Counteracting Hypoxia in Radio-Resistant Metastatic Lesions

  • Stefania Staibano


The identification of hypoxia-regulated genes and proteins, has provided the basis for the generation of new hypoxia-targeted drugs, conceived to re-oxygenate hypoxic tumor areas. In patients with advanced metastasizing prostate cancer (PC), these kinds of drugs are expected to optimize the effect of radiotherapy, reducing also its side effects. Immunohistochemistry, DNA, proteomic and, tissue array profiling, are increasingly providing us with exciting data, that could lead to the formulation of pre-treatment multimarker tests able to identify the individualized tumor response profiles to radiotherapy, basing on the specific cancer tissue hypoxia pattern and degree (Bussink et al., Radiother Oncol 67:3–15, 2003).

As an example, the recent discovery of the role of microRNA in PC tumor genesis points towards (Kulshreshtha et al., Cell Cycle 6(12):1426–1431, 2007) the, Inactivation of miRs affected by hypoxia as a promising synergistic therapeutic strategy for the radiotherapy-refractory subset of metastatic PC (Kulshreshtha et al., Cell Death Differ 15:667–671, 2008).

This chapter aims to give an outlook of the main hot-topics concerning the new trends of hypoxia-targeted molecular therapies for advanced metastasizing prostate cancers.


Prostate Cancer Vascular Endothelial Growth Factor Androgen Receptor Radical Prostatectomy Vascular Endothelial Growth Factor Expression 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Aebersold DM, Burri P, Beer KT et al (2001) Expression of hypoxiainducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res 61:2911–2916PubMedGoogle Scholar
  2. Anastasiadis AG, Ghafar MA, Salomon L et al (2002) Human hormone refractory prostate cancers can harbor mutations in the O(2)- dependent degradation domain of hypoxia inducible factor-1alpha (HIF-1alpha). J Cancer Res Clin Oncol 128:358–362PubMedGoogle Scholar
  3. Anastasiadis AG, Bemis DL, Stisser BC, Salomon L, Ghafar MA, Buttyan R (2003) Tumor cell hypoxia and the hypoxia-response signaling system as a target for prostate cancer therapy. Curr Drug Targets 4(3):191–196PubMedGoogle Scholar
  4. Aslan G, Cimen S, Yorukoglu K, Tuna B, Sonmez D, Mungan U et al (2005) Vascular endothelial growth factor expression in untreated and androgen-deprived patients with prostate cancer. Pathol Res Pract 201:593–598PubMedGoogle Scholar
  5. Bakin RE, Gioeli D, Sikes RA, Bissonette EA, Weber MJ (2003) Constitutive activation of the Ras/mitogen-activated protein kinase signaling pathway promotes androgen hypersensitivity in LNCaP prostate cancer cells. Cancer Res 63:1981–1989PubMedGoogle Scholar
  6. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297. ReviewPubMedGoogle Scholar
  7. Bashan N, Burdett E, Hundal HS, Klip A (1992) Regulation of glucose transport and GLUT1 glucose transporter expression by O2 in muscle cells in culture. Am J Physiol 262(3 Pt 1):C682–C690PubMedGoogle Scholar
  8. Bussink J, Kaanders JHAM, Rijken PFJW et al (1999) Vascular architecture and microenvironmental parameters in human squamous cell carcinoma xenografts: effects of carbogen and nicotinamide. Radiother Oncol 50:173–184PubMedGoogle Scholar
  9. Bussink J, Kaanders JHAM, van der Kogel AJ (2003) Tumor hypoxia at the micro-regional level: clinical relevance and predictive value of exogenous and endogenous hypoxic cell markers. Radiother Oncol 67:3–15PubMedGoogle Scholar
  10. Calin GA, Liu CG, Sevignani C, Ferracin M, Felli N, Dumitru CD, Shimizu M, Cimmino A, Zupo S, Dono M, Dell’Aquila ML, Alder H, Rassenti L, Kipps TJ, Bullrich F, Negrini M, Croce CM (2004) MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. Proc Natl Acad Sci USA 101:11755–11760PubMedGoogle Scholar
