Inflammatory Angiogenesis and the Tumor Microenvironment as Targets for Cancer Therapy and Prevention

  • Antonino Bruno
  • Arianna Pagani
  • Elena Magnani
  • Teresa Rossi
  • Douglas M. Noonan
  • Anna Rita Cantelmo
  • Adriana Albini
Conference paper
Part of the Cancer Treatment and Research book series (CTAR, volume 159)


In addition to aberrant transformed cells, tumors are tissues that contain host components, including stromal cells, vascular cells (ECs) and their precursors, and immune cells. All these constituents interact with each other at the cellular and molecular levels, resulting in the production of an intricate and heterogeneous complex of cells and matrix defined as the tumor microenvironment. Several pathways involved in these interactions have been investigated both in pathological and physiological scenarios, and diverse molecules are currently targets of chemotherapeutic and preventive drugs. Many phytochemicals and their derivatives show the ability to inhibit tumor progression, angiogenesis, and metastasis, exerting effects on the tumor microenvironment. In this review, we will outline the principal players and mechanisms involved in the tumor microenvironment network and we will discuss some interesting compounds aimed at interrupting these interactions and blocking tumor insurgence and progression. The considerations provided will be crucial for the design of new preventive approaches to the reduction in cancer risk that need to be applied to large populations composed of apparently healthy individuals.


Tumour microenvironment Angiogenesis Inflammation Anti-angiogenic therapy Chemoprevention 



Insulin-like growth factor 1-receptor


Inhibitor kinase B


Inhibitor kinase kinase










Interleukin-1 receptor-alpha


Interleukin-1 beta


Activating Janus kinase


Mitogen-activated phospho kinase


Murine double minute 2


Mouse double minute 4


myeloid-derived suppressor cell


Matrix metallo protease-1


Matrix metallo protease-2


Matrix metallo protease-7


Matrix metallo protease-9


Mammalian target of rapamycin


N1-polarized neutrophils


N2-polarized neutrophils




Nuclear factor-kappa B


Non-steroidal anti-inflammatory drugs


Non-small cell lung cancer


Platelet-derived growth factor


Platelet-derived growth factor receptor-beta


Platelet-derived growth factor receptor


Phosphoinositide 3-kinase


p53-inducible gene 3


Placental growth factor


Polymorphonuclear neutrophils


Root abundant factor


Retinoid acid receptors


Retinoid acid receptor-beta


Renal cell carcinoma


NFkB subunit-A


v-rel reticuloendotheliosis viral oncogene homolog B


Rearranged during transfection


Rel homology domain


Reactivation of p53 and induction of tumor cell apoptosis


Reactive oxygen species


Receptor tyrosine kinase


Signal transducer and activator of transcription


Signal transducer and activator of transcription 3


Simian virus 40


Tumor-associated macrophage


Tie2-expressing macrophage


Transforming growth factor-alpha


Transforming growth factor-beta


T helper


T helper type-2 polarization


Tyrosine kinase inhibitors


Tumor necrosis factor


Tumor necrosis factor-alpha


TP53 target 1




Vascular endothelial growth factor A isoform


Vascular endothelial growth factor


Vascular endothelial growth factor receptor


Vascular smooth muscle cell


Wound-induced protein 1



These studies were supported by grants from the AIRC (Associazione Italiana per la Ricerca sul Cancro), the Ministero della Salute, the and ISS (Istituto Superiore della Sanità). AB is a FIRC (Fondazione Italiana per la Ricerca sul Cancro) fellow. AP is the recipient of the “Caterina Forni” AIRC fellowship. We thank Dr Paola Corradino (Multimedica IRCCS) for data management.


