-e, Kennedy BWC, Boren J, Gallagher FA, Brindle KM (2011) Hyperpolarized [1-13C]-ascorbic and dehydroascorbic acid: vitamin C as a probe for imaging redox status in vivo. J Am Chem Soc 133(30):11795–11801Google Scholar
  9. Brown JQ, Wilke LG, Geradts J, Kennedy SA, Palmer GM, Ramanujam N (2009) Quantitative optical spectroscopy: a robust tool for direct measurement of breast cancer vascular oxygenation and total hemoglobin content in vivo. Cancer Res 69(7):2919–2926CrossRefGoogle Scholar
  10. Cai K, Xu HN, Singh A, Haris M, Reddy R, Li LZ (2012). Characterizing prostate tumor mouse xenografts with CEST & MT MRI and redox scanning. Adv Exp Med BiolGoogle Scholar
  11. Cairns RA, Harris IS, Mak TW (2011) Regulation of cancer cell metabolism. Nat Rev Cancer 11(2):85–95. doi: 10.1038/nrc2981 CrossRefGoogle Scholar
  12. Chance B (1966) Spectrophotometric and kinetic studies of flavoproteins in tissues, cell suspensions, mitochondria and their fragments. In: Slater EC (ed) Flavins and flavoproteins. Elsevier, Amsterdam, pp 498–510Google Scholar
  13. Chance B, Baltscheffsky H (1958) Respiratory enzymes in oxidative phosphorylation. 7. Binding of intramitochondrial reduced pyridine nucleotide. J Biol Chem 233(3):736–739Google Scholar
  14. Chance B, Cohen P, Jobsis F, Schoener B (1962) Intracellular oxidation-reduction states in vivo. Science 137:499–508CrossRefGoogle Scholar
  15. Chance B, Jobsis F (1959) Changes in fluorescence in a frog sartorius muscle following a twitch. Nature 184(4681):195–196CrossRefGoogle Scholar
  16. Chance B, Schoener B (1966) Fluorometric studies of flavin component of the respiratory chain. In: Slater EC (ed) Flavins and flavoproteins. Elsevier, Amsterdam, pp 510–519Google Scholar
  17. Chance B, Schoener B, Oshino R, Itshak F, Nakase Y (1979) Oxidation-reduction ratio studies of mitochondria in freeze-trapped samples. NADH and flavoprotein fluorescence signals. J Biol Chem 254(11):4764–4771Google Scholar
  18. Chance B, Williams GR (1955a) A method for the localization of sites for oxidative phosphorylation. Nature 176(4475):250–254CrossRefGoogle Scholar
  19. Chance B, Williams GR (1955b) Respiratory enzymes in oxidative phosphorylation. III. The steady state. J Biol Chem 217(1):409–428Google Scholar
  20. Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC (2008) The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452(7184):230–233. doi: 10.1038/nature06734 CrossRefGoogle Scholar
  21. Chung Y, Jue T (1992) 1H NMR observation of redox potential in liver. Biochemistry 31(45):11159–11165CrossRefGoogle Scholar
  22. Cook JA, Gius D, Wink DA, Krishna MC, Russo A, Mitchell JB (2004) Oxidative stress, redox, and the tumor microenvironment. Semin Radiat Oncol 14(3):259–266CrossRefGoogle Scholar
  23. Dang CV (1999) c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol Cell Biol 19:1–11Google Scholar
  24. Dooley CT, Dore TM, Hanson GT, Jackson WC, Remington SJ, Tsien RY (2004) Imaging dynamic redox changes in mammalian cells with green fluorescent protein indicators. J Biol Chem 279(21):22284–22293CrossRefGoogle Scholar
  25. Dorward A, Sweet S, Moorehead R, Singh G (1997) Mitochondrial contributions to cancer cell physiology: redox balance, cell cycle, and drug resistance. J Bioenerg Biomembr 29(4):385–392CrossRefGoogle Scholar
  26. Drezek R, Brookner C, Pavlova I, Boiko I, Malpica A, Lotan R, Follen M, Richards-Kortum R (2001) Autofluorescence microscopy of fresh cervical-tissue sections reveals alterations in tissue biochemistry with dysplasia. Photochem Photobiol 73(6):636–641CrossRefGoogle Scholar
