The tumor microenvironment is a complex system that involves the interaction between malignant and neighbor stromal cells embedded in a mesh of extracellular matrix (ECM) components. Stromal cells (fibroblasts, endothelial, and inflammatory cells) are co-opted at different stages to help malignant cells invade the surrounding ECM and disseminate. Malignant cells have developed adaptive mechanisms to survive under the extreme conditions of the tumor microenvironment such as restricted oxygen supply (hypoxia), nutrient deprivation, and a prooxidant state among others. These conditions could be eventually used to target drugs that will be activated specifically in this microenvironment. Preclinical studies have shown that modulating cellular/tissue redox state by different gene therapy (GT) approaches was able to control tumor growth. In this review, we describe the most relevant features of the tumor microenvironment, addressing reactive oxygen species-generating sources that promote a prooxidative microenvironment inside the tumor mass. We describe different GT approaches that promote either a decreased or exacerbated prooxidative microenvironment, and those that make use of the differential levels of ROS between cancer and normal cells to achieve tumor growth inhibition. Antioxid. Redox Signal. 19, 854–895.
AlbertssonPA, BassePH, HoklandM, GoldfarbRH, NagelkerkeJF, NannmarkU, KuppenPJ. NK cells and the tumour microenvironment: implications for NK-cell function and anti-tumour activity. Trends Immunol, 24:603–609. 2003.
8.
AllavenaP, SicaA, SolinasG, PortaC, MantovaniA. The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. Crit Rev Oncol Hematol, 66:1–9. 2008.
9.
AlvarezMJ, PradaF, SalvatierraE, BravoAI, LutzkyVP, CarboneC, PitossiFJ, ChuluyanHE, PodhajcerOL. Secreted protein acidic and rich in cysteine produced by human melanoma cells modulates polymorphonuclear leukocyte recruitment and antitumor cytotoxic capacity. Cancer Res, 65:5123–5132. 2005.
10.
Antico ArciuchVG, ElgueroME, PoderosoJJ, CarrerasMC. Mitochondrial regulation of cell cycle and proliferation. Antioxid Redox Signal, 16:1150–1180. 2012.
11.
Antico ArciuchVG, GalliS, FrancoMC, LamPY, CadenasE, CarrerasMC, PoderosoJJ. Akt1 intramitochondrial cycling is a crucial step in the redox modulation of cell cycle progression. PLoS One, 4:e7523. 2009.
12.
ArbiserJL, PetrosJ, KlafterR, GovindajaranB, McLaughlinER, BrownLF, CohenC, MosesM, KilroyS, ArnoldRS, LambethJD. Reactive oxygen generated by Nox1 triggers the angiogenic switch. Proc Natl Acad Sci U S A, 99:715–720. 2002.
13.
ArnerES. Focus on mammalian thioredoxin reductases—important selenoproteins with versatile functions. Biochim Biophys Acta, 1790:495–526. 2009.
14.
ArnerES, HolmgrenA. The thioredoxin system in cancer. Semin Cancer Biol, 16:420–426. 2006.
15.
ArnoldSA, RiveraLB, MillerAF, CarbonJG, DineenSP, XieY, CastrillonDH, SageEH, PuolakkainenP, BradshawAD, BrekkenRA. Lack of host SPARC enhances vascular function and tumor spread in an orthotopic murine model of pancreatic carcinoma. Dis Model Mech, 3:57–72. 2010.
16.
AzadMB, ChenY, GibsonSB. Regulation of autophagy by reactive oxygen species (ROS): implications for cancer progression and treatment. Antioxid Redox Signal, 11:777–790. 2009.
17.
BackmanE, BerghAC, LagerdahlI, RydbergB, SundstromC, TobinG, RosenquistR, LinderholmM, RosenA. Thioredoxin, produced by stromal cells retrieved from the lymph node microenvironment, rescues chronic lymphocytic leukemia cells from apoptosis in vitro. Haematologica, 92:1495–1504. 2007.
18.
BaggettoLG. Deviant energetic metabolism of glycolytic cancer cells. Biochimie, 74:959–974. 1992.
19.
BaharG, FeinmesserR, ShpitzerT, PopovtzerA, NaglerRM. Salivary analysis in oral cancer patients: DNA and protein oxidation, reactive nitrogen species, and antioxidant profile. Cancer, 109:54–59. 2007.
20.
Baj-KrzyworzekaM, BaranJ, WeglarczykK, SzatanekR, SzaflarskaA, SiedlarM, ZembalaM. Tumour-derived microvesicles (TMV) mimic the effect of tumour cells on monocyte subpopulations. Anticancer Res, 30:3515–3519. 2010.
21.
BalkwillF, MantovaniA. Inflammation and cancer: back to Virchow?Lancet, 357:539–545. 2001.
22.
BanjacA, PerisicT, SatoH, SeilerA, BannaiS, WeissN, KolleP, TschoepK, IsselsRD, DanielPT, ConradM, BornkammGW. The cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell death. Oncogene, 27:1618–1628. 2008.
23.
BanningA, KippA, SchmitmeierS, LowingerM, FlorianS, KrehlS, ThalmannS, ThierbachR, SteinbergP, Brigelius-FloheR. Glutathione peroxidase 2 inhibits cyclooxygenase-2-mediated migration and invasion of HT-29 adenocarcinoma cells but supports their growth as tumors in nude mice. Cancer Res, 68:9746–9753. 2008.
24.
BedardK, KrauseKH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev, 87:245–313. 2007.
25.
BergersG, BenjaminLE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer, 3:401–410. 2003.
26.
BertoutJA, PatelSA, SimonMC. The impact of O2 availability on human cancer. Nat Rev Cancer, 8:967–975. 2008.
BrandMD. The sites and topology of mitochondrial superoxide production. Exp Gerontol, 45:466–472. 2010.
33.
BristowRG, HillRP. Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer, 8:180–192. 2008.
34.
BrownJM, WilsonWR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer, 4:437–447. 2004.
35.
BussolatiB, DeregibusMC, CamussiG. Characterization of molecular and functional alterations of tumor endothelial cells to design anti-angiogenic strategies. Curr Vasc Pharmacol, 8:220–232. 2010.
36.
BussolatiB, GrangeC, CamussiG. Tumor exploits alternative strategies to achieve vascularization. FASEB J, 25:2874–2882. 2011.
37.
CabarcasSM, MathewsLA, FarrarWL. The cancer stem cell niche-there goes the neighborhood?Int J Cancer, 129:2315–2327. 2011.
38.
CadenasE, BoverisA, RaganCI, StoppaniAO. Production of superoxide radicals and hydrogen peroxide by NADH-ubiquinone reductase and ubiquinol-cytochrome c reductase from beef-heart mitochondria. Arch Biochem Biophys, 180:248–257. 1977.
39.
CairnsRA, HarrisIS, MakTW. Regulation of cancer cell metabolism. Nat Rev Cancer, 11:85–95. 2011.
40.
CaoY, CaoR, HedlundEM. R Regulation of tumor angiogenesis and metastasis by FGF and PDGF signaling pathways. J Mol Med (Berl), 86:785–789. 2008.
41.
CarmelietP, JainRK. Angiogenesis in cancer and other diseases. Nature, 407:249–257. 2000.
42.
CarrA, FreiB. Does vitamin C act as a pro-oxidant under physiological conditions?FASEB J, 13:1007–1024. 1999.
43.
CarrerasMC, PoderosoJJ. Mitochondrial nitric oxide in the signaling of cell integrated responses. Am J Physiol Cell Physiol, 292:C1569–C1580. 2007.
44.
CeccarelliJ, DelfinoL, ZappiaE, CastellaniP, BorghiM, FerriniS, TosettiF, RubartelliA. The redox state of the lung cancer microenvironment depends on the levels of thioredoxin expressed by tumor cells and affects tumor progression and response to prooxidants. Int J Cancer, 123:1770–1778. 2008.
45.
ChandelNS, McClintockDS, FelicianoCE, WoodTM, MelendezJA, RodriguezAM, SchumackerPT. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing. J Biol Chem, 275:25130–25138. 2000.
46.
ChandramathiS, SureshK, AnitaZB, KuppusamyUR. Comparative assessment of urinary oxidative indices in breast and colorectal cancer patients. J Cancer Res Clin Oncol, 135:319–323. 2009.
47.
ChangD, WangF, ZhaoYS, PanHZ. Evaluation of oxidative stress in colorectal cancer patients. Biomed Environ Sci, 21:286–289. 2008.
48.