  11. Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE, Iorio MV, Visone R, Sever NI, Fabbri M, Iuliano R, Palumbo T, Pichiorri F, Roldo C, Garzon R, Sevignani C, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM (2005) A microRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med 353:1793–1801PubMedGoogle Scholar
  12. Cheng AM, Byrom MW, Shelton J, Ford LP (2005) Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis. Nucleic Acids Res 33:1290–1297PubMedGoogle Scholar
  13. Chresta CM, Masters JR, Hickman JA (1996) Hypersensitivity of human testicular tumors to etoposide-induced apoptosis is associated with functional p53 and a high Bax: Bcl-2 ratio. Cancer Res 56:1834–1841PubMedGoogle Scholar
  14. Comerford KM, Wallace TJ, Karhausen J, Louis NA, Montalto MC, Colgan SP (2002) Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res 62:3387–3394PubMedGoogle Scholar
  15. Costello LC, Franklin RB, Feng P et al (2005) Zinc and prostate cancer: a critical scientific, medical, and public interest issue (United States). Cancer Causes Control 16:901–915PubMedGoogle Scholar
  16. Critz FA, Benton JB, Shrake P, Merlin ML (2013) 25-year disease-free survival rate after irradiation for prostate cancer calculated with the prostate specific antigen definition of recurrence used for radical prostatectomy. J Urol 189(3):878–883PubMedGoogle Scholar
  17. Croce CM, Calin GA (2005) miRNAs, cancer, and stem cell division. Cell 122:6–7PubMedGoogle Scholar
  18. Crosby ME, Devlin CM, Glazer PM, Calin GA, Ivan M (2009) Emerging roles of microRNAs in the molecular responses to hypoxia. Curr Pharm Des 15(33):3861–3866PubMedGoogle Scholar
  19. Culig Z, Bartsch G (2006) Androgen axis in prostate cancer. J Cell Biochem 99:373–381PubMedGoogle Scholar
  20. Cvetkovic D, Movsas B, Dicker AP et al (2001) Increased hypoxia correlates with increased expression of the angiogenesis marker vascular endothelial growth factor in human prostate cancer. Urology 57:821–825PubMedGoogle Scholar
  21. Denhardt DT, Guo X (1993) Osteopontin: a protein with diverse functions. FASEB J 7:1475–1482PubMedGoogle Scholar
  22. Dewhirst MW, Ong ET, Braun RD et al (1999) Quantification of longitudinal tissue pO2 gradients in window chamber tumours: impact on tumour hypoxia. Br J Cancer 79:1717–1722PubMedGoogle Scholar
  23. Dvorak HF (1986) Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 25:1650–1659Google Scholar
  24. Ferrara N (1995) The role of vascular endothelial growth factor in pathological angiogenesis. Breast Cancer Res Treat 36:127–137PubMedGoogle Scholar
  25. Forootan SS, Foster CS, Aachi VR et al (2006) Prognostic significance of osteopontin expression in human prostate cancer. Int J Cancer 118:2255–2261PubMedGoogle Scholar
  26. Gilbert M, Knox S (1997) Influence of Bcl-2 overexpression on Na+/K(+)-ATPase pump activity: correlation with radiationinduced programmed cell death. J Cell Physiol 171:299–304PubMedGoogle Scholar
  27. Godoy A, Watts A, Sotomayor P, Montecinos VP, Huss WJ, Onate SA, Smith GJ (2008) Androgen receptor is causally involved in the homeostasis of the human prostate endothelial cell. Endocrinology 149:2959–2969PubMedGoogle Scholar
  28. Godoy A, Montecinos VP, Gray DR, Sotomayor P, Yau JM, Vethanayagam RR, Singh S, Mohler JL, Smith GJ (2011) Androgen deprivation induces rapid involution and recovery of human prostate vasculature. Am J Physiol Endocrinol Metab 300:E263–E275PubMedGoogle Scholar
  29. Gray LH, Conger AD, Ebert M, Hornsey S, Scott OC (1953) The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol 26:638–648PubMedGoogle Scholar
  30. Harris AL (2002) Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer 2:38–47PubMedGoogle Scholar
  31. Harrison L, Blackwell K (2004) Hypoxia and anemia: factors in decreased sensitivity to radiation therapy and chemotherapy. Oncologist 9(suppl 5):31–40PubMedGoogle Scholar
  32. Helmlinger G, Yuan F, Dellian M, Jain RK (1997) Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nat Med 3:177–182PubMedGoogle Scholar