  1. 1.
    Aaltonen KJ, Virkki LM, Malmivaara A, Konttinen YT, Nordstrom DC, Blom M (2012) Systematic review and meta-analysis of the efficacy and safety of existing TNF blocking agents in treatment of rheumatoid arthritis. PLoS One 7:e30275PubMedCrossRefGoogle Scholar
  2. 2.
    Aggarwal BB, Vijayalekshmi RV, Sung B (2009) Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin Cancer Res 15:425–430PubMedCrossRefGoogle Scholar
  3. 3.
    Aitio ML (2006) N-acetylcysteine—passe-partout or much ado about nothing? Br J Clin Pharmacol 61:5–15PubMedCrossRefGoogle Scholar
  4. 4.
    Akino T, Hida K, Hida Y, Tsuchiya K, Freedman D, Muraki C, Ohga N, Matsuda K, Akiyama K, Harabayashi T, Shinohara N, Nonomura K, Klagsbrun M, Shindoh M (2009) Cytogenetic abnormalities of tumor-associated endothelial cells in human malignant tumors. Am J Pathol 175:2657–2667PubMedCrossRefGoogle Scholar
  5. 5.
    Akira S, Nishio Y, Inoue M, Wang XJ, Wei S, Matsusaka T, Yoshida K, Sudo T, Naruto M, Kishimoto T (1994) Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell 77:63–71PubMedCrossRefGoogle Scholar
  6. 6.
    Albini A, Morini M, D’Agostini F, Ferrari N, Campelli F, Arena G, Noonan DM, Pesce C, De Flora S (2001) Inhibition of angiogenesis-driven Kaposi’s sarcoma tumor growth in nude mice by oral N-acetylcysteine. Cancer Res 61:8171–8178PubMedGoogle Scholar
  7. 7.
    Albini A, Noonan DM (2012) Angiopoietin2 and tie2: tied to lymphangiogenesis and lung metastasis. New perspectives in antimetastatic antiangiogenic therapy. J Natl Cancer Inst 104:429–431PubMedCrossRefGoogle Scholar
  8. 8.
    Albini A, Sporn MB (2007) The tumour microenvironment as a target for chemoprevention. Nat Rev Cancer 7:139–147PubMedCrossRefGoogle Scholar
  9. 9.
    Albini A, Tosetti F, Benelli R, Noonan DM (2005) Tumor inflammatory angiogenesis and its chemoprevention. Cancer Res 65:10637–10641PubMedCrossRefGoogle Scholar
  10. 10.
    Albini A, Tosetti F, Li VW, Noonan DM, Li WW (2012) Cancer prevention by targeting angiogenesis. Nat Rev Clin Oncol 9:498–509PubMedCrossRefGoogle Scholar
  11. 11.
    Aradhya S, Nelson DL (2001) NF-kappaB signaling and human disease. Curr Opin Genet Dev 11:300–306PubMedCrossRefGoogle Scholar
  12. 12.
    Aravindaram K, Yang NS (2010) Anti-inflammatory plant natural products for cancer therapy. Planta Med 76:1103–1117PubMedCrossRefGoogle Scholar
  13. 13.
    Baldwin AS Jr (1996) The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol 14:649–683PubMedCrossRefGoogle Scholar
  14. 14.
    Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545PubMedCrossRefGoogle Scholar
  15. 15.
    Bello IO, Vered M, Dayan D, Dobriyan A, Yahalom R, Alanen K, Nieminen P, Kantola S, Laara E, Salo T (2011) Cancer-associated fibroblasts, a parameter of the tumor microenvironment, overcomes carcinoma-associated parameters in the prognosis of patients with mobile tongue cancer. Oral Oncol 47:33–38PubMedCrossRefGoogle Scholar
  16. 16.
    Benelli R, Morini M, Carrozzino F, Ferrari N, Minghelli S, Santi L, Cassatella M, Noonan DM, Albini A (2002) Neutrophils as a key cellular target for angiostatin: implications for regulation of angiogenesis and inflammation. FASEB J 16:267–269PubMedGoogle Scholar
  17. 17.
    Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D (2003) Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 111:1287–1295PubMedGoogle Scholar
  18. 18.
    Bian X, McAllister-Lucas LM, Shao F, Schumacher KR, Feng Z, Porter AG, Castle VP, Opipari AW Jr (2001) NF-kappa B activation mediates doxorubicin-induced cell death in N-type neuroblastoma cells. J Biol Chem 276:48921–48929PubMedCrossRefGoogle Scholar
  19. 19.
    Bu P, Wan YJ (2007) Fenretinide-induced apoptosis of Huh-7 hepatocellular carcinoma is retinoic acid receptor beta dependent. BMC Cancer 7:236PubMedCrossRefGoogle Scholar
  20. 20.
    Campbell MJ, Tonlaar NY, Garwood ER, Huo D, Moore DH, Khramtsov AI, Au A, Baehner F, Chen Y, Malaka DO, Lin A, Adeyanju OO, Li S, Gong C, McGrath M, Olopade OI, Esserman LJ (2011) Proliferating macrophages associated with high grade, hormone receptor negative breast cancer and poor clinical outcome. Breast Cancer Res Treat 128:703–711PubMedCrossRefGoogle Scholar
  21. 21.
    Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9:653–660PubMedCrossRefGoogle Scholar
  22. 22.
    Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407:249–257PubMedCrossRefGoogle Scholar
  23. 23.
    Chan KS, Sano S, Kiguchi K, Anders J, Komazawa N, Takeda J, DiGiovanni J (2004) Disruption of Stat3 reveals a critical role in both the initiation and the promotion stages of epithelial carcinogenesis. J Clin Invest 114:720–728PubMedGoogle Scholar
  24. 24.
    Chilov D, Kukk E, Taira S, Jeltsch M, Kaukonen J, Palotie A, Joukov V, Alitalo K (1997) Genomic organization of human and mouse genes for vascular endothelial growth factor C. J Biol Chem 272:25176–25183PubMedCrossRefGoogle Scholar
  25. 25.
    Chow LQ, Eckhardt SG (2007) Sunitinib: from rational design to clinical efficacy. J Clin Oncol 25:884–896PubMedCrossRefGoogle Scholar
  26. 26.
    Chung AS, Lee J, Ferrara N (2010) Targeting the tumour vasculature: insights from physiological angiogenesis. Nat Rev Cancer 10:505–514PubMedCrossRefGoogle Scholar
  27. 27.