ChangQ, PanJ, WangX, ZhangZ, ChenF, ShiX. Reduced reactive oxygen species-generating capacity contributes to the enhanced cell growth of arsenic-transformed epithelial cells. Cancer Res, 70:5127–5135. 2010.
49.
CheZM, JungTH, ChoiJH, Yoon doJ, JeongHJ, LeeEJ, KimJ. Collagen-based co-culture for invasive study on cancer cells-fibroblasts interaction. Biochem Biophys Res Commun, 346:268–275. 2006.
50.
ChenK, ChenX. Positron emission tomography imaging of cancer biology: current status and future prospects. Semin Oncol, 38:70–86. 2011.
51.
ChenMF, KengPC, ShauH, WuCT, HuYC, LiaoSK, ChenWC. Inhibition of lung tumor growth and augmentation of radiosensitivity by decreasing peroxiredoxin I expression. Int J Radiat Oncol Biol Phys, 64:581–591. 2006.
52.
ChenMF, LeeKD, YehCH, ChenWC, HuangWS, ChinCC, LinPY, WangJY. Role of peroxiredoxin I in rectal cancer and related to p53 status. Int J Radiat Oncol Biol Phys, 78:868–878. 2010.
53.
ChenRS, SongYM, ZhouZY, TongT, LiY, FuM, GuoXL, DongLJ, HeX, QiaoHX, ZhanQM, LiW. Disruption of xCT inhibits cancer cell metastasis via the caveolin-1/beta-catenin pathway. Oncogene, 28:599–609. 2009.
54.
ChengMY, LeeIP, JinM, SunG, ZhaoH, SteinbergGK, SapolskyRM. An insult-inducible vector system activated by hypoxia and oxidative stress for neuronal gene therapy. Transl Stroke Res, 2:92–100. 2011.
55.
This reference has been deleted.
56.
ChicheJ, Brahimi-HornMC, PouyssegurJ. Tumour hypoxia induces a metabolic shift causing acidosis: a common feature in cancer. J Cell Mol Med, 14:771–794. 2010.
57.
ChicheJ, IlcK, LaferriereJ, TrottierE, DayanF, MazureNM, Brahimi-HornMC, PouyssegurJ. Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH. Cancer Res, 69:358–368. 2009.
58.
ChristofkHR, Vander HeidenMG, WuN, AsaraJM, CantleyLC. Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature, 452:181–186. 2008.
59.
ChuaPJ, LeeEH, YuY, YipGW, TanPH, BayBH. Silencing the peroxiredoxin III gene inhibits cell proliferation in breast cancer. Int J Oncol, 36:359–364. 2010.
60.
ChurchSL, GrantJW, RidnourLA, OberleyLW, SwansonPE, MeltzerPS, TrentJM. Increased manganese superoxide dismutase expression suppresses the malignant phenotype of human melanoma cells. Proc Natl Acad Sci U S A, 90:3113–3117. 1993.
CitrinD, CamphausenK, WoodBJ, QuezadoM, DenobileJ, PingpankJF, RoyalRE, AlexanderHR, SeidelG, SteinbergSM, ShuttackY, LibuttiSK. A pilot feasibility study of TNFerade biologic with capecitabine and radiation therapy followed by surgical resection for the treatment of rectal cancer. Oncology, 79:382–388. 2010.
63.
CleversH. The cancer stem cell: premises, promises and challenges. Nat Med, 17:313–319. 2011.
64.
CorzoCA, CondamineT, LuL, CotterMJ, YounJI, ChengP, ChoHI, CelisE, QuicenoDG, PadhyaT, McCaffreyTV, McCaffreyJC, GabrilovichDI. HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med, 207:2439–2453. 2010.
CoussensLM, WerbZ. Inflammation and cancer. Nature, 420:860–867. 2002.
68.
CoxTR, ErlerJT. Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer. Dis Model Mech, 4:165–178. 2011.
69.
CutlerRG, PlummerJ, ChowdhuryK, HewardC. Oxidative stress profiling: part II. Theory, technology, and practice. Ann N Y Acad Sci, 1055:136–158. 2005.
70.
DattaR, TanejaN, SukhatmeVP, QureshiSA, WeichselbaumR, KufeDW. Reactive oxygen intermediates target CC(A/T)6GG sequences to mediate activation of the early growth response 1 transcription factor gene by ionizing radiation. Proc Natl Acad Sci U S A, 90:2419–2422. 1993.
71.
De SimoniS, GoemaereJ, KnoopsB. Silencing of peroxiredoxin 3 and peroxiredoxin 5 reveals the role of mitochondrial peroxiredoxins in the protection of human neuroblastoma SH-SY5Y cells toward MPP+Neurosci Lett, 433:219–224. 2008.
72.
de VisserKE, EichtenA, CoussensLM. Paradoxical roles of the immune system during cancer development. Nat Rev Cancer, 6:24–37. 2006.
73.
DearlingJL, FlynnAA, Sutcliffe-GouldenJ, PetrieIA, BodenR, GreenAJ, BoxerGM, BegentRH, PedleyRB. Analysis of the regional uptake of radiolabeled deoxyglucose analogs in human tumor xenografts. J Nucl Med, 45:101–107. 2004.
74.
DeBerardinisRJ, LumJJ, HatzivassiliouG, ThompsonCB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab, 7:11–20. 2008.
75.
DemizuY, SasakiR, TrachoothamD, PelicanoH, ColacinoJA, LiuJ, HuangP. Alterations of cellular redox state during NNK-induced malignant transformation and resistance to radiation. Antioxid Redox Signal, 10:951–961. 2008.
76.
DeNardoDG, AndreuP, CoussensLM. Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity. Cancer Metastasis Rev, 29:309–316. 2010.
DenkoNC. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer, 8:705–713. 2008.
79.
DewhirstMW. Relationships between cycling hypoxia, HIF-1, angiogenesis and oxidative stress. Radiat Res, 172:653–665. 2009.
80.
DewhirstMW, CaoY, MoellerB. Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer, 8:425–437. 2008.
81.
DiazB, ShaniG, PassI, AndersonD, QuintavalleM, CourtneidgeSA. Tks5-dependent, nox-mediated generation of reactive oxygen species is necessary for invadopodia formation. Sci Signal, 2:ra53. 2009.
82.
DiehnM, ChoRW, LoboNA, KaliskyT, DorieMJ, KulpAN, QianD, LamJS, AillesLE, WongM, JoshuaB, KaplanMJ, WapnirI, DirbasFM, SomloG, GarberoglioC, PazB, ShenJ, LauSK, QuakeSR, BrownJM, WeissmanIL, ClarkeMF. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature, 458:780–783. 2009.
83.
DingWQ, LindSE. Phospholipid hydroperoxide glutathione peroxidase plays a role in protecting cancer cells from docosahexaenoic acid-induced cytotoxicity. Mol Cancer Ther, 6:1467–1474. 2007.
84.
DixitD, SharmaV, GhoshS, KoulN, MishraPK, SenE. Manumycin inhibits STAT3, telomerase activity, and growth of glioma cells by elevating intracellular reactive oxygen species generation. Free Radic Biol Med, 47:364–374. 2009.
85.
DlaskovaA, HlavataL, JezekP. Oxidative stress caused by blocking of mitochondrial complex I H(+) pumping as a link in aging/disease vicious cycle. Int J Biochem Cell Biol, 40:1792–1805. 2008.
86.
DomeB, HendrixMJ, PakuS, TovariJ, TimarJ. Alternative vascularization mechanisms in cancer: pathology and therapeutic implications. Am J Pathol, 170:1–15. 2007.
87.
DrogeW. Free radicals in the physiological control of cell function. Physiol Rev, 82:47–95. 2002.
88.
DuJ, LiuJ, SmithBJ, TsaoMS, CullenJJ. Role of Rac1-dependent NADPH oxidase in the growth of pancreatic cancer. Cancer Gene Ther, 18:135–143. 2011.
89.
DunnLL, BuckleAM, CookeJP, NgMK. The emerging role of the thioredoxin system in angiogenesis. Arterioscler Thromb Vasc Biol, 30:2089–2098. 2010.
90.
ElsabahyM, NazaraliA, FoldvariM. Non-viral nucleic acid delivery: key challenges and future directions. Curr Drug Deliv, 8:235–244. 2011.
91.
EpperlyMW, MelendezJA, ZhangX, NieS, PearceL, PetersonJ, FranicolaD, DixonT, GreenbergerBA, KomanduriP, WangH, GreenbergerJS. Mitochondrial targeting of a catalase transgene product by plasmid liposomes increases radioresistance in vitro and in vivo. Radiat Res, 171:588–595. 2009.
