Skip to main content
SpringerLink
Log in
SpringerLink
Log in

Intratumoral Hypoxia as the Genesis of Genetic Instability and Clinical Prognosis in Prostate Cancer

  • Conference paper
  • First Online:
Tumor Microenvironment and Cellular Stress

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 772))

Abstract

Intratumoral hypoxia is prevalent in many solid tumors and is a marker of poor clinical prognosis in prostate cancer. The presence of hypoxia is associated with increased chromosomal instability, gene amplification, downregulation of DNA damage repair pathways, and altered sensitivity to agents that damage DNA. These genomic changes could also lead to oncogene activation or tumor suppressor gene inactivation during prostate cancer progression. We review here the concept of repair-deficient hypoxic tumor cells that can adapt to low oxygen levels and acquire an aggressive “unstable mutator” phenotype. We speculate that hypoxia-induced genomic instability may also be a consequence of aberrant mitotic function in hypoxic cells, which leads to increased chromosomal instability and aneuploidy. Because both hypoxia and aneuploidy are prognostic factors in prostate cancer, a greater understanding of these biological states in prostate cancer may lead to novel prognostic and predictive tests and drive new therapeutic strategies in the context of personalized cancer medicine.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Ahn G, Brown M (2007) Targeting tumors with hypoxia-activated cytotoxins. Front Biosci 12:3483–3501

    Article  PubMed  CAS  Google Scholar 

  • Amling CL, Lerner SE, Martin SK, Slezak JM, Blute ML, Zincke H (1999) Deoxyribonucleic acid ploidy and serum prostate specific antigen predict outcome following salvage prostatectomy for radiation refractory prostate cancer. J Urol 161:857–863

    Article  PubMed  CAS  Google Scholar 

  • Arlt MF, Durkin SG, Ragland RL, Glover TW (2006) Common fragile sites as targets for chromosome rearrangements. DNA Repair 5:1126–1135

    Article  PubMed  CAS  Google Scholar 

  • Baker DJ, Jin F, Jeganathan KB, Van Deursen JM (2009) Whole chromosome instability caused by Bub1 insufficiency drives tumorigenesis through tumor suppressor gene loss of heterozygosity. Cancer Cell 16:475–486

    Article  PubMed  CAS  Google Scholar 

  • Boddy JL, Fox SB, Han C, Campo L, Turley H, Kanga S, Malone PR, Harris AL (2005) The androgen receptor is significantly associated with vascular endothelial growth factor and hypoxia sensing via hypoxia-inducible factors HIF-1a, HIF-2a, and the prolyl hydroxylases in human prostate cancer. Clin Cancer Res 11:7658–7663. doi:10.1158/1078-0432.CCR-05-0460

    Article  PubMed  CAS  Google Scholar 

  • Bourke E, Dodson H, Merdes A, Cuffe L, Zachos G, Walker M, Gillespie D, Morrison CG (2007) DNA damage induces Chk1-dependent centrosome amplification. EMBO Rep 8:603–609

    Article  PubMed  CAS  Google Scholar 

  • Bristow RG, Hill RP (2008) Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer 8:180–192

    Article  PubMed  CAS  Google Scholar 

  • Brown JM, Wilson WR (2004) Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 4(6):437–447

    Google Scholar 

  • Cappelli E, Townsend S, Griffin C, Thacker J (2011) Homologous recombination proteins are associated with centrosomes and are required for mitotic stability. Exp Cell Res 317:1203–1213. doi:10.1016/j.yexcr.2011.01.021

    Article  PubMed  CAS  Google Scholar 

  • Carnell DM, Smith RE, Daley FM, Saunders MI, Bentzen SM, Hoskin PJ (2006) An immunohistochemical assessment of hypoxia in prostate carcinoma using pimonidazole: implications for radioresistance. Int J Radiat Oncol Biol Phys 65:91–99. doi:10.1016/j.ijrobp.2005.11.044

    Article  PubMed  CAS  Google Scholar 

  • Chalmers AJ, Lakshman M, Chan N, Bristow RG (2010) Poly(ADP-ribose) polymerase inhibition as a model for synthetic lethality in developing radiation oncology targets. Semin Radiat Oncol 20:274–281