  33. Henk JM (1986) Late results of a trial of hyperbaric oxygen and radiotherapy in head and neck cancer: a rationale for hypoxic cell sensitizers? Int J Radiat Oncol Biol Phys 12:1339–1341PubMedGoogle Scholar
  34. Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23:1011–1027PubMedGoogle Scholar
  35. Höckel M, Vaupel P (2001) Tumor hypoxia: definitions and current clinical, biological and molecular aspects. J Natl Cancer Inst 93:266–276PubMedGoogle Scholar
  36. Höckel M, Schlenger K, Knoop C, Vaupel P (1991) Oxygenation of carcinomas of the uterine cervix: evaluation by computerized O2 tension measurements. Cancer Res 51:6098–6102PubMedGoogle Scholar
  37. Horsman MR, Overgaard J (2002) The oxygen effect and tumour microenvironment. In: Steel GG (ed) Basic clinical radiobiology. Arnold, London, pp 158–168Google Scholar
  38. Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC (2003) Differential roles of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α in hypoxic gene regulation. Mol Cell Biol 23:9361–9374PubMedGoogle Scholar
  39. Huang A, Gandour-Edwards R, Rosenthal SA, Siders DB, Deitch RW, White RW (1998a) p53 and bcl-2 immunohistochemical alterations in prostate cancer treated with radiation therapy. Urology 51:346–351PubMedGoogle Scholar
  40. Huang LE, Jie GU, Schau M, Bunn HF (1998b) Regulation of hypoxia-inducible factor-1a is mediated by an O2-dependent degradation domain via the ubiquitinproteasome pathway. Proc Natl Acad Sci USA 95:7989–7992Google Scholar
  41. Huang Y, Yu J, Yan C, Hou J, Pu J, Zhang G, Fu Z, Wang X (2012) Effect of small interfering RNA targeting hypoxia-inducible factor-1α on radiosensitivity of PC3 cell line. Urology 79(3):744.e17–744.e24Google Scholar
  42. Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, Magri E, Pedriali M, Fabbri M, Campiglio M, Menard S, Palazzo JP, Rosenberg A, Musiani P, Volinia S, Nenci I, Calin GA, Querzoli P, Negrini M, Croce CM (2005) MicroRNA gene expression deregulation in human breast cancer. Cancer Res 65:7065–7070PubMedGoogle Scholar
  43. Isa AY, Ward TH, West CML, Slevin NJ, Homer JJ (2006) Hypoxia in head and neck cancer. Br J Radiol 79:791–798PubMedGoogle Scholar
  44. Jain RK (1999) Transport of molecules, particles, and cells in solid tumors. Annu Rev Biomed Eng 1:241–263PubMedGoogle Scholar
  45. Kaelin WG Jr (2005) ROS: really involved in oxygen sensing. Cell Metab 1:357–358PubMedGoogle Scholar
  46. Kennedy AS, Raleigh JA, Perez GM et al (1997) Proliferation and hypoxia in human squamous cell carcinoma of the cervix: first report of combined immunohistochemical assays. Int J Radiat Oncol Biol Phys 37:897–905PubMedGoogle Scholar
  47. Kenny PA, Bissell MJ (2003) Tumor reversion: correction of malignant behavior by microenvironmental cues. Int J Cancer 107:688–695PubMedGoogle Scholar
  48. Kimbro KS, Simons JW (2006) Hypoxia-inducible factor-1 in human breast and prostate cancer. Endocr Relat Cancer 13:739–749PubMedGoogle Scholar
  49. Koukourakis MI, Giatromanolaki A, Sivridis E et al (2002) Hypoxiainducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer. Int J Radiat Oncol Biol Phys 53:1192–1202PubMedGoogle Scholar
  50. Koukourakis MI, Bentzen SM, Giatromanolaki A et al (2006) Endogenous markers of two separate hypoxia response pathways (hypoxia inducible factor 2 alpha and carbonic anhydrase 9) are associated with radiotherapy failure in head and neck cancer patients recruited in the CHART randomized trial. J Clin Oncol 24:727–735PubMedGoogle Scholar
  51. Kroemer G (2006) Mitochondria in cancer. Oncogene 25:4630–4632PubMedGoogle Scholar
  52. Krutzfeldt J, Kuwajima S, Braich R, Rajeev KG, Pena J, Tuschl T, Manoharan M, Stoffel M (2007) Specificity, duplex degradation and subcellular localization of antagomirs. Nucleic Acids Res 35:2885–2892PubMedGoogle Scholar
  53. Ku JH, Seo SY, Kwak C et al (2010) The role of survivin and Bcl-2 in zinc-induced apoptosis in prostate cancer cells. Urol Oncol 30:562–568PubMedGoogle Scholar