92.
EpperlyMW, WegnerR, KanaiAJ, KaganV, GreenbergerEE, NieS, GreenbergerJS. Effects of MnSOD-plasmid liposome gene therapy on antioxidant levels in irradiated murine oral cavity orthotopic tumors. Radiat Res, 167:289–297. 2007.
EvansMD, DizdarogluM, CookeMS. Oxidative DNA damage and disease: induction, repair and significance. Mutat Res, 567:1–61. 2004.
95.
FangJ, SekiT, MaedaH. Therapeutic strategies by modulating oxygen stress in cancer and inflammation. Adv Drug Deliv Rev, 61:290–302. 2009.
96.
FedericoA, MorgilloF, TuccilloC, CiardielloF, LoguercioC. Chronic inflammation and oxidative stress in human carcinogenesis. Int J Cancer, 121:2381–2386. 2007.
97.
FerbeyreG, MorigglR. The role of Stat5 transcription factors as tumor suppressors or oncogenes. Biochim Biophys Acta, 1815:104–114. 2011.
98.
FischerK, HoffmannP, VoelklS, MeidenbauerN, AmmerJ, EdingerM, GottfriedE, SchwarzS, RotheG, HovesS, RennerK, TimischlB, MackensenA, Kunz-SchughartL, AndreesenR, KrauseSW, KreutzM. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood, 109:3812–3819. 2007.
99.
FolbergR, HendrixMJ, ManiotisAJ. Vasculogenic mimicry and tumor angiogenesis. Am J Pathol, 156:361–381. 2000.
FreyRS, Ushio-FukaiM, MalikAB. NADPH oxidase-dependent signaling in endothelial cells: role in physiology and pathophysiology. Antioxid Redox Signal, 11:791–810. 2009.
102.
FridlenderZG, SunJ, KimS, KapoorV, ChengG, LingL, WorthenGS, AlbeldaSM. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell, 16:183–194. 2009.
103.
FruehaufJP, MeyskensFLJr.Reactive oxygen species: a breath of life or death?Clin Cancer Res, 13:789–794. 2007.
104.
FukumuraD, DudaDG, MunnLL, JainRK. Tumor microvasculature and microenvironment: novel insights through intravital imaging in pre-clinical models. Microcirculation, 17:206–225. 2010.
105.
FunesJM, QuinteroM, HendersonS, MartinezD, QureshiU, WestwoodC, ClementsMO, BourbouliaD, PedleyRB, MoncadaS, BoshoffC. Transformation of human mesenchymal stem cells increases their dependency on oxidative phosphorylation for energy production. Proc Natl Acad Sci U S A, 104:6223–6228. 2007.
106.
GaengelK, GenoveG, ArmulikA, BetsholtzC. Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler Thromb Vasc Biol, 29:630–638. 2009.
GarzonR, CalinGA, CroceCM. MicroRNAs in cancer. Annu Rev Med, 60:167–179. 2009.
109.
GatenbyRA, GawlinskiET, GmitroAF, KaylorB, GilliesRJ. Acid-mediated tumor invasion: a multidisciplinary study. Cancer Res, 66:5216–5223. 2006.
110.
GiannoniE, BianchiniF, CaloriniL, ChiarugiP. Cancer associated fibroblasts exploit reactive oxygen species through a proinflammatory signature leading to epithelial mesenchymal transition and stemness. Antioxid Redox Signal, 14:2361–2371. 2011.
111.
GiembyczMA, LindsayMA. Pharmacology of the eosinophil. Pharmacol Rev, 51:213–340. 1999.
112.
GiusD, SpitzDR. Redox signaling in cancer biology. Antioxid Redox Signal, 8:1249–1252. 2006.
113.
GlorieuxC, DejeansN, SidB, BeckR, CalderonPB, VerraxJ. Catalase overexpression in mammary cancer cells leads to a less aggressive phenotype and an altered response to chemotherapy. Biochem Pharmacol, 82:1384–1390. 2011.
114.
GohJ, EnnsL, FatemieS, HopkinsH, MortonJ, Pettan-BrewerC, LadigesW. Mitochondrial targeted catalase suppresses invasive breast cancer in mice. BMC Cancer, 11:191. 2011.
115.
GordilloG, FangH, ParkH, RoyS. Nox-4-dependent nuclear H2O2 drives DNA oxidation resulting in 8-OHdG as urinary biomarker and hemangioendothelioma formation. Antioxid Redox Signal, 12:933–943. 2010.
116.
GravesJA, RothermundK, WangT, QianW, Van HoutenB, ProchownikEV. Point mutations in c-Myc uncouple neoplastic transformation from multiple other phenotypes in rat fibroblasts. PLoS One, 5:e13717. 2010.
117.
GregoryAD, HoughtonAM. Tumor-associated neutrophils: new targets for cancer therapy. Cancer Res, 71:2411–2416. 2011.
118.
GreitherT, WurlP, GrocholaL, BondG, BacheM, KapplerM, LautenschlagerC, HolzhausenHJ, WachS, EckertAW, TaubertH. Expression of microRNA 210 associates with poor survival and age of tumor onset of soft-tissue sarcoma patients. Int J Cancer, 130:1230–1235. 2012.
HatfieldDL, YooMH, CarlsonBA, GladyshevVN. Selenoproteins that function in cancer prevention and promotion. Biochim Biophys Acta, 1790:1541–1545. 2009.
124.
HayesJD, McMahonM. NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. Trends Biochem Sci, 34:176–188. 2009.
125.
HoggRT, ThorpeP, GerardRD. Retargeting adenoviral vectors to improve gene transfer into tumors. Cancer Gene Ther, 18:275–287. 2011.
126.
HolePS, PearnL, TonksAJ, JamesPE, BurnettAK, DarleyRL, TonksA. Ras-induced reactive oxygen species promote growth factor-independent proliferation in human CD34+ hematopoietic progenitor cells. Blood, 115:1238–1246. 2010.
127.
HoneggarM, BeckR, MoosPJ. Thioredoxin reductase 1 ablation sensitizes colon cancer cells to methylseleninate-mediated cytotoxicity. Toxicol Appl Pharmacol, 241:348–355. 2009.
128.
HoughtonAM. The paradox of tumor-associated neutrophils: fueling tumor growth with cytotoxic substances. Cell Cycle, 9:1732–1737. 2010.
129.
HsiehCH, ChangHT, ShenWC, ShyuWC, LiuRS. Imaging the impact of Nox4 in cycling hypoxia-mediated U87 glioblastoma invasion and infiltration. Mol Imaging Biol, 14:489–499. 2012.
130.
HuY, RosenDG, ZhouY, FengL, YangG, LiuJ, HuangP. Mitochondrial manganese-superoxide dismutase expression in ovarian cancer: role in cell proliferation and response to oxidative stress. J Biol Chem, 280:39485–39492. 2005.
HwangES, KimGH. Biomarkers for oxidative stress status of DNA, lipids, and proteins in vitro and in vivo cancer research. Toxicology, 229:1–10. 2007.
133.
HynesRO. The extracellular matrix: not just pretty fibrils. Science, 326:1216–1219. 2009.
134.
IbanezIL, PolicastroLL, TropperI, BracalenteC, PalmieriMA, RojasPA, MolinariBL, DuranH. H2O2 scavenging inhibits G1/S transition by increasing nuclear levels of p27KIP1. Cancer Lett, 305:58–68. 2011.
135.
IdoA, UtoH, MoriuchiA, NagataK, OnagaY, OnagaM, HoriT, HironoS, HayashiK, TamaokiT, TsubouchiH. Gene therapy targeting for hepatocellular carcinoma: selective and enhanced suicide gene expression regulated by a hypoxia-inducible enhancer linked to a human alpha-fetoprotein promoter. Cancer Res, 61:3016–3021. 2001.
136.
IndoHP, DavidsonM, YenHC, SuenagaS, TomitaK, NishiiT, HiguchiM, KogaY, OzawaT, MajimaHJ. Evidence of ROS generation by mitochondria in cells with impaired electron transport chain and mitochondrial DNA damage. Mitochondrion, 7:106–118. 2007.
137.
IraniK, XiaY, ZweierJL, SollottSJ, DerCJ, FearonER, SundaresanM, FinkelT, Goldschmidt-ClermontPJ. Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts. Science, 275:1649–1652. 1997.
JarugaP, ZastawnyTH, SkokowskiJ, DizdarogluM, OlinskiR. Oxidative DNA base damage and antioxidant enzyme activities in human lung cancer. FEBS Lett, 341:59–64. 1994.