    Coffelt SB, Hughes R, Lewis CE (2009) Tumor-associated macrophages: effectors of angiogenesis and tumor progression. Biochim Biophys Acta 1796:11–18PubMedGoogle Scholar
  28. 28.
    Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A (2009) Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 30:1073–1081PubMedCrossRefGoogle Scholar
  29. 29.
    Cook KM, Figg WD (2010) Angiogenesis inhibitors: current strategies and future prospects. CA Cancer J Clin 60:222–243PubMedCrossRefGoogle Scholar
  30. 30.
    Courtois G, Smahi A (2006) NF-kappaB-related genetic diseases. Cell Death Differ 13:843–851PubMedCrossRefGoogle Scholar
  31. 31.
    Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867PubMedCrossRefGoogle Scholar
  32. 32.
    Crawford LV, Pim DC, Gurney EG, Goodfellow P, Taylor-Papadimitriou J (1981) Detection of a common feature in several human tumor cell lines–a 53,000-dalton protein. Proc Natl Acad Sci USA 78:41–45PubMedCrossRefGoogle Scholar
  33. 33.
    Cuperus R, Leen R, Tytgat GA, Caron HN, van Kuilenburg AB (2010) Fenretinide induces mitochondrial ROS and inhibits the mitochondrial respiratory chain in neuroblastoma. Cell Mol Life Sci 67:807–816PubMedCrossRefGoogle Scholar
  34. 34.
    Dalwadi H, Krysan K, Heuze-Vourc’h N, Dohadwala M, Elashoff D, Sharma S, Cacalano N, Lichtenstein A, Dubinett S (2005) Cyclooxygenase-2-dependent activation of signal transducer and activator of transcription 3 by interleukin-6 in non-small cell lung cancer. Clin Cancer Res 11:7674–7682PubMedCrossRefGoogle Scholar
  35. 35.
    Darnell JE Jr, Kerr IM, Stark GR (1994) Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264:1415–1421PubMedCrossRefGoogle Scholar
  36. 36.
    De Clercq E (2010) Recent advances on the use of the CXCR4 antagonist plerixafor (AMD3100, Mozobil) and potential of other CXCR4 antagonists as stem cell mobilizers. Pharmacol Ther 128:509–518PubMedCrossRefGoogle Scholar
  37. 37.
    De Flora S, Bennicelli C, Zanacchi P, Camoirano A, Morelli A, De Flora A (1984) In vitro effects of N-acetylcysteine on the mutagenicity of direct-acting compounds and procarcinogens. Carcinogenesis 5:505–510PubMedCrossRefGoogle Scholar
  38. 38.
    De Flora S, D’Agostini F, Izzotti A, Balansky R (1991) Prevention by N-acetylcysteine of benzo[a]pyrene clastogenicity and DNA adducts in rats. Mutat Res 250:87–93PubMedCrossRefGoogle Scholar
  39. 39.
    De Flora S, Izzotti A, D’Agostini F, Balansky RM (2001) Mechanisms of N-acetylcysteine in the prevention of DNA damage and cancer, with special reference to smoking-related end-points. Carcinogenesis 22:999–1013PubMedCrossRefGoogle Scholar
  40. 40.
    Decramer M, Rutten-van Molken M, Dekhuijzen PN, Troosters T, van Herwaarden C, Pellegrino R, van Schayck CP, Olivieri D, Del Donno M, De Backer W, Lankhorst I, Ardia A (2005) Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet 365:1552–1560PubMedCrossRefGoogle Scholar
  41. 41.
    Deo DD, Axelrad TW, Robert EG, Marcheselli V, Bazan NG, Hunt JD (2002) Phosphorylation of STAT-3 in response to basic fibroblast growth factor occurs through a mechanism involving platelet-activating factor, JAK-2, and Src in human umbilical vein endothelial cells. Evidence for a dual kinase mechanism. J Biol Chem 277:21237–21245PubMedCrossRefGoogle Scholar
  42. 42.
    Duignan IJ, Corcoran E, Pennello A, Plym MJ, Amatulli M, Claros N, Iacolina M, Youssoufian H, Witte L, Samakoglu S, Schwartz J, Surguladze D, Tonra JR (2011) Pleiotropic stromal effects of vascular endothelial growth factor receptor 2 antibody therapy in renal cell carcinoma models. Neoplasia 13:49–59PubMedGoogle Scholar
  43. 43.
    Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS (2009) Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15:232–239PubMedCrossRefGoogle Scholar
  44. 44.
    Egeblad M, Nakasone ES, Werb Z (2010) Tumors as organs: complex tissues that interface with the entire organism. Dev Cell 18:884–901PubMedCrossRefGoogle Scholar
  45. 45.
    Ferrari N, Morini M, Pfeffer U, Minghelli S, Noonan DM, Albini A (2003) Inhibition of Kaposi’s sarcoma in vivo by fenretinide. Clin Cancer Res 9:6020–6029PubMedGoogle Scholar
  46. 46.
    Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186PubMedCrossRefGoogle Scholar
  47. 47.
    Folkman J (2002) Role of angiogenesis in tumor growth and metastasis. Semin Oncol 29:15–18PubMedGoogle Scholar
  48. 48.
    Fridlender ZG, Albelda SM (2012) Tumor-associated neutrophils: friend or foe? CarcinogenesisGoogle Scholar
  49. 49.
    Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, Worthen GS, Albelda SM (2009) Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell 16:183–194PubMedCrossRefGoogle Scholar
  50. 50.
    Gabellini C, Del Bufalo D, Zupi G (2006) Involvement of RB gene family in tumor angiogenesis. Oncogene 25:5326–5332PubMedCrossRefGoogle Scholar
  51. 51.
    Garg AK, Aggarwal BB (2002) Reactive oxygen intermediates in TNF signaling. Mol Immunol 39:509–517PubMedCrossRefGoogle Scholar
  52. 52.
    Ghosh N, Chaki R, Mandal V, Mandal SC (2010) COX-2 as a target for cancer chemotherapy. Pharmacol Rep 62:233–244PubMedGoogle Scholar
  53. 53.
    Ghosh S, Karin M (2002) Missing pieces in the NF-kappaB puzzle. Cell 109(Suppl):S81–S96PubMedCrossRefGoogle Scholar
  54. 54.