  54. Kulshreshtha R, Ferracin M, Negrini M, Calin GA, Davuluri RV, Ivan M (2007) Regulation of microRNA expression the hypoxic component. Cell Cycle 6(12):1426–1431PubMedGoogle Scholar
  55. Kulshreshtha R, Davuluri RV, Calin GA, Ivan MA (2008) microRNA component of the hypoxic response. Cell Death Differ 15:667–671PubMedGoogle Scholar
  56. Le QT, Courter D (2008) Clinical biomarkers for hypoxia targeting. Cancer Metastasis Rev 27(3):351–362PubMedGoogle Scholar
  57. Lekas A, Lazaris AC, Deliveliotis C, Chrisofos M, Zoubouli C, Lapas D et al (2006) The expression of hypoxia-inducible factor- 1alpha (HIF-1alpha) and angiogenesis markers in hyperplastic and malignant prostate tissue. Anticancer Res 26:2989–2993PubMedGoogle Scholar
  58. Levy AP, Levy NS, Goldberg MA (1996) Hypoxia-inducible protein binding to vascular endothelial growth factor mRNA and its modulation by the von Hippel-Lindau protein. J Biol Chem 271:25492–25497PubMedGoogle Scholar
  59. Ljungkvist ASE, Bussink J, Rijken PFJW, Kaanders JHAM, van der Kogel AJ, Denekamp J (2002) Vascular architecture, hypoxia, and proliferation in the first passage of xenografts of human head and neck squamous cell carcinomas. Int J Radiat Oncol Biol Phys 54:215–228PubMedGoogle Scholar
  60. Lundgren K, Holm C, Landberg G (2007) Hypoxia and breast cancer: prognostic and therapeutic implications. Cell Mol Life Sci 64(24):3233–3247PubMedGoogle Scholar
  61. Mabjeesh NJ, Willard MT, Frederickson CE, Zhong H, Simons JW (2003) Androgens stimulate hypoxia-inducible factor 1 activation via autocrine loop of tyrosine kinase receptor/phosphatidylinositol 30-kinase/protein kinase B in prostate cancer cells. Clin Cancer Res 9:2416–2425PubMedGoogle Scholar
  62. Maxwell PH, Wiesener MS, Chang GW et al (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271–275PubMedGoogle Scholar
  63. Merino M, Pinto A, González R et al (2011) Antiangiogenic agents and endothelin antagonists in advanced castration resistant prostate cancer. Eur J Cancer 47:1846–1851PubMedGoogle Scholar
  64. Milosevic M, Chung P, Parker C, Bristow R, Toi A, Panzarella T et al (2007) Androgen withdrawal in patients reduces prostate cancer hypoxia: implications for disease progression and radiation response. Cancer Res 67:6022–6025PubMedGoogle Scholar
  65. Moeller BJ, Dewhirst MW (2006) HIF-1 and tumour radiosensitivity. Br J Cancer 95:1–5. (Review)PubMedGoogle Scholar
  66. Moll UM, Marchenko N, Zhang XK (2006) p53 and Nur77/TR3 – transcription factors that directly target mitochondria for cell death induction. Oncogene 25:4725–4743PubMedGoogle Scholar
  67. Morales A, Miranda M, Sánchez-Reyes A, Biete A, Fernández-Checa JC (1998) Oxidative damage of mitochondrial and nuclear DNA induced by ionizing radiation in human hepatoblastoma cells. Int J Radiat Oncol Biol Phys 42:191–203PubMedGoogle Scholar
  68. Movsas B, Chapman JD, Hanlon AL et al (2002) Hypoxic prostate/muscle pO2 ratio predicts for biochemical failure in patients with prostate cancer: preliminary findings. Urology 60:634–639PubMedGoogle Scholar
  69. Muzandu K, Shaban Z, Ishizuka M, Kazusaka A, Fujita S (2005) Nitric oxide enhances catechol estrogen-induced oxidative stress in LNCaP cells. Free Radic Res 39:389–398PubMedGoogle Scholar
  70. Nilsson MB, Zage PE, Zeng L et al (2010) Multiple receptor tyrosine kinases regulate HIF-1alpha and HIF-2alpha in normoxia and hypoxia in neuroblastoma: implications for anti-angiogenic mechanisms of multikinase inhibitors. Oncogene 29:2938–2949PubMedGoogle Scholar
  71. Nordgren IK, Tavassoli A (2011) Targeting tumour angiogenesis with small molecule inhibitors of hypoxia inducible factor. Chem Soc Rev 40:4307–4317PubMedGoogle Scholar
  72. Nordsmark M, Hoyer M, Keller J, Nielsen OS, Jensen OM, Overgaard J (1996) The relationship between tumor oxygenation and cell proliferation in human soft tissue sarcomas. Int J Radiat Oncol Biol Phys 35:701–708PubMedGoogle Scholar