140.
JezekP, Plecita-HlavataL. Mitochondrial reticulum network dynamics in relation to oxidative stress, redox regulation, and hypoxia. Int J Biochem Cell Biol, 41:1790–1804. 2009.
141.
JiangJ, TangYL, LiangXH. EMT: a new vision of hypoxia promoting cancer progression. Cancer Biol Ther, 11:714–723. 2011.
142.
JiangT, ChenN, ZhaoF, WangXJ, KongB, ZhengW, ZhangDD. High levels of Nrf2 determine chemoresistance in type II endometrial cancer. Cancer Res, 70:5486–5496. 2010.
143.
JinC, RajabiH, KufeD. miR-1226 targets expression of the mucin 1 oncoprotein and induces cell death. Int J Oncol, 37:61–69. 2010.
144.
JochemsC, SchlomJ. Tumor-infiltrating immune cells and prognosis: the potential link between conventional cancer therapy and immunity. Exp Biol Med (Maywood), 236:567–579. 2011.
145.
JonesRG, ThompsonCB. Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev, 23:537–548. 2009.
146.
JoseC, BellanceN, RossignolR. Choosing between glycolysis and oxidative phosphorylation: a tumor's dilemma?Biochim Biophys Acta, 1807:552–561. 2011.
147.
JozkowiczA, WasH, DulakJ. Heme oxygenase-1 in tumors: is it a false friend?Antioxid Redox Signal, 9:2099–2117. 2007.
148.
KaelinWGJr.The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer. Nat Rev Cancer, 8:865–873. 2008.
149.
KaelinWGJr., RatcliffePJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell, 30:393–402. 2008.
150.
KalininaEV, ChernovNN, SaprinAN. Involvement of thio-, peroxi-, and glutaredoxins in cellular redox-dependent processes. Biochemistry (Mosc), 73:1493–1510. 2008.
151.
KamataT. Roles of Nox1 and other Nox isoforms in cancer development. Cancer Sci, 100:1382–1388. 2009.
152.
KampDW, ShacterE, WeitzmanSA. Chronic inflammation and cancer: the role of the mitochondria. Oncology (Williston Park), 25:400–4104132011.
KenslerTW, WakabayashiN, BiswalS. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol, 47:89–116. 2007.
157.
KeppO, GalluzziL, LipinskiM, YuanJ, KroemerG. Cell death assays for drug discovery. Nat Rev Drug Discov, 10:221–237. 2011.
158.
KimHM, HaraguchiN, IshiiH, OhkumaM, OkanoM, MimoriK, EguchiH, YamamotoH, NaganoH, SekimotoM, DokiY, MoriM. Increased CD13 Expression reduces reactive oxygen species, promoting survival of liver cancer stem cells via an epithelial-mesenchymal transition-like phenomenon. Ann Surg Oncol, 19:539–548. 2011.
159.
KimSJ, MiyoshiY, TaguchiT, TamakiY, NakamuraH, YodoiJ, KatoK, NoguchiS. High thioredoxin expression is associated with resistance to docetaxel in primary breast cancer. Clin Cancer Res, 11:8425–8430. 2005.
160.
KimYR, EomJI, KimSJ, JeungHK, CheongJW, KimJS, MinYH. Myeloperoxidase expression as a potential determinant of parthenolide-induced apoptosis in leukemia bulk and leukemia stem cells. J Pharmacol Exp Ther, 335:389–400. 2010.
161.
KinnulaVL, CrapoJD. Superoxide dismutases in malignant cells and human tumors. Free Radic Biol Med, 36:718–744. 2004.
162.
KlimovaT, ChandelNS. Mitochondrial complex III regulates hypoxic activation of HIF. Cell Death Differ, 15:660–666. 2008.
163.
KlotzschE, SmithML, KubowKE, MuntwylerS, LittleWC, BeyelerF, GourdonD, NelsonBJ, VogelV. Fibronectin forms the most extensible biological fibers displaying switchable force-exposed cryptic binding sites. Proc Natl Acad Sci U S A, 106:18267–18272. 2009.
164.
KobayashiA, KangMI, OkawaH, OhtsujiM, ZenkeY, ChibaT, IgarashiK, YamamotoM. Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol, 24:7130–7139. 2004.
165.
KobayashiA, OhtaT, YamamotoM. Unique function of the Nrf2-Keap1 pathway in the inducible expression of antioxidant and detoxifying enzymes. Methods Enzymol, 378:273–286. 2004.
166.
KondoS, ToyokuniS, IwasaY, TanakaT, OnoderaH, HiaiH, ImamuraM. Persistent oxidative stress in human colorectal carcinoma, but not in adenoma. Free Radic Biol Med, 27:401–410. 1999.
167.
KongQ, BeelJA, LilleheiKO. A threshold concept for cancer therapy. Med Hypotheses, 55:29–35. 2000.
168.
KoppenolWH, BoundsPL, DangCV. Otto Warburg's contributions to current concepts of cancer metabolism. Nat Rev Cancer, 11:325–337. 2011.
169.
KowaltowskiAJ, de Souza-PintoNC, CastilhoRF, VercesiAE. Mitochondria and reactive oxygen species. Free Radic Biol Med, 47:333–343. 2009.
170.
KrishnaS, LowIC, PervaizS. Regulation of mitochondrial metabolism: yet another facet in the biology of the oncoprotein Bcl-2. Biochem J, 435:545–551. 2011.
KuoHW, ChouSY, HuTW, WuFY, ChenDJ. Urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) and genetic polymorphisms in breast cancer patients. Mutat Res, 631:62–68. 2007.
173.
LadelfaMF, ToledoMF, LaisecaJE, MonteM. Interaction of p53 with tumor suppressive and oncogenic signaling pathways to control cellular reactive oxygen species production. Antioxid Redox Signal, 15:1749–1761. 2011.
174.
LambethJD. NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol, 4:181–189. 2004.
175.
LandriscinaM, MaddalenaF, LaudieroG, EspositoF. Adaptation to oxidative stress, chemoresistance, and cell survival. Antioxid Redox Signal, 11:2701–2716. 2009.
176.
LardnerA. The effects of extracellular pH on immune function. J Leukoc Biol, 69:522–530. 2001.
177.
LauA, VilleneuveNF, SunZ, WongPK, ZhangDD. Dual roles of Nrf2 in cancer. Pharmacol Res, 58:262–270. 2008.
178.
LawendaBD, KellyKM, LadasEJ, SagarSM, VickersA, BlumbergJB. Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy?J Natl Cancer Inst, 100:773–783. 2008.
179.
LeXF, MerchantO, BastRC, CalinGA. The Roles of microRNAs in the cancer invasion-metastasis cascade. Cancer Microenviron, 3:137–147. 2010.
180.
LeeJJ, JacobsenEA, McGarryMP, SchleimerRP, LeeNA. Eosinophils in health and disease: the LIAR hypothesis. Clin Exp Allergy, 40:563–575. 2010.
181.
LeiY, HuangK, GaoC, LauQC, PanH, XieK, LiJ, LiuR, ZhangT, XieN, Shan NaiH, WuH, ZhaoX, ECN, HuangC, WeiY. Proteomics identification of ITGB3 as a key regulator in ROS-induced migration and invasion of colorectal cancer cells. Mol Cell Proteomics, 10:M110.0053972011.
182.
Leite de OliveiraR, HammA, MazzoneM. Growing tumor vessels: more than one way to skin a cat - implications for angiogenesis targeted cancer therapies. Mol Aspects Med, 32:71–87. 2011.
183.
LevineAJ, Puzio-KuterAM. The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science, 330:1340–1344. 2010.
184.
LiHJ, EvertsM, PereboevaL, KomarovaS, IdanA, CurielDT, HerschmanHR. Adenovirus tumor targeting and hepatic untargeting by a coxsackie/adenovirus receptor ectodomain anti-carcinoembryonic antigen bispecific adapter. Cancer Res, 67:5354–5361. 2007.
185.
LiLZ, ZhouR, XuHN, MoonL, ZhongT, KimEJ, QiaoH, ReddyR, LeeperD, ChanceB, GlicksonJD. Quantitative magnetic resonance and optical imaging biomarkers of melanoma metastatic potential. Proc Natl Acad Sci U S A, 106:6608–6613. 2009.
186.
LiZ, RichJN. Hypoxia and hypoxia inducible factors in cancer stem cell maintenance. Curr Top Microbiol Immunol, 345:21–30. 2010.
187.