  27. Fidler IJ, Hart IR (1982) Biological diversity in metastatic neoplasms - origins and implications. Science 217(4564):998–1003CrossRefGoogle Scholar
  28. Fidler IJ, Kripke ML (1977) Metastasis results from preexisting variant cells within a malignant-tumor. Science 197(4306):893–895CrossRefGoogle Scholar
  29. Fisher AB, Furia L, Chance B (1976) Evaluation of redox state of isolated perfused rat lung. Am J Physiol 230(5):1198–1204Google Scholar
  30. Gaustad JV, Benjaminsen IC, Graff BA, Brurberg KG, Ruud EBM, Rofstad EK (2005) Intratumor heterogeneity in blood perfusion in orthotopic human melanoma xenografts assessed by dynamic contrast-enhanced magnetic resonance imaging. J Magn Reson Imaging 21(6):792–800CrossRefGoogle Scholar
  31. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366(10):883–892CrossRefGoogle Scholar
  32. Gough NR (2009) Focus issue: the long and short of redox signaling. Sci Signal 2(90):eg12CrossRefGoogle Scholar
  33. Grek CL, Tew KD (2010) Redox metabolism and malignancy. Curr Opin Pharmacol 10(4):362–368CrossRefGoogle Scholar
  34. Gu Y, Qian Z, Chen J, Blessington D, Ramanujam N, Chance B (2002) High-resolution three-dimensional scanning optical image system for intrinsic and extrinsic contrast agents in tissue. Rev Sci Instrum 73(1):172–178CrossRefGoogle Scholar
  35. Gutscher M, Pauleau AL, Marty L, Brach T, Wabnitz GH, Samstag Y, Meyer AJ, Dick TP (2008) Real-time imaging of the intracellular glutathione redox potential. Nature Methods 5(6):553–559CrossRefGoogle Scholar
  36. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674CrossRefGoogle Scholar
  37. Haselgrove JC, Bashford CL, Barlow CH, Quistorff B, Chance B, Mayevsky A (1990) Time resolved 3-dimensional recording of redox ratio during spreading depression in gerbil brain. Brain Res 506(1):109–114CrossRefGoogle Scholar
  38. Hassinen I, Chance B (1968) Oxidation-reduction properties of the mitochondrial flavoprotein chain. Biochem Biophys Res Commun 31(6):895–900CrossRefGoogle Scholar
  39. Hsu PP, Sabatini DM (2008) Cancer cell metabolism: Warburg and beyond. Cell 134(5):703–707CrossRefGoogle Scholar
  40. Hung Yin P, Albeck John G, Tantama M, Yellen G (2011) Imaging cytosolic NADH-NAD+ redox state with a genetically encoded fluorescent biosensor. Cell Metabolism 14(4):545–554CrossRefGoogle Scholar
  41. Hyodo F, Matsumoto K, Matsumoto A, Mitchell JB, Krishna MC (2006) Probing the intracellular redox status of tumors with magnetic resonance imaging and redox-sensitive contrast agents. Cancer Res 66(20):9921–9928CrossRefGoogle Scholar
  42. Hyodo F, Murugesan R, Matsumoto K, Hyodo E, Subramanian S, Mitchell JB, Krishna MC (2008) Monitoring redox-sensitive paramagnetic contrast agent by EPRI, OMRI and MRI. J Magn Reson 190(1):105–112CrossRefGoogle Scholar
  43. Ido Y (2007) Pyridine nucleotide redox abnormalities in diabetes. Antioxid Redox Signal 9(7):931–942CrossRefGoogle Scholar
  44. Ishikawa K, Koshikawa N, Takenaga K, Nakada K, Hayashi JI (2008a) Reversible regulation of metastasis by ROS-generating mtDNA mutations. Mitochondrion 8(4):339–344CrossRefGoogle Scholar
  45. Ishikawa K, Takenaga K, Akimoto M, Koshikawa N, Yamaguchi A, Imanishi H, Nakada K, Honma Y, Hayashi J (2008b) ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science 320(5876):661–664CrossRefGoogle Scholar