  73. Orom UA, Kauppinen S, Lund AH (2006) LNA-modified oligonucleotides mediate specific inhibition of microRNA function. Gene 372:137–141PubMedGoogle Scholar
  74. Overgaard J, Horsman MR (1996) Modification of hypoxia-induced radioresistance in tumors by the use of oxygen and sensitizers. Semin Radiat Oncol 6:10–21PubMedGoogle Scholar
  75. Overgaard J, Hansen HS, Overgaard M et al (1998) A randomized double blind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of the Danish Head and Neck Cancer Study (DAHANCA) Protocol 5–85. Radiother Oncol 46:135–146PubMedGoogle Scholar
  76. Overgaard J, Eriksen JG, Nordsmark M, Alsner J, Horsman MR (2005) Plasma osteopontin, hypoxia, and response to the hypoxia sensitiser nimorazole in radiotherapy of head and neck cancer: results from the DAHANCA 5 randomised doubleblind placebo-controlled trial. Lancet Oncol 6:757–764PubMedGoogle Scholar
  77. Park SY, Kim YJ, Gao AC, Mohler JL, Onate SA, Hidalgo AA et al (2006) Hypoxia increases androgen receptor activity in prostate cancer cells. Cancer Res 66:5121–5129PubMedGoogle Scholar
  78. Park SE, Park JW, Cho YS et al (2007) HIF-1&;_ promotes survival of prostate cells at a high zinc environment. Prostate 67:1514–1523PubMedGoogle Scholar
  79. Parker C, Milosevic M, Toi A et al (2004) Polarographic electrode study of tumour oxygenation in clinically localised prostate cancer. Int J Radiat Oncol Biol Phys 58:750–757PubMedGoogle Scholar
  80. Pfeil K, Eder IE, Putz T, Ramoner R, Culig Z, Ueberall F et al (2004) Long-term androgen-ablation causes increased resistance to PI3K/Akt pathway inhibition in prostate cancer cells. Prostate 58:259–268PubMedGoogle Scholar
  81. Pugh CW, Ratcliffe PJ (2003) Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 9:677–684PubMedGoogle Scholar
  82. Quintero M, Mackenzie N, Brennan PA (2004) Hypoxia-inducible factor 1 (HIF-1) in cancer. Eur J Surg Oncol 30:465–468PubMedGoogle Scholar
  83. Revelos K, Petraki C, Gregorakis A, Scorilas A, Papanastasiou M, Koutsilieris M (2005) Immunohistochemical expression of Bcl-2 is an independent predictor of time-to-biochemical failure in patients with clinically localized prostate cancer following radical prostatectomy. Anticancer Res 25:3123–3133PubMedGoogle Scholar
  84. Rohwer N, Cramer T (2011) Hypoxia-mediated drug resistance: novel insights on the functional interaction of HIFs and cell death pathways. Drug Resist Updat 14:191–201PubMedGoogle Scholar
  85. Romashkova JA, Makarov SS (1999) NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature 401:86–90PubMedGoogle Scholar
  86. Rothermund CA, Gopalakrishnan VK, Eudy JD, Vishwanatha JK (2005) Casodex treatment induces hypoxia-related gene expression in the LNCaP prostate cancer progression model. BMC Urol 5:5PubMedGoogle Scholar
  87. Rugo RE, Schiestl RH (2004) Increases in oxidative stress in the progeny of X-irradiated cells. Radiat Res 162:416–425PubMedGoogle Scholar
  88. Scherr DS, Vaughan ED Jr, Wei J, Chung M, Felsen D, Allbright R et al (1999) BCL-2 and p53 expression in clinically localized prostate cancer predicts response to external beam radiotherapy. J Urol 162:12–16PubMedGoogle Scholar
  89. Schmaltz C, Hardenbergh PH, Wells A, Fisher DE (1998) Regulation of proliferation-survival decisions during tumor cell hypoxia. Mol Cell Biol 18:2845–2854PubMedGoogle Scholar
  90. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732PubMedGoogle Scholar
  91. Semenza GL, Nejfelt MK, Chi SM, Antonarakis SE (1991) Hypoxiainducible nuclear factors bind to an enhancer element located 30 to the human erythropoietin gene. Proc Natl Acad Sci USA 88:5680–5684PubMedGoogle Scholar
  92. Senger DR, Galli SJ, Dvorak AM et al (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219:983–985PubMedGoogle Scholar