Limon-PachecoJ, GonsebattME. The role of antioxidants and antioxidant-related enzymes in protective responses to environmentally induced oxidative stress. Mutat Res, 674:137–147. 2009.
188.
LisantiMP, Martinez-OutschoornUE, ChiavarinaB, PavlidesS, Whitaker-MenezesD, TsirigosA, WitkiewiczA, LinZ, BallietR, HowellA, SotgiaF. Understanding the “lethal” drivers of tumor-stroma co-evolution: emerging role(s) for hypoxia, oxidative stress and autophagy/mitophagy in the tumor micro-environment. Cancer Biol Ther, 10:537–542. 2010.
189.
LiuJ, CaoL, ChenJ, SongS, LeeIH, QuijanoC, LiuH, KeyvanfarK, ChenH, CaoLY, AhnBH, KumarNG, RoviraII, XuXL, van LohuizenM, MotoyamaN, DengCX, FinkelT. Bmi1 regulates mitochondrial function and the DNA damage response pathway. Nature, 459:387–392. 2009.
190.
LiuJ, DuJ, ZhangY, SunW, SmithBJ, OberleyLW, CullenJJ. Suppression of the malignant phenotype in pancreatic cancer by overexpression of phospholipid hydroperoxide glutathione peroxidase. Hum Gene Ther, 17:105–116. 2006.
191.
LiuJ, HinkhouseMM, SunW, WeydertCJ, RitchieJM, OberleyLW, CullenJJ. Redox regulation of pancreatic cancer cell growth: role of glutathione peroxidase in the suppression of the malignant phenotype. Hum Gene Ther, 15:239–250. 2004.
192.
LleraAS, GirottiMR, BenedettiLG, PodhajcerOL. Matricellular proteins and inflammatory cells: a task force to promote or defeat cancer?Cytokine Growth Factor Rev, 21:67–76. 2010.
193.
LopezCA, KimchiET, MauceriHJ, ParkJO, MehtaN, MurphyKT, BeckettMA, HellmanS, PosnerMC, KufeDW, WeichselbaumRR. Chemoinducible gene therapy: a strategy to enhance doxorubicin antitumor activity. Mol Cancer Ther, 3:1167–1175. 2004.
194.
Lopez-LazaroM. Excessive superoxide anion generation plays a key role in carcinogenesis. Int J Cancer, 120:1378–1380. 2007.
195.
LuJM, LinPH, YaoQ, ChenC. Chemical and molecular mechanisms of antioxidants: experimental approaches and model systems. J Cell Mol Med, 14:840–860. 2010.
196.
LuX, KangY. Hypoxia and hypoxia-inducible factors: master regulators of metastasis. Clin Cancer Res, 16:5928–5935. 2010.
197.
LuY, MaduCO. Viral-based gene delivery and regulated gene expression for targeted cancer therapy. Expert Opin Drug Deliv, 7:19–35. 2010.
198.
MaD, WarabiE, YanagawaT, KimuraS, HaradaH, YamagataK, IshiiT. Peroxiredoxin I plays a protective role against cisplatin cytotoxicity through mitogen activated kinase signals. Oral Oncol, 45:1037–1043. 2009.
199.
MaY, AymericL, LocherC, KroemerG, ZitvogelL. The dendritic cell-tumor cross-talk in cancer. Curr Opin Immunol, 23:146–152. 2011.
200.
MaciagA, SithanandamG, AndersonLM. Mutant K-rasV12 increases COX-2, peroxides and DNA damage in lung cells. Carcinogenesis, 25:2231–2237. 2004.
201.
MajmundarAJ, WongWJ, SimonMC. Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell, 40:294–309. 2010.
202.
MaltbyS, KhazaieK, McNagnyKM. Mast cells in tumor growth: angiogenesis, tissue remodelling and immune-modulation. Biochim Biophys Acta, 1796:19–26. 2009.
203.
MannelloF. What does matrix metalloproteinase-1 expression in patients with breast cancer really tell us?BMC Med, 9:95. 2011.
204.
MannelloF, MeddaV, TontiGA. Hypoxia and neural stem cells: from invertebrates to brain cancer stem cells. Int J Dev Biol, 55:569–581. 2011.
205.
MannelloF, QinW, ZhuW, FabbriL, TontiGA, SauterER. Nipple aspirate fluids from women with breast cancer contain increased levels of group IIa secretory phospholipase A2. Breast Cancer Res Treat, 111:209–218. 2008.
206.
MannelloF, TontiGA, MeddaV. Protein oxidation in breast microenvironment: nipple aspirate fluid collected from breast cancer women contains increased protein carbonyl concentration. Cell Oncol, 31:383–392. 2009.
207.
MannelloF, TontiGA, PederzoliA, SimoneP, SmaniottoA, MeddaV. Detection of superoxide dismutase-1 in nipple aspirate fluids: a reactive oxygen species-regulating enzyme in the breast cancer microenvironment. Clin Breast Cancer, 10:238–45. 2010.
208.
MantovaniA, SavinoB, LocatiM, ZammataroL, AllavenaP, BonecchiR. The chemokine system in cancer biology and therapy. Cytokine Growth Factor Rev, 21:27–39. 2010.
209.
MantovaniA, SozzaniS, LocatiM, AllavenaP, SicaA. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol, 23:549–555. 2002.
210.
Martinez-OutschoornUE, BallietRM, RivadeneiraDB, ChiavarinaB, PavlidesS, WangC, Whitaker-MenezesD, DaumerKM, LinZ, WitkiewiczAK, FlomenbergN, HowellA, PestellRG, KnudsenES, SotgiaF, LisantiMP. Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution: a new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells. Cell Cycle, 9:3256–3276. 2010.
211.
Martinez-OutschoornUE, TrimmerC, LinZ, Whitaker-MenezesD, ChiavarinaB, ZhouJ, WangC, PavlidesS, Martinez-CantarinMP, CapozzaF, WitkiewiczAK, FlomenbergN, HowellA, PestellRG, CaroJ, LisantiMP, SotgiaF. Autophagy in cancer associated fibroblasts promotes tumor cell survival: role of hypoxia, HIF1 induction and NFkappaB activation in the tumor stromal microenvironment. Cell Cycle, 9:3515–3533. 2010.
212.
MathewR, WhiteE. Autophagy in tumorigenesis and energy metabolism: friend by day, foe by night. Curr Opin Genet Dev, 21:113–119. 2011.
MazumdarJ, DondetiV, SimonMC. Hypoxia-inducible factors in stem cells and cancer. J Cell Mol Med, 13:4319–4328. 2009.
215.
MazurekS, BoschekCB, HugoF, EigenbrodtE. Pyruvate kinase type M2 and its role in tumor growth and spreading. Semin Cancer Biol, 15:300–308. 2005.
216.
MeyerY, BuchananBB, VignolsF, ReichheldJP. Thioredoxins and glutaredoxins: unifying elements in redox biology. Annu Rev Genet, 43:335–367. 2009.
217.
MillerTW, IsenbergJS, RobertsDD. Molecular regulation of tumor angiogenesis and perfusion via redox signaling. Chem Rev, 109:3099–3124. 2009.
218.
MinJY, LimSO, JungG. Downregulation of catalase by reactive oxygen species via hypermethylation of CpG island II on the catalase promoter. FEBS Lett, 584:2427–2432. 2010.
219.
MochizukiT, FurutaS, MitsushitaJ, ShangWH, ItoM, YokooY, YamauraM, IshizoneS, NakayamaJ, KonagaiA, HiroseK, KiyosawaK, KamataT. Inhibition of NADPH oxidase 4 activates apoptosis via the AKT/apoptosis signal-regulating kinase 1 pathway in pancreatic cancer PANC-1 cells. Oncogene, 25:3699–3707. 2006.
220.
MohyeldinA, Garzon-MuvdiT, Quinones-HinojosaA. Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell, 7:150–161. 2010.
221.
MorabitoF, CristaniM, SaijaA, StelitanoC, CalleaV, TomainoA, MinciulloPL, GangemiS. Lipid peroxidation and protein oxidation in patients affected by Hodgkin's lymphoma. Mediators Inflamm, 13:381–383. 2004.
222.
Moreno-SanchezR, Rodriguez-EnriquezS, SaavedraE, Marin-HernandezA, Gallardo-PerezJC. The bioenergetics of cancer: is glycolysis the main ATP supplier in all tumor cells?Biofactors, 35:209–225. 2009.
223.
MorganD, ChernyVV, MurphyR, KatzBZ, DeCourseyTE. The pH dependence of NADPH oxidase in human eosinophils. J Physiol, 569:419–431. 2005.