    Goh PP, Sze DM, Roufogalis BD (2007) Molecular and cellular regulators of cancer angiogenesis. Curr Cancer Drug Targets 7:743–758PubMedCrossRefGoogle Scholar
  55. 55.
    Gouaze-Andersson V, Flowers M, Karimi R, Fabrias G, Delgado A, Casas J, Cabot MC (2011) Inhibition of acid ceramidase by a 2-substituted aminoethanol amide synergistically sensitizes prostate cancer cells to N-(4-hydroxyphenyl) retinamide. Prostate 71:1064–1073PubMedCrossRefGoogle Scholar
  56. 56.
    Green DR, Kroemer G (2009) Cytoplasmic functions of the tumour suppressor p53. Nature 458:1127–1130PubMedCrossRefGoogle Scholar
  57. 57.
    Greten FR, Karin M (2004) The IKK/NF-kappaB activation pathway-a target for prevention and treatment of cancer. Cancer Lett 206:193–199PubMedCrossRefGoogle Scholar
  58. 58.
    Gupta S, Yan H, Wong LH, Ralph S, Krolewski J, Schindler C (1996) The SH2 domains of Stat1 and Stat2 mediate multiple interactions in the transduction of IFN-alpha signals. EMBO J 15:1075–1084PubMedGoogle Scholar
  59. 59.
    Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353–364PubMedCrossRefGoogle Scholar
  60. 60.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674PubMedCrossRefGoogle Scholar
  61. 61.
    Harris CC (1993) p53: at the crossroads of molecular carcinogenesis and risk assessment. Science 262:1980–1981PubMedCrossRefGoogle Scholar
  62. 62.
    Harris CC, Hollstein M (1993) Clinical implications of the p53 tumor-suppressor gene. N Engl J Med 329:1318–1327PubMedCrossRefGoogle Scholar
  63. 63.
    Hermeking H (2007) p53 enters the microRNA world. Cancer Cell 12:414–418PubMedCrossRefGoogle Scholar
  64. 64.
    Holash J, Davis S, Papadopoulos N, Croll SD, Ho L, Russell M, Boland P, Leidich R, Hylton D, Burova E, Ioffe E, Huang T, Radziejewski C, Bailey K, Fandl JP, Daly T, Wiegand SJ, Yancopoulos GD, Rudge JS (2002) VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA 99:11393–11398PubMedCrossRefGoogle Scholar
  65. 65.
    Hou J, Schindler U, Henzel WJ, Ho TC, Brasseur M, McKnight SL (1994) An interleukin-4-induced transcription factor: IL-4 Stat. Science 265:1701–1706PubMedCrossRefGoogle Scholar
  66. 66.
    Hristov M, Erl W, Weber PC (2003) Endothelial progenitor cells: mobilization, differentiation, and homing. Arterioscler Thromb Vasc Biol 23:1185–1189PubMedCrossRefGoogle Scholar
  67. 67.
    Hsia CY, Cheng S, Owyang AM, Dowdy SF, Liou HC (2002) c-Rel regulation of the cell cycle in primary mouse B lymphocytes. Int Immunol 14:905–916PubMedCrossRefGoogle Scholar
  68. 68.
    Huang S, DeGuzman A, Bucana CD, Fidler IJ (2000) Nuclear factor-kappaB activity correlates with growth, angiogenesis, and metastasis of human melanoma cells in nude mice. Clin Cancer Res 6:2573–2581PubMedGoogle Scholar
  69. 69.
    Hudes GR (2009) Targeting mTOR in renal cell carcinoma. Cancer 115:2313–2320PubMedCrossRefGoogle Scholar
  70. 70.
    Issaeva N, Bozko P, Enge M, Protopopova M, Verhoef LG, Masucci M, Pramanik A, Selivanova G (2004) Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nat Med 10:1321–1328PubMedCrossRefGoogle Scholar
  71. 71.
    Jain RK (2002) Tumor angiogenesis and accessibility: role of vascular endothelial growth factor. Semin Oncol 29:3–9PubMedGoogle Scholar
  72. 72.
    Jiang L, Pan X, Chen Y, Wang K, Du Y, Zhang J (2011) Preferential involvement of both ROS and ceramide in fenretinide-induced apoptosis of HL60 rather than NB4 and U937 cells. Biochem Biophys Res Commun 405:314–318PubMedCrossRefGoogle Scholar
  73. 73.
    Kaipainen A, Kieran MW, Huang S, Butterfield C, Bielenberg D, Mostoslavsky G, Mulligan R, Folkman J, Panigrahy D (2007) PPARalpha deficiency in inflammatory cells suppresses tumor growth. PLoS One 2:e260PubMedCrossRefGoogle Scholar
  74. 74.
    Kalluri R (2009) EMT: when epithelial cells decide to become mesenchymal-like cells. J Clin Invest 119:1417–1419PubMedCrossRefGoogle Scholar
  75. 75.
    Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6:392–401PubMedCrossRefGoogle Scholar
  76. 76.
    Kamper P, Bendix K, Hamilton-Dutoit S, Honore B, Nyengaard JR, d’Amore F (2011) Tumor-infiltrating macrophages correlate with adverse prognosis and Epstein-Barr virus status in classical Hodgkin’s lymphoma. Haematologica 96:269–276PubMedCrossRefGoogle Scholar
  77. 77.
    Karin M, Lin A (2002) NF-kappaB at the crossroads of life and death. Nat Immunol 3:221–227PubMedCrossRefGoogle Scholar
  78. 78.
    Kasinski AL, Slack FJ (2010) Potential microRNA therapies targeting Ras, NFkappaB and p53 signaling. Curr Opin Mol Ther 12:147–157PubMedGoogle Scholar
  79. 79.
    Kerbel RS (2008) Tumor angiogenesis. N Engl J Med 358:2039–2049PubMedCrossRefGoogle Scholar
  80. 80.
    Kim S (1993) Liposomes as carriers of cancer chemotherapy. Current status and future prospects. Drugs 46:618–638PubMedCrossRefGoogle Scholar
  81. 81.
    Kong D, Park EJ, Stephen AG, Calvani M, Cardellina JH, Monks A, Fisher RJ, Shoemaker RH, Melillo G (2005) Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Cancer Res 65:9047–9055PubMedCrossRefGoogle Scholar
  82. 82.
    Ku GY, Haaland BA, de Lima Lopes G (2012) Cetuximab in the first-line treatment of K-ras wild-type metastatic colorectal cancer: the choice and schedule of fluoropyrimidine matters. Cancer Chemother Pharmacol 70:231–238PubMedCrossRefGoogle Scholar