  46. Ishimoto T, Nagano O, Yae T, Tamada M, Motohara T, Oshima H, Oshima M, Ikeda T, Asaba R, Yagi H, Masuko T, Shimizu T, Ishikawa T, Kai K, Takahashi E, Imamura Y, Baba Y, Ohmura M, Suematsu M, Baba H, Saya H (2011) CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc and thereby promotes tumor growth. Cancer Cell 19(3):387–400CrossRefGoogle Scholar
  47. Kaelin WG, Thompson CB (2010) Q&A: cancer: clues from cell metabolism. Nature 465(7298):562–564CrossRefGoogle Scholar
  48. Keshari KR, Kurhanewicz J, Bok R, Larson PEZ, Vigneron DB, Wilson DM (2011) Hyperpolarized (13)C dehydroascorbate as an endogenous redox sensor for in vivo metabolic imaging. Proc Natl Acad Sci U S A 108(46):18606–18611CrossRefGoogle Scholar
  49. King A, Selak MA, Gottlieb E (2006) Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene 25(34):4675–4682CrossRefGoogle Scholar
  50. Kitai T, Tanaka A, Tokuka A, Ozawa K, Iwata S, Chance B (1992) Changes in the redox distribution of rat liver by ischemia. Anal Biochem 206(1):131–136CrossRefGoogle Scholar
  51. Koppenol WH, Bounds PL, Dang CV (2011) Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer 11(5):325–337. doi: 10.1038/nrc3038 CrossRefGoogle Scholar
  52. Lehninger AL, Nelson DL, Cox MM (1993) Principles of biochemistry, 2nd edn. Worth Publishers, New YorkGoogle Scholar
  53. Lemasters JJ, Nieminen AL (2001) Mitochondria in pathogenesis. Kluwer Academic/Plenum Publishers, New YorkGoogle Scholar
  54. Levitt JM, McLaughlin-Drubin ME, Munger K, Georgakoudi I (2011) Automated biochemical, morphological, and organizational assessment of precancerous changes from endogenous two-photon fluorescence images. PLoS One 6(9)Google Scholar
  55. Li LZ, Xu HN, Ranji M, Nioka S, Chance B (2009a) Mitochondrial redox imaging for cancer diagnostic and therapeutic studies. Journal of Innovative Optical Health Sciences 2:325–341CrossRefGoogle Scholar
  56. Li LZ, Zhou R, Xu HN, Moon L, Zhong TX, Kim EJ, Qiao H, Reddy R, Leeper D, Chance B, Glickson JD (2009b) Quantitative magnetic resonance and optical imaging biomarkers of melanoma metastatic potential. Proc Natl Acad Sci U S A 106(16):6608–6613CrossRefGoogle Scholar
  57. Li LZJ, Zhou R, Zhong TX, Moon L, Kim EJ, Qiao H, Pickup S, Hendrix MJ, Leeper D, Chance B, Glickson JD (2007) Predicting melanoma metastatic potential by optical and magnetic resonance imaging. In: Maguire DJ, Bruley DF, Harrison DK (eds) Oxygen transport to tissue Xxviii (Vol. 599, Advances in Experimental Medicine and Biology). Springer, Berlin, pp 67–78CrossRefGoogle Scholar
  58. Lisanti MP, Martinez-Outschoorn UE, Lin Z, Pavlides S, Whitaker-Menezes D, Pestell RG, Howell A, Sotgia F (2011) Hydrogen peroxide fuels aging, inflammation, cancer metabolism and metastasis The seed and soil also needs “fertilizer”. Cell Cycle 10(15):2440–2449CrossRefGoogle Scholar
  59. Liu Q, Grant G, Li JJ, Zhang Y, Hu FY, Li SQ, Wilson C, Chen K, Bigner D, Tuan VD (2011) Compact point-detection fluorescence spectroscopy system for quantifying intrinsic fluorescence redox ratio in brain cancer diagnostics. J Biomed Opt 16(3)Google Scholar
  60. Locasale Jason W, Cantley Lewis C (2011) Metabolic flux and the regulation of mammalian cell growth. Cell Metabolism 14(4):443–451CrossRefGoogle Scholar
  61. Lum JJ, Bauer DE, Kong M, Harris MH, Li C, Lindsten T, Thompson CB (2005) Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 120(2):237–248CrossRefGoogle Scholar