224.
MorikawaS, BalukP, KaidohT, HaskellA, JainRK, McDonaldDM. Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol, 160:985–1000. 2002.
225.
MurakamiA, OhigashiH. Targeting NOX, INOS and COX-2 in inflammatory cells: chemoprevention using food phytochemicals. Int J Cancer, 121:2357–2363. 2007.
226.
MytarB, WoloszynM, Macura-BiegunA, HajtoB, RuggieroI, PiekarskaB, ZembalaM. Involvement of pattern recognition receptors in the induction of cytokines and reactive oxygen intermediates production by human monocytes/macrophages stimulated with tumour cells. Anticancer Res, 24:2287–2293. 2004.
227.
NagarajS, GabrilovichDI. Tumor escape mechanism governed by myeloid-derived suppressor cells. Cancer Res, 68:2561–2563. 2008.
228.
Naiki-ItoA, AsamotoM, HokaiwadoN, TakahashiS, YamashitaH, TsudaH, OgawaK, ShiraiT. Gpx2 is an overexpressed gene in rat breast cancers induced by three different chemical carcinogens. Cancer Res, 67:11353–11358. 2007.
229.
NeumannCA, FangQ. Are peroxiredoxins tumor suppressors?Curr Opin Pharmacol, 7:375–380. 2007.
230.
NitureSK, JaiswalAK. Nrf2 protein up-regulates antiapoptotic protein Bcl-2 and prevents cellular apoptosis. J Biol Chem, 287:9873–9886. 2012.
231.
OberleyLW. Mechanism of the tumor suppressive effect of MnSOD overexpression. Biomed Pharmacother, 59:143–148. 2005.
232.
OberleyLW, BuettnerGR. Role of superoxide dismutase in cancer: a review. Cancer Res, 39:1141–1149. 1979.
233.
OldbergA, KalamajskiS, SalnikovAV, StuhrL, MorgelinM, ReedRK, HeldinNE, RubinK. Collagen-binding proteoglycan fibromodulin can determine stroma matrix structure and fluid balance in experimental carcinoma. Proc Natl Acad Sci U S A, 104:13966–13971. 2007.
234.
OnumahOE, JulesGE, ZhaoY, ZhouL, YangH, GuoZ. Overexpression of catalase delays G0/G1- to S-phase transition during cell cycle progression in mouse aortic endothelial cells. Free Radic Biol Med, 46:1658–1667. 2009.
OzbenT. Oxidative stress and apoptosis: impact on cancer therapy. J Pharm Sci, 96:2181–2196. 2007.
237.
PaniG, GaleottiT, ChiarugiP. Metastasis: cancer cell's escape from oxidative stress. Cancer Metastasis Rev, 29:351–378. 2010.
238.
PaniG, GiannoniE, GaleottiT, ChiarugiP. Redox-based escape mechanism from death: the cancer lesson. Antioxid Redox Signal, 11:2791–2806. 2009.
239.
PappLV, LuJ, HolmgrenA, KhannaKK. From selenium to selenoproteins: synthesis, identity, and their role in human health. Antioxid Redox Signal, 9:775–806. 2007.
240.
ParkJJ, ChangHW, JeongEJ, RohJL, ChoiSH, JeonSY, KoGH, KimSY. Peroxiredoxin IV protects cells from radiation-induced apoptosis in head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys, 73:1196–1202. 2009.
241.
ParksSK, ChicheJ, PouyssegurJ. pH control mechanisms of tumor survival and growth. J Cell Physiol, 226:299–308. 2011.
242.
PasqualiniR, ArapW, McDonaldDM. Probing the structural and molecular diversity of tumor vasculature. Trends Mol Med, 8:563–571. 2002.
243.
PerumalSS, ShanthiP, SachdanandamP. Combined efficacy of tamoxifen and coenzyme Q10 on the status of lipid peroxidation and antioxidants in DMBA induced breast cancer. Mol Cell Biochem, 273:151–160. 2005.
244.
PhangJM, PandhareJ, ZabirnykO, LiuY. PPARgamma and proline oxidase in cancer. PPAR Res, 2008:542694. 2008.
245.
PietrasK, OstmanA. Hallmarks of cancer: interactions with the tumor stroma. Exp Cell Res, 316:1324–1331. 2010.
246.
PingYF, BianXW. Cancer stem cells switch on tumor neovascularization. Curr Mol Med, 11:69–75. 2011.
247.
PizzoAM, KokiniK, VaughnLC, WaisnerBZ, Voytik-HarbinSL. Extracellular matrix (ECM) microstructural composition regulates local cell-ECM biomechanics and fundamental fibroblast behavior: a multidimensional perspective. J Appl Physiol, 98:1909–1921. 2005.
248.
PoerschkeRL, MoosPJ. Thioredoxin reductase 1 knockdown enhances selenazolidine cytotoxicity in human lung cancer cells via mitochondrial dysfunction. Biochem Pharmacol, 81:211–221. 2011.
249.
PolicastroL, MolinariB, LarcherF, BlancoP, PodhajcerOL, CostaCS, RojasP, DuranH. Imbalance of antioxidant enzymes in tumor cells and inhibition of proliferation and malignant features by scavenging hydrogen peroxide. Mol Carcinog, 39:103–113. 2004.
250.
PolicastroLL, IbanezIL, DuranHA, SoriaG, GottifrediV, PodhajcerOL. Suppression of cancer growth by nonviral gene therapy based on a novel reactive oxygen species-responsive promoter. Mol Ther, 17:1355–1364. 2009.
251.
PriesAR, CornelissenAJ, SlootAA, HinkeldeyM, DreherMR, HopfnerM, DewhirstMW, SecombTW. Structural adaptation and heterogeneity of normal and tumor microvascular networks. PLoS Comput Biol, 5:e1000394. 2009.
252.
ProvenzanoPP, InmanDR, EliceiriKW, KnittelJG, YanL, RuedenCT, WhiteJG, KeelyPJ. Collagen density promotes mammary tumor initiation and progression. BMC Med, 6:11. 2008.
253.
ProwT, GrebeR, MergesC, SmithJN, McLeodDS, LearyJF, LuttyGA. Nanoparticle tethered antioxidant response element as a biosensor for oxygen induced toxicity in retinal endothelial cells. Mol Vis, 12:616–625. 2006.
254.
Puzio-KuterAM. The role of p53 in metabolic regulation. Genes Cancer, 2:385–391. 2011.
255.
QuY, WangJ, RayPS, GuoH, HuangJ, Shin-SimM, BukoyeBA, LiuB, LeeAV, LinX, HuangP, MartensJW, GiulianoAE, ZhangN, ChengNH, CuiX. Thioredoxin-like 2 regulates human cancer cell growth and metastasis via redox homeostasis and NF-kappaB signaling. J Clin Invest, 121:212–225. 2011.
256.
QuY, ZhaoS, HongJ, TangS. Radiosensitive gene therapy through imRNA expression for silencing manganese superoxide dismutase. J Cancer Res Clin Oncol, 136:953–959. 2010.
257.
RabinowitzJD, WhiteE. Autophagy and metabolism. Science, 330:1344–1348. 2010.
258.
RadiskyDC, LevyDD, LittlepageLE, LiuH, NelsonCM, FataJE, LeakeD, GoddenEL, AlbertsonDG, NietoMA, WerbZ, BissellMJ. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature, 436:123–127. 2005.
259.
RafiiS, HeissigB, HattoriK. Efficient mobilization and recruitment of marrow-derived endothelial and hematopoietic stem cells by adenoviral vectors expressing angiogenic factors. Gene Ther, 9:631–641. 2002.
RaimundoN, BaysalBE, ShadelGS. Revisiting the TCA cycle: signaling to tumor formation. Trends Mol Med, 17:641–649. 2012.
262.
RajL, IdeT, GurkarAU, FoleyM, SchenoneM, LiX, TollidayNJ, GolubTR, CarrSA, ShamjiAF, SternAM, MandinovaA, SchreiberSL, LeeSW. Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature, 475:231–234. 2011.
263.
RalphSJ, Rodriguez-EnriquezS, NeuzilJ, SaavedraE, Moreno-SanchezR. The causes of cancer revisited: “mitochondrial malignancy” and ROS-induced oncogenic transformation - why mitochondria are targets for cancer therapy. Mol Aspects Med, 31:145–170. 2010.
264.
RankinEB, GiacciaAJ. The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ, 15:678–685. 2008.
265.