  83. 83.
    Kubbutat MH, Jones SN, Vousden KH (1997) Regulation of p53 stability by Mdm2. Nature 387:299–303PubMedCrossRefGoogle Scholar
  84. 84.
    Kumar A, Takada Y, Boriek AM, Aggarwal BB (2004) Nuclear factor-kappaB: its role in health and disease. J Mol Med (Berl) 82:434–448CrossRefGoogle Scholar
  85. 85.
    Lane DP, Crawford LV (1979) T antigen is bound to a host protein in SV40-transformed cells. Nature 278:261–263PubMedCrossRefGoogle Scholar
  86. 86.
    Lee H, Herrmann A, Deng JH, Kujawski M, Niu G, Li Z, Forman S, Jove R, Pardoll DM, Yu H (2009) Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors. Cancer Cell 15:283–293PubMedCrossRefGoogle Scholar
  87. 87.
    Leen AM, Christin A, Khalil M, Weiss H, Gee AP, Brenner MK, Heslop HE, Rooney CM, Bollard CM (2008) Identification of hexon-specific CD4 and CD8 T-cell epitopes for vaccine and immunotherapy. J Virol 82:546–554PubMedCrossRefGoogle Scholar
  88. 88.
    Levine AJ (1989) The p53 tumor suppressor gene and gene product. Princess Takamatsu Symp 20:221–230PubMedGoogle Scholar
  89. 89.
    Lewis CE, Pollard JW (2006) Distinct role of macrophages in different tumor microenvironments. Cancer Res 66:605–612PubMedCrossRefGoogle Scholar
  90. 90.
    Linares LK, Hengstermann A, Ciechanover A, Muller S, Scheffner M (2003) HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53. Proc Natl Acad Sci USA 100:12009–12014PubMedCrossRefGoogle Scholar
  91. 91.
    Lu T, Sathe SS, Swiatkowski SM, Hampole CV, Stark GR (2004) Secretion of cytokines and growth factors as a general cause of constitutive NFkappaB activation in cancer. Oncogene 23:2138–2145PubMedCrossRefGoogle Scholar
  92. 92.
    Lu-Emerson C, Norden AD, Drappatz J, Quant EC, Beroukhim R, Ciampa AS, Doherty LM, Lafrankie DC, Ruland S, Wen PY (2011) Retrospective study of dasatinib for recurrent glioblastoma after bevacizumab failure. J Neurooncol 104:287–291Google Scholar
  93. 93.
    Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L, Chadburn A, Heissig B, Marks W, Witte L, Wu Y, Hicklin D, Zhu Z, Hackett NR, Crystal RG, Moore MA, Hajjar KA, Manova K, Benezra R, Rafii S (2001) Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 7:1194–1201PubMedCrossRefGoogle Scholar
  94. 94.
    Ma WW, Adjei AA (2009) Novel agents on the horizon for cancer therapy. CA Cancer J Clin 59:111–137PubMedCrossRefGoogle Scholar
  95. 95.
    Mabjeesh NJ, Post DE, Willard MT, Kaur B, Van Meir EG, Simons JW, Zhong H (2002) Geldanamycin induces degradation of hypoxia-inducible factor 1alpha protein via the proteosome pathway in prostate cancer cells. Cancer Res 62:2478–2482PubMedGoogle Scholar
  96. 96.
    Mantovani A, Cassatella MA, Costantini C, Jaillon S (2011) Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 11:519–531PubMedCrossRefGoogle Scholar
  97. 97.
    Mercer WE, Avignolo C, Baserga R (1984) Role of the p53 protein in cell proliferation as studied by microinjection of monoclonal antibodies. Mol Cell Biol 4:276–281PubMedGoogle Scholar
  98. 98.
    Messner MC, Cabot MC (2011) Cytotoxic responses to N-(4-hydroxyphenyl) retinamide in human pancreatic cancer cells. Cancer Chemother Pharmacol 68:477–487PubMedCrossRefGoogle Scholar
  99. 99.
    Miller RB, Reece G, Kroll SS, Chang D, Langstein H, Ziogas A, Robb G, Evans GR (2007) Microvascular breast reconstruction in the diabetic patient. Plast Reconstr Surg 119: 38–45; discussion 46–48Google Scholar
  100. 100.
    Milner BJ, Allan LA, Eccles DM, Kitchener HC, Leonard RC, Kelly KF, Parkin DE, Haites NE (1993) p53 mutation is a common genetic event in ovarian carcinoma. Cancer Res 53:2128–2132PubMedGoogle Scholar
  101. 101.
    Moll UM, Schramm LM (1998) p53–an acrobat in tumorigenesis. Crit Rev Oral Biol Med 9:23–37PubMedCrossRefGoogle Scholar
  102. 102.
    Momand J, Zambetti GP, Olson DC, George D, Levine AJ (1992) The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69:1237–1245PubMedCrossRefGoogle Scholar
  103. 103.
    Monti E, Gariboldi MB (2011) HIF-1 as a target for cancer chemotherapy, chemosensitization and chemoprevention. Curr Mol Pharmacol 4:62–77Google Scholar
  104. 104.
    Murdoch C, Muthana M, Coffelt SB, Lewis CE (2008) The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8:618–631PubMedCrossRefGoogle Scholar
  105. 105.
    Naugler WE, Karin M (2008) The wolf in sheep’s clothing: the role of interleukin-6 in immunity, inflammation and cancer. Trends Mol Med 14:109–119PubMedCrossRefGoogle Scholar
  106. 106.
    Noonan DM, De Lerma Barbaro A, Vannini N, Mortara L, Albini A (2008) Inflammation, inflammatory cells and angiogenesis: decisions and indecisions. Cancer Metastasis Rev 27:31–40PubMedCrossRefGoogle Scholar
  107. 107.
    Nozawa H, Chiu C, Hanahan D (2006) Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Natl Acad Sci USA 103:12493–12498PubMedCrossRefGoogle Scholar
  108. 108.
    Oikawa S, Yamada K, Yamashita N, Tada-Oikawa S, Kawanishi S (1999) N-acetylcysteine, a cancer chemopreventive agent, causes oxidative damage to cellular and isolated DNA. Carcinogenesis 20:1485–1490PubMedCrossRefGoogle Scholar
  109. 109.
    Olivier M, Hollstein M, Hainaut P (2010) TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol 2: a001008Google Scholar
  110. 110.
    Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL, Weinberg RA (2005) Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121:335–348PubMedCrossRefGoogle Scholar
  111. 111.
    Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, Inoue M, Bergers G, Hanahan D, Casanovas O (2009) Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15:220–231PubMedCrossRefGoogle Scholar
  112. 112.
    Perkins ND (2004) Regulation of NF-kappaB by atypical activators and tumour suppressors. Biochem Soc Trans 32:936–939PubMedCrossRefGoogle Scholar
  113. 113.
    Pezzolo A, Parodi F, Corrias MV, Cinti R, Gambini C, Pistoia V (2007) Tumor origin of endothelial cells in human neuroblastoma. J Clin Oncol 25:376–383PubMedCrossRefGoogle Scholar
  114. 114.
    Philip M, Rowley DA, Schreiber H (2004) Inflammation as a tumor promoter in cancer induction. Semin Cancer Biol 14:433–439PubMedCrossRefGoogle Scholar
  115. 115.
    Pienta KJ, Nguyen NM, Lehr JE (1993) Treatment of prostate cancer in the rat with the synthetic retinoid fenretinide. Cancer Res 53:224–226PubMedGoogle Scholar
  116. 116.
    Pietras K, Ostman A (2010) Hallmarks of cancer: interactions with the tumor stroma. Exp Cell Res 316:1324–1331PubMedCrossRefGoogle Scholar
  117. 117.
    Pietras K, Pahler J, Bergers G, Hanahan D (2008) Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting. PLoS Med 5:e19PubMedCrossRefGoogle Scholar
  118. 118.
    Pollicita M, Muscoli C, Sgura A, Biasin A, Granato T, Masuelli L, Mollace V, Tanzarella C, Del Duca C, Rodino P, Perno CF, Aquaro S (2009) Apoptosis and telomeres shortening related to HIV-1 induced oxidative stress in an astrocytoma cell line. BMC Neurosci 10:51PubMedCrossRefGoogle Scholar
  119. 119.
    Poppe JK (1964) Clinical Experiences with Acetylcysteine as a Mucolytic Agent. Dis Chest 46:66–69PubMedCrossRefGoogle Scholar
  120. 120.
    Pore N, Gupta AK, Cerniglia GJ, Jiang Z, Bernhard EJ, Evans SM, Koch CJ, Hahn SM, Maity A (2006) Nelfinavir down-regulates hypoxia-inducible factor 1alpha and VEGF expression and increases tumor oxygenation: implications for radiotherapy. Cancer Res 66:9252–9259PubMedCrossRefGoogle Scholar
  121. 121.
    Pucci F, Venneri MA, Biziato D, Nonis A, Moi D, Sica A, Di Serio C, Naldini L, De Palma M (2009) A distinguishing gene signature shared by tumor-infiltrating Tie2-expressing monocytes, blood “resident” monocytes, and embryonic macrophages suggests common functions and developmental relationships. Blood 114:901–914PubMedCrossRefGoogle Scholar
  122. 122.
    Qian H, Wang T, Naumovski L, Lopez CD, Brachmann RK (2002) Groups of p53 target genes involved in specific p53 downstream effects cluster into different classes of DNA binding sites. Oncogene 21:7901–7911PubMedCrossRefGoogle Scholar
  123. 123.
    Rak J, Klement G (2000) Impact of oncogenes and tumor suppressor genes on deregulation of hemostasis and angiogenesis in cancer. Cancer Metastasis Rev 19:93–96PubMedCrossRefGoogle Scholar
  124. 124.
    Rak J, Yu JL, Kerbel RS, Coomber BL (2002) What do oncogenic mutations have to do with angiogenesis/vascular dependence of tumors? Cancer Res 62:1931–1934PubMedGoogle Scholar
  125. 125.
    Rasanen K, Vaheri A (2010) Activation of fibroblasts in cancer stroma. Exp Cell Res 316:2713–2722PubMedCrossRefGoogle Scholar
  126. 126.
    Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, Zeng Q, Dillehay LE, Madan A, Semenza GL, Bedi A (2000) Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev 14:34–44PubMedGoogle Scholar
  127. 127.
    Rayet B, Gelinas C (1999) Aberrant rel/nfkb genes and activity in human cancer. Oncogene 18:6938–6947PubMedCrossRefGoogle Scholar
  128. 128.
    Raza A, Franklin MJ, Dudek AZ (2010) Pericytes and vessel maturation during tumor angiogenesis and metastasis. Am J Hematol 85:593–598PubMedCrossRefGoogle Scholar
  129. 129.
    Sabichi AL, Lerner SP, Grossman HB, Lippman SM (1998) Retinoids in the chemoprevention of bladder cancer. Curr Opin Oncol 10:479–484PubMedCrossRefGoogle Scholar
  130. 130.
    Sakamoto J, Kodaira S, Hamada C, Ito K, Maehara Y, Takagi H, Sugimachi K, Nakazato H, Ohashi Y (2001) An individual patient data meta-analysis of long supported adjuvant chemotherapy with oral carmofur in patients with curatively resected colorectal cancer. Oncol Rep 8:697–703PubMedGoogle Scholar
  131. 131.
    Scapini P, Morini M, Tecchio C, Minghelli S, Di Carlo E, Tanghetti E, Albini A, Lowell C, Berton G, Noonan DM, Cassatella MA (2004) CXCL1/macrophage inflammatory protein-2-induced angiogenesis in vivo is mediated by neutrophil-derived vascular endothelial growth factor-A. J Immunol 172:5034–5040PubMedGoogle Scholar
  132. 132.
    Secchiero P, Corallini F, Gonelli A, Dell’Eva R, Vitale M, Capitani S, Albini A, Zauli G (2007) Antiangiogenic activity of the MDM2 antagonist nutlin-3. Circ Res 100:61–69PubMedCrossRefGoogle Scholar
  133. 133.
    Semenza GL (2010) Vascular responses to hypoxia and ischemia. Arterioscler Thromb Vasc Biol 30:648–52Google Scholar
  134. 134.
    Sen R, Baltimore D (1986) Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. Cell 47:921–928PubMedCrossRefGoogle Scholar
  135. 135.
    Senftleben U, Cao Y, Xiao G, Greten FR, Krahn G, Bonizzi G, Chen Y, Hu Y, Fong A, Sun SC, Karin M (2001) Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. Science 293:1495–1499PubMedCrossRefGoogle Scholar