  62. Ma X-H, Piao S, Wang D, McAfee QW, Nathanson KL, Lum JJ, *Li LZ, *Amaravadi RK (Equal contribution) (2011) Measurements of tumor cell autophagy predict invasiveness, resistance to chemotherapy, and survival in melanoma. Clin Canc Res 17(10):3478–3489Google Scholar
  63. Mac Manus M, Hicks RJ (2008) The use of positron emission tomography (PET) in the staging/evaluation, treatment, and follow-up of patients with lung cancer: a critical review. Int J Radiat Oncol Biol Phys 72(5):1298–1306CrossRefGoogle Scholar
  64. Maccarrone M, Brune B (2009) Redox regulation in acute and chronic inflammation. Cell Death Differ 16(8):1184–1186CrossRefGoogle Scholar
  65. Masters BR, Falk S, Chance B (1981) In vivo flavoprotein redox measurements of rabbit corneal normoxic-anoxic transitions. Curr Eye Res 1(10):623–627CrossRefGoogle Scholar
  66. Matsumoto K, Hyodo F, Matsumoto A, Koretsky AP, Sowers AL, Mitchell JB, Krishna MC (2006) High-resolution mapping of tumor redox status by magnetic resonance imaging using nitroxides as redox-sensitive contrast agents. Clin Cancer Res 12(8):2455–2462CrossRefGoogle Scholar
  67. Mayevsky A (2009) Mitochondrial function and energy metabolism in cancer cells: past overview and future perspectives. Mitochondrion 9(3):165–179CrossRefGoogle Scholar
  68. Mayevsky A, Rogatsky GG (2007) Mitochondrial function in vivo evaluated by NADH fluorescence: from animal models to human studies. Am J Physiol Cell Physiol 292(2):C615–640CrossRefGoogle Scholar
  69. Mayevsky A, Zarchin N, Kaplan H, Haveri J, Haselgroove J, Chance B (1983) Brain metabolic responses to ischemia in the mongolian gerbil: in vivo and freeze trapped redox scanning. Brain Res 276(1):95–107CrossRefGoogle Scholar
  70. Modica-Napolitano JS, Kulawiec M, Singh KK (2007) Mitochondria and human cancer. Curr Mol Med 7(1):121–131CrossRefGoogle Scholar
  71. Mueller-Klieser W, Kroeger M, Walenta S, Rofstad EK (1991) Comparative imaging of structure and metabolites in tumors. Int J Radiat Biol 60(1–2):147–159CrossRefGoogle Scholar
  72. Mueller-Klieser W, Walenta S (1993) Geographical mapping of metabolites in biological tissue with quantitative bioluminescence and single photon imaging. Histochem J 25(6):407–420CrossRefGoogle Scholar
  73. Nichols MG, Barth EE, Nichols JA (2005) Reduction in DNA synthesis during two-photon microscopy of intrinsic reduced nicotinamide adenine dinucleotide fluorescence. Photochem Photobiol 81(2):259–269CrossRefGoogle Scholar
  74. Nkabyo YS, Ziegler TR, Gu LH, Watson WH, Jones DP (2002) Glutathione and thioredoxin redox during differentiation in human colon epithelial (Caco-2) cells. Am J Physiol Gastrointest Liver Physiol 283(6):G1352–G1359Google Scholar
  75. Nowell PC (1976) Clonal evolution of tumor-cell populations. Science 194(4260):23–28CrossRefGoogle Scholar
  76. Olovnikov IA, Kravchenko JE, Chumakova PM (2009) Homeostatic functions of the p53 tumor suppressor: regulation of energy metabolism and antioxidant defense. Semin Canc Biol 19(1):32–41CrossRefGoogle Scholar
  77. Olschewski A, Hong ZG, Peterson DA, Nelson DP, Porter VA, Weir EK (2004) Opposite effects of redox status on membrane potential, cytosolic calcium, and tone in pulmonary arteries and ductus arteriosus. Am J Physiol Lung Cell Mol Physiol 286(1):L15–L22CrossRefGoogle Scholar
  78. Orrenius S, Gogvadze A, Zhivotovsky B (2007) Mitochondrial oxidative stress: implications for cell death. Annu Rev Pharmacol Toxicol 47:143–183CrossRefGoogle Scholar