Rao GogineniV, Kumar NallaA, GuptaR, GorantlaB, GujratiM, DinhDH, RaoJS. Radiation-inducible silencing of uPA and uPAR in vitro and in vivo in meningioma. Int J Oncol, 36:809–816. 2010.
266.
RaviD, MuniyappaH, DasKC. Endogenous thioredoxin is required for redox cycling of anthracyclines and p53-dependent apoptosis in cancer cells. J Biol Chem, 280:40084–40096. 2005.
ReddyNM, KleebergerSR, BreamJH, FallonPG, KenslerTW, YamamotoM, ReddySP. Genetic disruption of the Nrf2 compromises cell-cycle progression by impairing GSH-induced redox signaling. Oncogene, 27:5821–5832. 2008.
269.
RheeSG, BaeYS, LeeSR, KwonJ. Hydrogen peroxide: a key messenger that modulates protein phosphorylation through cysteine oxidation. Sci STKE, 2000:pe1. 2000.
270.
RiemannA, SchneiderB, IhlingA, NowakM, SauvantC, ThewsO, GekleM. Acidic environment leads to ROS-induced MAPK signaling in cancer cells. PLoS One, 6:e22445. 2011.
271.
SagaY, OhwadaM, SuzukiM, KonnoR, KigawaJ, UenoS, ManoH. Glutathione peroxidase 3 is a candidate mechanism of anticancer drug resistance of ovarian clear cell adenocarcinoma. Oncol Rep, 20:1299–1303. 2008.
272.
SamantRS, ShevdeLA. Recent advances in anti-angiogenic therapy of cancer. Oncotarget, 2:122–134. 2011.
273.
SampsonN, KozielR, ZenzmaierC, BubendorfL, PlasE, Jansen-DurrP, BergerP. ROS signaling by NOX4 drives fibroblast-to-myofibroblast differentiation in the diseased prostatic stroma. Mol Endocrinol, 25:503–515. 2011.
274.
SarsourEH, KumarMG, ChaudhuriL, KalenAL, GoswamiPC. Redox control of the cell cycle in health and disease. Antioxid Redox Signal, 11:2985–3011. 2009.
275.
Scherz-ShouvalR, ElazarZ. Regulation of autophagy by ROS: physiology and pathology. Trends Biochem Sci, 36:30–38. 2011.
276.
SemenzaGL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer, 3:721–732. 2003.
277.
SharmaA, LiX, BangariDS, MittalSK. Adenovirus receptors and their implications in gene delivery. Virus Res, 143:184–194. 2009.
278.
ShlomaiJ. Redox control of protein-DNA interactions: from molecular mechanisms to significance in signal transduction, gene expression, and DNA replication. Antioxid Redox Signal, 13:1429–1476. 2010.
279.
Shoshan-BarmatzV, De PintoV, ZweckstetterM, RavivZ, KeinanN, ArbelN. VDAC, a multi-functional mitochondrial protein regulating cell life and death. Mol Aspects Med, 31:227–285. 2010.
280.
SicaA. Role of tumour-associated macrophages in cancer-related inflammation. Exp Oncol, 32:153–158. 2010.
281.
SicaA, LarghiP, MancinoA, RubinoL, PortaC, TotaroMG, RimoldiM, BiswasSK, AllavenaP, MantovaniA. Macrophage polarization in tumour progression. Semin Cancer Biol, 18:349–355. 2008.
282.
SimsGP, RoweDC, RietdijkST, HerbstR, CoyleAJ. HMGB1 and RAGE in inflammation and cancer. Annu Rev Immunol, 28:367–388. 2010.
283.
SinghA, Boldin-AdamskyS, ThimmulappaRK, RathSK, AshushH, CoulterJ, BlackfordA, GoodmanSN, BunzF, WatsonWH, GabrielsonE, FeinsteinE, BiswalS. RNAi-mediated silencing of nuclear factor erythroid-2-related factor 2 gene expression in non-small cell lung cancer inhibits tumor growth and increases efficacy of chemotherapy. Cancer Res, 68:7975–7984. 2008.
284.
SmolkovaK, Plecita-HlavataL, BellanceN, BenardG, RossignolR, JezekP. Waves of gene regulation suppress and then restore oxidative phosphorylation in cancer cells. Int J Biochem Cell Biol, 43:950–968.
285.
This reference has been deleted.
286.
SoiniY, KahlosK, NapankangasU, Kaarteenaho-WiikR, SailyM, KoistinenP, PaaakkoP, HolmgrenA, KinnulaVL. Widespread expression of thioredoxin and thioredoxin reductase in non-small cell lung carcinoma. Clin Cancer Res, 7:1750–1757. 2001.
SotgiaF, Martinez-OutschoornUE, LisantiMP. Mitochondrial oxidative stress drives tumor progression and metastasis: should we use antioxidants as a key component of cancer treatment and prevention?BMC Med, 9:62. 2011.
289.
St-PierreJ, BuckinghamJA, RoebuckSJ, BrandMD. Topology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem, 277:44784–44790. 2002.
SwietachP, HulikovaA, Vaughan-JonesRD, HarrisAL. New insights into the physiological role of carbonic anhydrase IX in tumour pH regulation. Oncogene, 29:6509–6521. 2010.
292.
SzatrowskiTP, NathanCF. Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res, 51:794–798. 1991.
293.
TaddeiML, ParriM, MelloT, CatalanoA, LevineAD, RaugeiG, RamponiG, ChiarugiP. Integrin-mediated cell adhesion and spreading engage different sources of reactive oxygen species. Antioxid Redox Signal, 9:469–481. 2007.
294.
TaguchiK, MotohashiH, YamamotoM. Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution. Genes Cells, 16:123–140. 2011.
295.
TangD, KangR, ZehHJ3rd, LotzeMT. High-mobility group box 1 and cancer. Biochim Biophys Acta, 1799:131–140. 2010.
296.
TangD, KangR, ZehHJ3rd, LotzeMT. High-mobility group box 1, oxidative stress, and disease. Antioxid Redox Signal, 14:1315–1335. 2011.
297.
TeohML, FitzgeraldMP, OberleyLW, DomannFE. Overexpression of extracellular superoxide dismutase attenuates heparanase expression and inhibits breast carcinoma cell growth and invasion. Cancer Res, 69:6355–6363. 2009.
298.
TeohML, SunW, SmithBJ, OberleyLW, CullenJJ. Modulation of reactive oxygen species in pancreatic cancer. Clin Cancer Res, 13:7441–7450. 2007.
299.
ThapaD, GhoshR. Antioxidants for prostate cancer chemoprevention: challenges and opportunities. Biochem Pharmacol, 83:1319–1330. 2012.
300.
ThomlinsonRH, GrayLH. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer, 9:539–549. 1955.
301.
TlstyTD, CoussensLM. Tumor stroma and regulation of cancer development. Annu Rev Pathol, 1:119–150. 2006.
302.
ToppoS, FloheL, UrsiniF, VaninS, MaiorinoM. Catalytic mechanisms and specificities of glutathione peroxidases: variations of a basic scheme. Biochim Biophys Acta, 1790:1486–1500. 2009.
303.
ToyokuniS, OkamotoK, YodoiJ, HiaiH. Persistent oxidative stress in cancer. FEBS Lett, 358:1–3. 1995.
304.
TrachoothamD, AlexandreJ, HuangP. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?Nat Rev Drug Discov, 8:579–591. 2009.
305.
TrimmerC, SotgiaF, Whitaker-MenezesD, BallietRM, EatonG, Martinez-OutschoornUE, PavlidesS, HowellA, IozzoRV, PestellRG, SchererPE, CapozzaF, LisantiMP. Caveolin-1 and mitochondrial SOD2 (MnSOD) function as tumor suppressors in the stromal microenvironment: a new genetically tractable model for human cancer associated fibroblasts. Cancer Biol Ther, 11:383–394. 2011.
306.
TuBP, WeissmanJS. Oxidative protein folding in eukaryotes: mechanisms and consequences. J Cell Biol, 164:341–346. 2004.
307.
TuzgenS, HanimogluH, TanriverdiT, KaciraT, SanusGZ, AtukerenP, DashtiR, GumustasK, CanbazB, KaynarMY. Relationship between DNA damage and total antioxidant capacity in patients with glioblastoma multiforme. Clin Oncol (R Coll Radiol), 19:177–181. 2007.
308.
UetaE, YonedaK, KimuraT, TatemotoY, DoiS, YamamotoT, OsakiT. Mn-SOD antisense upregulates in vivo apoptosis of squamous cell carcinoma cells by anticancer drugs and gamma-rays regulating expression of the BCL-2 family proteins, COX-2 and p21. Int J Cancer, 94:545–550. 2001.