  136. 136.
    Sharpless NE, DePinho RA (2002) p53: good cop/bad cop. Cell 110:9–12PubMedCrossRefGoogle Scholar
  137. 137.
    Shuai K, Horvath CM, Huang LH, Qureshi SA, Cowburn D, Darnell JE Jr (1994) Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions. Cell 76:821–828PubMedCrossRefGoogle Scholar
  138. 138.
    Sogno I, Vene R, Ferrari N, De Censi A, Imperatori A, Noonan DM, Tosetti F, Albini A (2010) Angioprevention with fenretinide: targeting angiogenesis in prevention and therapeutic strategies. Crit Rev Oncol Hematol 75:2–14PubMedCrossRefGoogle Scholar
  139. 139.
    Sogno I, Vene R, Sapienza C, Ferrari N, Tosetti F, Albini A (2009) Anti-angiogenic properties of chemopreventive drugs: fenretinide as a prototype. Recent Results Cancer Res 181:71–76PubMedCrossRefGoogle Scholar
  140. 140.
    Sohur US, Dixit MN, Chen CL, Byrom MW, Kerr LA (1999) Rel/NF-kappaB represses bcl-2 transcription in pro-B lymphocytes. Gene Expr 8:219–229PubMedGoogle Scholar
  141. 141.
    Solinas G, Germano G, Mantovani A, Allavena P (2009) Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol 86:1065–1073PubMedCrossRefGoogle Scholar
  142. 142.
    Sparmann A, Bar-Sagi D (2004) Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 6:447–458PubMedCrossRefGoogle Scholar
  143. 143.
    Staab A, Loeffler J, Said HM, Diehlmann D, Katzer A, Beyer M, Fleischer M, Schwab F, Baier K, Einsele H, Flentje M, Vordermark D (2007) Effects of HIF-1 inhibition by chetomin on hypoxia-related transcription and radiosensitivity in HT 1080 human fibrosarcoma cells. BMC Cancer 7:213PubMedCrossRefGoogle Scholar
  144. 144.
    Steeghs N, Nortier JW, Gelderblom H (2007) Small molecule tyrosine kinase inhibitors in the treatment of solid tumors: an update of recent developments. Ann Surg Oncol 14:942–953PubMedCrossRefGoogle Scholar
  145. 145.
    Stein RC (2001) Prospects for phosphoinositide 3-kinase inhibition as a cancer treatment. Endocr Relat Cancer 8:237–248PubMedCrossRefGoogle Scholar
  146. 146.
    Streubel B, Chott A, Huber D, Exner M, Jager U, Wagner O, Schwarzinger I (2004) Lymphoma-specific genetic aberrations in microvascular endothelial cells in B-cell lymphomas. N Engl J Med 351:250–259PubMedCrossRefGoogle Scholar
  147. 147.
    Sun Y, Chen J, Rigas B (2009) Chemopreventive agents induce oxidative stress in cancer cells leading to COX-2 overexpression and COX-2-independent cell death. Carcinogenesis 30:93–100PubMedCrossRefGoogle Scholar
  148. 148.
    Takeda K, Kamanaka M, Tanaka T, Kishimoto T, Akira S (1996) Impaired IL-13-mediated functions of macrophages in STAT6-deficient mice. J Immunol 157:3220–3222PubMedGoogle Scholar
  149. 149.
    Tazzyman S, Lewis CE, Murdoch C (2009) Neutrophils: key mediators of tumour angiogenesis. Int J Exp Pathol 90:222–231PubMedCrossRefGoogle Scholar
  150. 150.
    Teodoro JG, Evans SK, Green MR (2007) Inhibition of tumor angiogenesis by p53: a new role for the guardian of the genome. J Mol Med (Berl) 85:1175–1186CrossRefGoogle Scholar
  151. 151.
    Teodoro JG, Parker AE, Zhu X, Green MR (2006) p53-mediated inhibition of angiogenesis through up-regulation of a collagen prolyl hydroxylase. Science 313:968–971PubMedCrossRefGoogle Scholar
  152. 152.
    Tergaonkar V (2009) p53 and NFkappaB: fresh breath in the cross talk. Cell Res 19:1313–1315PubMedCrossRefGoogle Scholar
  153. 153.
    Tosetti F, Ferrari N, De Flora S, Albini A (2002) Angioprevention’: angiogenesis is a common and key target for cancer chemopreventive agents. Faseb J 16:2–14PubMedCrossRefGoogle Scholar
  154. 154.
    Tosetti F, Vene R, Arena G, Morini M, Minghelli S, Noonan DM, Albini A (2003) N-(4-hydroxyphenyl) retinamide inhibits retinoblastoma growth through reactive oxygen species-mediated cell death. Mol Pharmacol 63:565–573PubMedCrossRefGoogle Scholar
  155. 155.
    Ulanet DB, Hanahan D (2010) Loss of p19 (Arf) facilitates the angiogenic switch and tumor initiation in a multi-stage cancer model via p53-dependent and independent mechanisms. PLoS One 5:e12454Google Scholar
  156. 156.
    van Zandwijk N, Dalesio O, Pastorino U, de Vries N, van Tinteren H (2000) EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. For the European organization for research and treatment of cancer head and neck and lung cancer cooperative groups. J Natl Cancer Inst 92:977–986PubMedCrossRefGoogle Scholar
  157. 157.
    Vassilev LT (2004) Small-molecule antagonists of p53-MDM2 binding: research tools and potential therapeutics. Cell Cycle 3:419–421PubMedCrossRefGoogle Scholar
  158. 158.
    Veltman JD, Lambers ME, van Nimwegen M, Hendriks RW, Hoogsteden HC, Hegmans JP, Aerts JG (2010) Zoledronic acid impairs myeloid differentiation to tumour-associated macrophages in mesothelioma. Br J Cancer 103:629–641PubMedCrossRefGoogle Scholar
  159. 159.
    Vene R, Arena G, Poggi A, D’Arrigo C, Mormino M, Noonan DM, Albini A, Tosetti F (2007) Novel cell death pathways induced by N-(4-hydroxyphenyl) retinamide: therapeutic implications. Mol Cancer Ther 6:286–298PubMedCrossRefGoogle Scholar
  160. 160.
    Venugopal D, Zahid M, Mailander PC, Meza JL, Rogan EG, Cavalieri EL, Chakravarti D (2008) Reduction of estrogen-induced transformation of mouse mammary epithelial cells by N-acetylcysteine. J Steroid Biochem Mol Biol 109:22–30PubMedCrossRefGoogle Scholar