  93. Shannon AM, Bouchier-Hayes DJ, Condron CM, Toomey D (2003) Tumour hypoxia, chemotherapeutic resistance and hypoxia-related therapies. Cancer Treat Rev 29:297–307PubMedGoogle Scholar
  94. Shweiki D, Itin A, Soffer D, Keshet E (1992) Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359:843–845PubMedGoogle Scholar
  95. Srigley JR, Delahunt B, Evans AJ (2012) Therapy-associated effects in the prostate gland. Histopathology 60:153–165PubMedGoogle Scholar
  96. Strohmeyer D, Strauss F, Rossing C et al (2004) Expression of bFGF, VEGF and c-met and their correlation with microvessel density and progression in prostate carcinoma. Anticancer Res 24:1797–1804PubMedGoogle Scholar
  97. Szostak MJ, Kyprianou N (2000) Radiation-induced apoptosis: predictive and therapeutic significance in radiotherapy of prostate cancer (review). Oncol Rep 7:699–706PubMedGoogle Scholar
  98. Thomlinson RH, Gray LH (1955) The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 9:539–549PubMedGoogle Scholar
  99. Vaupel P, Kelleher DK (2013) Blood flow and oxygenation status of prostate cancers. Adv Exp Med Biol 765:299–305PubMedGoogle Scholar
  100. Vaupel P, Kallinowski F, Okunieff P (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 49:6449–6465PubMedGoogle Scholar
  101. Vaupel P, Thews O, Hoeckel M (2001) Treatment resistance of solid tumors. Role of hypoxia and anemia. Med Oncol 18:243–259PubMedGoogle Scholar
  102. Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F et al (2006) A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA 103:2257–2261PubMedGoogle Scholar
  103. Wang G, Reed E, Li QQ (2004) Apoptosis in prostate cancer: progressive and therapeutic implications (Review). Int J Mol Med 14:23–34PubMedGoogle Scholar
  104. Watson ER, Halnan KE, Dische S et al (1978) Hyperbaric oxygen and radiotherapy: a Medical Research Council trial in carcinoma of the cervix. Br J Radiol 51:879–887PubMedGoogle Scholar
  105. Webster L, Hodgkiss RJ, Wilson GD (1995) Simultaneous triple staining for hypoxia, proliferation, and DNA content in murine tumours. Cytometry 21:344–351PubMedGoogle Scholar
  106. Weiler J, Hunziker J, Hall J (2006) Anti-miRNA oligonucleotides (AMOs): ammunition to target miRNAs implicated in human disease? Gene Ther 13:496–502PubMedGoogle Scholar
  107. Wilson WR, Hay MP (2011) Targeting hypoxia in cancer therapy. Nat Rev Cancer 11:393–410PubMedGoogle Scholar
  108. Wouters BG, van den Beucken T, Magagnin MG, Lambin P, Koumenis C (2004) Targeting hypoxia tolerance in cancer. Drug Resist Updat 7:25–40PubMedGoogle Scholar
  109. Xie Y, Xu K, Dai B, Guo Z, Jiang T, Chen H et al (2006) The 44 kDa Pim-1 kinase directly interacts with tyrosine kinase Etk/BMX and protects human prostate cancer cells from apoptosis induced by chemotherapeutic drugs. Oncogene 25:70–78PubMedGoogle Scholar
  110. Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, Stephens RM, Okamoto A, Yokota J, Tanaka T, Calin GA, Liu CG, Croce CM, Harris CC (2006) Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 9:189–198PubMedGoogle Scholar
  111. Yasuda H (2008) Solid tumor physiology and hypoxia-induced chemo/radio-resistance: novel strategy for cancer therapy: nitric oxide donor as a therapeutic enhancer. Nitric Oxide 19(2):205–216PubMedGoogle Scholar
  112. Zhao Y, Samal E, Srivastava D (2005) Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature 436:214–220PubMedGoogle Scholar
  113. Zhivotovsky B, Joseph B, Orrenius S (1999) Tumor radiosensitivity and apoptosis. Exp Cell Res 248:10–17PubMedGoogle Scholar
  114. Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D et al (1999) Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res 59:5830–5835PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.Department of Advanced Biomedical Sciences, Pathology Section, Faculty of Medicine and SurgeryUniversity of Naples “Federico II”NaplesItaly

Personalised recommendations