309.
UngerstedtJS, SowaY, XuWS, ShaoY, DokmanovicM, PerezG, NgoL, HolmgrenA, JiangX, MarksPA. Role of thioredoxin in the response of normal and transformed cells to histone deacetylase inhibitors. Proc Natl Acad Sci U S A, 102:673–678. 2005.
310.
Ushio-FukaiM. Redox signaling in angiogenesis: role of NADPH oxidase. Cardiovasc Res, 71:226–235. 2006.
311.
Ushio-FukaiM, NakamuraY. Reactive oxygen species and angiogenesis: NADPH oxidase as target for cancer therapy. Cancer Lett, 266:37–52. 2008.
312.
Ushio-FukaiM, UraoN. Novel role of NADPH oxidase in angiogenesis and stem/progenitor cell function. Antioxid Redox Signal, 11:2517–2533. 2009.
313.
ValkoM, LeibfritzD, MoncolJ, CroninMT, MazurM, TelserJ. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol, 39:44–84. 2007.
314.
VaupelP. Hypoxia and aggressive tumor phenotype: implications for therapy and prognosis. Oncologist, 13,Suppl 3:21–26. 2008.
315.
VenkataramanS, AlimovaI, FanR, HarrisP, ForemanN, VibhakarR. MicroRNA 128a increases intracellular ROS level by targeting Bmi-1 and inhibits medulloblastoma cancer cell growth by promoting senescence. PLoS One, 5:e10748. 2010.
316.
VerschoorML, WilsonLA, SinghG. Mechanisms associated with mitochondrial-generated reactive oxygen species in cancer. Can J Physiol Pharmacol, 88:204–219. 2010.
317.
Vivas-MejiaPE, OzpolatB, ChenX, Lopez-BeresteinG. Downregulation of the c-MYC target gene, peroxiredoxin III, contributes to arsenic trioxide-induced apoptosis in acute promyelocytic leukemia. Int J Cancer, 125:264–275. 2009.
WalshB, PearlA, SuchyS, TartaglioJ, ViscoK, PhelanSA. Overexpression of Prdx6 and resistance to peroxide-induced death in Hepa1-6 cells: Prdx suppression increases apoptosis. Redox Rep, 14:275–284. 2009.
320.
WangC, SongB, SongW, LiuJ, SunA, WuD, YuH, LianJ, ChenL, HanJ. Underexpressed microRNA-199b-5p targets hypoxia-inducible factor-1alpha in hepatocellular carcinoma and predicts prognosis of hepatocellular carcinoma patients. J Gastroenterol Hepatol, 26:1630–1637. 2011.
321.
WangJ, YiJ. Cancer cell killing via ROS: to increase or decrease, that is the question. Cancer Biol Ther, 7:1875–1884. 2008.
322.
WangT, TamaeD, LeBonT, ShivelyJE, YenY, LiJJ. The role of peroxiredoxin II in radiation-resistant MCF-7 breast cancer cells. Cancer Res, 65:10338–10346. 2005.
323.
WarburgO. On the origin of cancer cells. Science, 123:309–314. 1956.
WeinbergF, HamanakaR, WheatonWW, WeinbergS, JosephJ, LopezM, KalyanaramanB, MutluGM, BudingerGR, ChandelNS. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci U S A, 107:8788–8793. 2010.
327.
WeirB, ZhaoX, MeyersonM. Somatic alterations in the human cancer genome. Cancer Cell, 6:433–438. 2004.
328.
WengerRH, StiehlDP, CamenischG. Integration of oxygen signaling at the consensus HRE. Sci STKE, 2005:re12. 2005.
329.
WernerE, WerbZ. Integrins engage mitochondrial function for signal transduction by a mechanism dependent on Rho GTPases. J Cell Biol, 158:357–368. 2002.
330.
WeydertCJ, ZhangY, SunW, WaughTA, TeohML, AndringaKK, Aykin-BurnsN, SpitzDR, SmithBJ, OberleyLW. Increased oxidative stress created by adenoviral MnSOD or CuZnSOD plus BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) inhibits breast cancer cell growth. Free Radic Biol Med, 44:856–867. 2008.
XingF, SaidouJ, WatabeK. Cancer associated fibroblasts (CAFs) in tumor microenvironment. Front Biosci, 15:166–179. 2010.
336.
XiongJ, SunWJ, WangWF, LiaoZK, ZhouFX, KongHY, XuY, XieCH, ZhouYF. Novel, chimeric, cancer-specific, and radiation-inducible gene promoters for suicide gene therapy of cancer. Cancer, 118:536–548. 2012.
337.
XouriG, ChristianS. Origin and function of tumor stroma fibroblasts. Semin Cell Dev Biol, 21:40–46. 2010.
338.
XuHN, NiokaS, GlicksonJD, ChanceB, LiLZ. Quantitative mitochondrial redox imaging of breast cancer metastatic potential. J Biomed Opt, 15:036010. 2010.
339.
XuY, FangF, ZhangJ, JossonS, St. ClairWH, St. ClairDK. miR-17* suppresses tumorigenicity of prostate cancer by inhibiting mitochondrial antioxidant enzymes. PLoS One, 5:e14356. 2010.
340.
YamakuchiM, YagiS, ItoT, LowensteinCJ. MicroRNA-22 regulates hypoxia signaling in colon cancer cells. PLoS One, 6:e20291. 2011.
341.
YangY, TianY, YanC, JinX, TangJ, ShenX. Determinants of urinary 8-hydroxy-2′-deoxyguanosine in Chinese children with acute leukemia. Environ Toxicol, 24:446–452. 2009.
342.
YeXQ, LiQ, WangGH, SunFF, HuangGJ, BianXW, YuSC, QianGS. Mitochondrial and energy metabolism-related properties as novel indicators of lung cancer stem cells. Int J Cancer, 129:820–831. 2011.
343.
YehCC, HouMF, TsaiSM, LinSK, HsiaoJK, HuangJC, WangLH, WuSH, HouLA, MaH, TsaiLY. Superoxide anion radical, lipid peroxides and antioxidant status in the blood of patients with breast cancer. Clin Chim Acta, 361:104–111. 2005.
344.
YeungBH, WongKY, LinMC, WongCK, MashimaT, TsuruoT, WongAS. Chemosensitisation by manganese superoxide dismutase inhibition is caspase-9 dependent and involves extracellular signal-regulated kinase 1/2. Br J Cancer, 99:283–293. 2008.
345.
YooMH, XuXM, CarlsonBA, PattersonAD, GladyshevVN, HatfieldDL. Targeting thioredoxin reductase 1 reduction in cancer cells inhibits self-sufficient growth and DNA replication. PLoS One, 2:e1112. 2007.
ZangarRC, DavydovDR, VermaS. Mechanisms that regulate production of reactive oxygen species by cytochrome P450. Toxicol Appl Pharmacol, 199:316–331. 2004.
348.
ZhangB, WangY, LiuK, YangX, SongM, BaiY. Adenovirus-mediated transfer of siRNA against peroxiredoxin I enhances the radiosensitivity of human intestinal cancer. Biochem Pharmacol, 75:660–667. 2008.
349.
ZhangB, WangY, SuY. Peroxiredoxins, a novel target in cancer radiotherapy. Cancer Lett, 286:154–160. 2009.
350.
ZhangDD. Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev, 38:769–789. 2006.
351.
ZhangL, WuYD, LiP, TuJ, NiuYL, XuCM, ZhangST. Effects of cyclooxygenase-2 on human esophageal squamous cell carcinoma. World J Gastroenterol, 17:4572–4580. 2011.
352.
ZhangX, ZhengY, FriedLE, DuY, MontanoSJ, SohnA, LefkoveB, HolmgrenL, ArbiserJL, HolmgrenA, LuJ. Disruption of the mitochondrial thioredoxin system as a cell death mechanism of cationic triphenylmethanes. Free Radic Biol Med, 50:811–820. 2011.
353.
ZhangY, DuY, LeW, WangK, KiefferN, ZhangJ. Redox control of the survival of healthy and diseased cells. Antioxid Redox Signal, 15:2867–2908. 2011.
354.
This reference has been deleted.
355.
ZhangY, GuJ, ZhaoL, HeL, QianW, WangJ, WangY, QianQ, QianC, WuJ, LiuXY. Complete elimination of colorectal tumor xenograft by combined manganese superoxide dismutase with tumor necrosis factor-related apoptosis-inducing ligand gene virotherapy. Cancer Res, 66:4291–4298. 2006.