  79. Ozawa K, Chance B, Tanaka A, Iwata S, Kitai T, Ikai I (1992) Linear correlation between acetoacetate beta-hydroxybutyrate in arterial blood and oxidized flavoprotein reduced pyridine-nucleotide in freeze-trapped human liver-tissue. Biochimica Et Biophysica Acta 1138(4):350–352CrossRefGoogle Scholar
  80. Pani G, Galeotti T, Chiarugi P (2010) Metastasis: cancer cell’s escape from oxidative stress. Cancer Metastasis Rev 29:351–378CrossRefGoogle Scholar
  81. Pani G, Giannoni E, Galeotti T, Chiarugi P (2009) Redox-based escape mechanism from death: the cancer lesson. Antioxidants & Redox Signaling 11:2791–2806CrossRefGoogle Scholar
  82. Pedersen PL (2007) Warburg, me and hexokinase 2: multiple discoveries of key molecular events underlying one of cancers’ most common phenotypes, the “Warburg Effect”, i.e., elevated glycolysis in the presence of oxygen. J Bioenerg Biomembr 39(3):211–222CrossRefGoogle Scholar
  83. Pelicano H, Lu W, Zhou Y, Zhang W, Chen Z, Hu Y, Huang P (2009) Mitochondrial dysfunction and reactive oxygen species imbalance promote breast cancer cell motility through a CXCL14-mediated mechanism. Cancer Res 69(6):2375–2383CrossRefGoogle Scholar
  84. Puppi A, Dely M (1983) Tissue redox-state potential (E0) – As regulator of physiological processes. Acta Biologica Hungarica 34:323–350Google Scholar
  85. Quistorff B, Haselgrove JC, Chance B (1985) High resolution readout of 3-D metabolic organ structure: an automated, low-temperature redox ratio-scanning instrument. Anal Biochem 148:389–400CrossRefGoogle Scholar
  86. Quon A, Gambhir SS (2005) FDG-PET and beyond: molecular breast cancer imaging. J Clin Oncol 23(8):1664–1673CrossRefGoogle Scholar
  87. Ramanujam N, Richards-Kortum R, Thomsen S, Mahadevan-Jansen A, Follen M, Chance B (2001) Low temperature fluorescence imaging of freeze-trapped human cervical tissues. Opt Express 8(6):335–343CrossRefGoogle Scholar
  88. Ramanujan VK, Zhang JH, Biener E, Herman B (2005) Multiphoton fluorescence lifetime contrast in deep tissue imaging: prospects in redox imaging and disease diagnosis. J Biomed Opt 10(5)Google Scholar
  89. Ranji M, Nioka S, Xu N, Wu B, Li LZ, Jaggard DL, Chance B (2009) Fluorescent images of mitochondrial redox states in in situ mouse hypoxic ischemic intestines. Journal of International Optical Health Sciences 2:365–374CrossRefGoogle Scholar
  90. Rocheleau JV, Head WS, Piston DW (2004) Quantitative NAD(P)H/flavoprotein autofluorescence imaging reveals metabolic mechanisms of pancreatic islet pyruvate response. J Biol Chem 279(30):31780–31787CrossRefGoogle Scholar
  91. Sarsour EH, Kumar MG, Chaudhuri L, Kalen AL, Goswami PC (2009) Redox control of the cell cycle in health and disease. Antioxid Redox Signal 11:2985–3011CrossRefGoogle Scholar
  92. Sato B, Tanaka A, Mori S, Yanabu N, Kitai T, Tokuka A, Inomoto T, Iwata S, Yamaoka Y, Chance B (1995) Quantitative analysis of redox gradient within the rat liver acini by fluorescence images: effects of glucagon perfusion. Biochim Biophys Acta 1268(1):20–26CrossRefGoogle Scholar
  93. Sattlar UGA, Walenta S, Mueller-Klieser W (2007) A bioluminescence technique for quantitative and structure-associated imaging of pyruvate. Lab Investig 87(1):84–92CrossRefGoogle Scholar
  94. Sattler UGA, Walenta S, Mueller-Klieser W (2007) Lactate and redox status in malignant tumors. Anaesthesist 56(5):466–469CrossRefGoogle Scholar