  161. 161.
    Vousden KH, Lu X (2002) Live or let die: the cell’s response to p53. Nat Rev Cancer 2:594–604PubMedCrossRefGoogle Scholar
  162. 162.
    Vousden KH, Ryan KM (2009) p53 and metabolism. Nat Rev Cancer 9:691–700PubMedCrossRefGoogle Scholar
  163. 163.
    Walkley CR, Olsen GH, Dworkin S, Fabb SA, Swann J, McArthur GA, Westmoreland SV, Chambon P, Scadden DT, Purton LE (2007) A microenvironment-induced myeloproliferative syndrome caused by retinoic acid receptor gamma deficiency. Cell 129:1097–1110PubMedCrossRefGoogle Scholar
  164. 164.
    Walkley CR, Shea JM, Sims NA, Purton LE, Orkin SH (2007) Rb regulates interactions between hematopoietic stem cells and their bone marrow microenvironment. Cell 129:1081–1095PubMedCrossRefGoogle Scholar
  165. 165.
    Wang L, Zheng GG, Ma CH, Lin YM, Zhang HY, Ma YY, Chong JH, Wu KF (2008) A special linker between macrophage and hematopoietic malignant cells: membrane form of macrophage colony-stimulating factor. Cancer Res 68:5639–5647PubMedCrossRefGoogle Scholar
  166. 166.
    Welte T, Zhang SS, Wang T, Zhang Z, Hesslein DG, Yin Z, Kano A, Iwamoto Y, Li E, Craft JE, Bothwell AL, Fikrig E, Koni PA, Flavell RA, Fu XY (2003) STAT3 deletion during hematopoiesis causes Crohn’s disease-like pathogenesis and lethality: a critical role of STAT3 in innate immunity. Proc Natl Acad Sci USA 100:1879–1884PubMedCrossRefGoogle Scholar
  167. 167.
    Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M (2008) Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther 7:3129–3140PubMedCrossRefGoogle Scholar
  168. 168.
    Wisniewski T, Bayne E, Flanagan J, Shao Q, Wnek R, Matheravidathu S, Fischer P, Forrest MJ, Peterson L, Song X, Yang L, Demartino JA, Struthers M (2010) Assessment of chemokine receptor function on monocytes in whole blood: In vitro and ex vivo evaluations of a CCR2 antagonist. J Immunol Methods 352:101–110PubMedCrossRefGoogle Scholar
  169. 169.
    Wu X, Bayle JH, Olson D, Levine AJ (1993) The p53-mdm-2 autoregulatory feedback loop. Genes Dev 7:1126–1132PubMedCrossRefGoogle Scholar
  170. 170.
    Xian X, Hakansson J, Stahlberg A, Lindblom P, Betsholtz C, Gerhardt H, Semb H (2006) Pericytes limit tumor cell metastasis. J Clin Invest 116:642–651PubMedCrossRefGoogle Scholar
  171. 171.
    Xiao ZL, Sun GY, Xia QM, Qian GS (2001) Experimental research on permeability injury of pulmonary microvascular endothelial cells monolayer induced by tumor necrosis factor. Zhongguo Ying Yong Sheng Li Xue Za Zhi 17:79–81PubMedGoogle Scholar
  172. 172.
    Xing F, Saidou J, Watabe K (2010) Cancer associated fibroblasts (CAFs) in tumor microenvironment. Front Biosci 15:166–179CrossRefGoogle Scholar
  173. 173.
    Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW (2007) Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445:656–660PubMedCrossRefGoogle Scholar
  174. 174.
    Yamakuchi M, Lotterman CD, Bao C, Hruban RH, Karim B, Mendell JT, Huso D, Lowenstein CJ P53-induced microRNA-107 inhibits HIF-1 and tumor angiogenesis. Proc Natl Acad Sci U S A 107: 6334-9Google Scholar
  175. 175.
    Yang G, Yu F, Fu H, Lu F, Huang B, Bai L, Zhao Z, Yao L, Lu Z (2007) Identification of the distinct promoters for the two transcripts of apoptosis related protein 3 and their transcriptional regulation by NFAT and NFkappaB. Mol Cell Biochem 302:187–194PubMedCrossRefGoogle Scholar
  176. 176.
    Yang H, Bushue N, Bu P, Wan YJ (2010) Induction and intracellular localization of Nur77 dictate fenretinide-induced apoptosis of human liver cancer cells. Biochem Pharmacol 79:948–954PubMedCrossRefGoogle Scholar
  177. 177.
    Yu CL, Meyer DJ, Campbell GS, Larner AC, Carter-Su C, Schwartz J, Jove R (1995) Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science 269:81–83PubMedCrossRefGoogle Scholar
  178. 178.
    Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9:798–809PubMedCrossRefGoogle Scholar
  179. 179.
    Zafarullah M, Li WQ, Sylvester J, Ahmad M (2003) Molecular mechanisms of N-acetylcysteine actions. Cell Mol Life Sci 60:6–20PubMedCrossRefGoogle Scholar
  180. 180.
    Zhang Q, Zhang ZF, Rao JY, Sato JD, Brown J, Messadi DV, Le AD (2004) Treatment with siRNA and antisense oligonucleotides targeted to HIF-1alpha induced apoptosis in human tongue squamous cell carcinomas. Int J Cancer 111:849–857PubMedCrossRefGoogle Scholar
  181. 181.
    Zhong Z, Wen Z, Darnell JE Jr (1994) Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264:95–98PubMedCrossRefGoogle Scholar
  182. 182.
    Zhu X, Fujita M, Snyder LA, Okada H (2011) Systemic delivery of neutralizing antibody targeting CCL2 for glioma therapy. J Neurooncol 104:83–92PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Antonino Bruno
    • 1
  • Arianna Pagani
    • 1
    • 3
  • Elena Magnani
    • 4
  • Teresa Rossi
    • 2
  • Douglas M. Noonan
    • 3
    • 4
  • Anna Rita Cantelmo
    • 4
  • Adriana Albini
    • 2
  1. 1.Polo Scientifico e TecnologicoMultiMedica OnlusMilanoItaly
  2. 2.Research InfrastructureIRCCS Arcispedale Santa Maria NuovaReggio EmiliaItaly
  3. 3.Department of Biotechnologies and Life SciencesUniversity of InsubriaVareseItaly
  4. 4.Polo Scientifico e TecnologicoMultiMedica IRCCSMilanoItaly

Personalised recommendations