  95. Scholz R, Thurman RG, Williamson JR, Chance B, Bucher T (1969) Flavin and pyridine nucleotide oxidation-reduction changes in perfused rat liver. I. Anoxia and subcellular localization of fluorescent flavoproteins. J Biol Chem 244(9):2317–2324Google Scholar
  96. Schroeder T, Yuan H, Viglianti BL, Peltz C, Asopa S, Vujaskovic Z, Dewhirst MW (2005) Spatial heterogeneity and oxygen dependence of glucose consumption in R3230Ac and fibrosarcomas of the Fischer 344 rat. Cancer Res 65(12):5163–5171CrossRefGoogle Scholar
  97. Semenza GL (2010) HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev 20(1):51–56CrossRefGoogle Scholar
  98. Senda T, Senda M, Kimura S, Ishida T (2009) Redox control of protein conformation in flavoproteins. Antioxid Redox Signal 11(7):1741–1766CrossRefGoogle Scholar
  99. Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y, Turashvili G, Ding J, Tse K, Haffari G, Bashashati A, Prentice LM, Khattra J, Burleigh A, Yap D, Bernard V, McPherson A, Shumansky K, Crisan A, Giuliany R, Heravi-Moussavi A, Rosner J, Lai D, Birol I, Varhol R, Tam A, Dhalla N, Zeng T, Ma K, Chan SK, Griffith M, Moradian A, Cheng SWG, Morin GB, Watson P, Gelmon K, Chia S, Chin S-F, Curtis C, Rueda OM, Pharoah PD, Damaraju S, Mackey J, Hoon K, Harkins T, Tadigotla V, Sigaroudinia M, Gascard P, Tlsty T, Costello JF, Meyer IM, Eaves CJ, Wasserman WW, Jones S, Huntsman D, Hirst M, Caldas C, Marra MA, Aparicio S (2012) The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature, advance online publication. doi: 10.1038/nature10933
  100. Shiino A, Haida M, Beauvoit B, Chance B (1999) Three-dimensional redox image of the normal gerbil brain. Neuroscience 91(4):1581–1585CrossRefGoogle Scholar
  101. Skala MC, Riching KM, Gendron-Fitzpatrick A, Eickhoff J, Eliceiri KW, White JG, Ramanujam N (2007a) In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia. [Research Support, N.I.H., Extramural Research Support, U.S. Gov’t, Non-P.H.S.]. Proc Natl Acad Sci U S A 104(49):19494–19499CrossRefGoogle Scholar
  102. Skala MC, Riching KM, Gendron-Fitzpatrick A, Eickhoff J, Eliceiri KW, White JG, Ramanujam N (2007b) In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia. Proc Natl Acad Sci U S A 104(49):19494–19499CrossRefGoogle Scholar
  103. Tachtsidis I, Tisdall MM, Pritchard C, Leung TS, Ghosh A, Elwell CE, Smith M (2011) Analysis of the changes in the oxidation of brain tissue cytochrome-c-oxidase in traumatic brain injury patients during hypercapnoea a broadband NIRS study. In: LaManna JC, Puchowicz MA, Xu K, Harrison DK, Bruley DF (eds) Oxygen transport to tissue Xxxii (Vol. 701, Advances in Experimental Medicine and Biology). Springer, Berlin, pp 9–14Google Scholar
  104. Taylor BL, Rebbapragada A, Johnson MS (2001) The FAD-PAS domain as a sensor for behavioral responses in escherichia coli. Antioxid Redox Signal 3(5):867–879CrossRefGoogle Scholar
  105. Thompson CB (2009) Metabolic enzymes as oncogenes or tumor suppressors. N Engl J Med 360(8):813–815CrossRefGoogle Scholar
  106. Tisdall MM, Tachtsidis I, Leung TS, Elwell CE, Smith M (2007) Near-infrared spectroscopic quantification of changes in the concentration of oxidized cytochrome c oxidase in the healthy human brain during hypoxemia. J Biomed Opt 12(2)Google Scholar
  107. Veech RL (2006) The determination of the redox states and phosphorylation potential in living tissues and their relationship to metabolic control of disease phenotypes. Biochem Mol Biol Educ 34(3):168–179CrossRefGoogle Scholar
  108. Weir EK, Hong ZG, Porter VA, Reeve HL (2002) Redox signaling in oxygen sensing by vessels. Respir Physiol Neurobiol 132(1):121–130CrossRefGoogle Scholar
  109. Xu HN, Addis RC, Goings DF, Nioka S, Chance B, Gearhart JD, Li LZ (2011a) Imaging redox state heterogeneity within individual embryonic stem cell colonies. Journal of Innovative Optical Health Sciences 4:279–288CrossRefGoogle Scholar
  110. Xu HN, Nioka S, Chance B, Li LZ (2011b) Heterogeneity of mitochondrial redox state in premalignant pancreas in a PTEN null transgenic mouse model. Adv Exp Med Biol 701:207–213CrossRefGoogle Scholar
  111. Xu HN, Nioka S, Chance B, Zheng G, Li LZ (2011c) High-resolution simultaneous mapping of mitochondrial redox state and glucose uptake in human breast tumor xenografts. In: Advances in experimental medicine and biology (Vol. 737, Advances in Experimental Medicine and Biology). Springer, New York, pp 175–179Google Scholar
  112. Xu HN, Nioka S, Glickson J, Chance B, Li LZ (2010) Quantitative mitochondrial redox imaging of breast cancer metastatic potential. J Biomed Opt 15:036010CrossRefGoogle Scholar
  113. Xu HN, Tchou J, Chance B, Li LZ (2012) Imaging the redox states of human breast cancer core biopsies. Adv Exp Med BiolGoogle Scholar
  114. Xu HN, Wu B, Nioka S, Chance B, Li LZ (2009a) Calibration of CCD-based redox imaging for biological tissues. Paper presented at the Proceedings of SPIE - Medical Imaging 2009: Biomedical Applications in Molecular, Structural, and Functional Imaging, Lake Buena Vista, FL, USAGoogle Scholar
  115. Xu HN, Wu B, Nioka S, Chance B, Li LZ (2009b) Quantitative redox scanning of tissue samples using a calibration procedure. Journal of Innovative Optical Health Sciences 2:375–385CrossRefGoogle Scholar
  116. Xu HN, Zhou R, Nioka S, Chance B, Glickson JD, Li LZ (2009c) Histological basis of MR/optical imaging of human melanoma mouse xenografts spanning a range of metastatic potentials. Adv Exp Med Biol 645:247–253CrossRefGoogle Scholar
  117. Ying WH (2008) NAD(+)/ NADH and NADP(+)/NADPH in cellular functions and cell death: regulation and biological consequences. Antioxid Redox Signal 10(2):179–206CrossRefGoogle Scholar
  118. Zhang Q, Wang SY, Nottke AC, Rocheleau JV, Piston DW, Goodman RH (2006) Redox sensor CtBP mediates hypoxia-induced tumor cell migration. Proc Natl Acad Sci U S A 103(24):9029–9033CrossRefGoogle Scholar
  119. Zhang Z, Blessington D, Li H, Busch TM, Glickson J, Luo Q, Chance B, Zheng G (2004a) Redox ratio of mitochondria as an indicator for the response of photodynamic therapy. J Biomed Opt 9(4):772–778CrossRefGoogle Scholar
  120. Zhang ZH, Li H, Liu Q, Zhou LL, Zhang M, Luo QM, Glickson J, Chance B, Zheng G (2004b) Metabolic imaging of tumors using intrinsic and extrinsic fluorescent markers. Biosens Bioelectron 20(3):643–650CrossRefGoogle Scholar
  121. Zhu C, Burnside ES, Sisney GA, Salkowski LR, Harter JM, Yu B, Ramanujam N (2009) Fluorescence spectroscopy: an adjunct diagnostic tool to image-guided core needle biopsy of the breast. IEEE Trans Biomed Eng 56(10):2518–2528CrossRefGoogle Scholar
  122. Ziegler M (2005) A vital link between energy and signal transduction. Regulatory functions of NAD(P). FEBS J 272(18):4561–4564CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Molecular Imaging Laboratory, Department of Radiology, Britton Chance Laboratory of Redox Imaging, Johnson Research Foundation, Department of Biochemistry and Biophysics, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA

Personalised recommendations