    Article  PubMed  Google Scholar 

  • Chan JY (2011) A clinical overview of centrosome amplification in human cancers. Int J Biol Sci 7:1122–1144

    Article  PubMed  CAS  Google Scholar 

  • Chan N, Bristow RG (2010) “Contextual” synthetic lethality and/or loss of heterozygosity: tumor hypoxia and modification of DNA repair. Clin Cancer Res 16:4553–4560

    Article  PubMed  CAS  Google Scholar 

  • Chan N, Milosevic M, Bristow RG (2007) Tumor hypoxia, DNA repair and prostate cancer progression: new targets and new therapies. Future Oncol (London, England) 3:329–341

    Article  CAS  Google Scholar 

  • Chan N, Koritzinsky M, Zhao H, Bindra R, Glazer PM, Powell S, Belmaaza A, Wouters B, Bristow RG (2008) Chronic hypoxia decreases synthesis of homologous recombination proteins to offset chemoresistance and radioresistance. Cancer Res 68:605–614

    Article  PubMed  CAS  Google Scholar 

  • Chan N, Pires IM, Bencokova Z et al (2010) Contextual synthetic lethality of cancer cell kill based on the tumor microenvironment. Cancer Res 70:8045–8054

    Article  PubMed  CAS  Google Scholar 

  • Coquelle A, Toledo F, Stern S, Bieth A, Dabatisse M (1998) A new role for hypoxia in tumor progression: induction of fragile site triggering genomic rearrangements and formation of complex DMs and HSRs. Mol Cell 2:259–265

    Article  PubMed  CAS  Google Scholar 

  • Crosby ME, Kulshreshtha R, Ivan M, Glazer PM (2009) MicroRNA regulation of DNA repair gene expression in hypoxic stress. Cancer Res 69:1221–1229

    Article  PubMed  CAS  Google Scholar 

  • Di Silverio F, D'Eramo G, Buscarini M, Sciarra A, Casale P, Di Nicola S, Loreto A, Seccareccia F, De Vita R (1996) DNA ploidy, Gleason score, pathological stage and serum PSA levels as predictors of disease-free survival in C-D1 prostatic cancer patients submitted to radical retropubic prostatectomy. Eur Urol 30:316–321

    PubMed  Google Scholar 

  • Dodson H, Bourke E, Jeffers LJ, Vagnarelli P, Sonoda E, Takeda S, Earnshaw WC, Merdes A, Morrison C (2004) Centrosome amplification induced by DNA damage occurs during a prolonged G2 phase and involves ATM. EMBO J 23:3864–3873. doi:10.1038/sj.emboj.7600393

    Article  PubMed  CAS  Google Scholar 

  • Fong PC, Boss DS, Yap TA et al (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. New Engl J Med 361:123–134

    Article  PubMed  CAS  Google Scholar 

  • Geiersbach KB, Samowitz WS (2011) Microsatellite instability and colorectal cancer. Arch Pathol Lab Med 135:1269–1277

    Article  PubMed  CAS  Google Scholar 

  • Geigl JB, Obenauf AC, Schwarzbraun T, Speicher MR (2008) Defining “chromosomal instability”. Trends Genet 24:64–69

    Article  PubMed  CAS  Google Scholar 

  • Gisselsson D (2003) Chromosome instability in cancer: how, when, and why? Adv Cancer Res 87:1–29

    Article  PubMed  CAS  Google Scholar 

  • Green MML, Hiley CT, Shanks JH, Bottomley IC, West CML, Cowan RA, Stratford IJ (2007) Expression of vascular endothelial growth factor (VEGF) in locally invasive prostate cancer is prognostic for radiotherapy outcome. Int J Radiat Oncol Biol Phys 67:84–90. doi:10.1016/j.ijrobp.2006.08.077

    Article  PubMed  CAS  Google Scholar 

  • Hegan DC, Lu Y, Stachelek GC, Crosby ME, Bindra RS, Glazer PM (2010) Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130. Proc Natl Acad Sci U S A 107:2201–2206

    Article  PubMed  CAS  Google Scholar 

  • Helleday T, Lo J, Van Gent DC, Engelward BP (2007) DNA double-strand break repair: from mechanistic understanding to cancer treatment. DNA Repair 6:923–935

    Article  PubMed  CAS  Google Scholar 

  • Hsieh P, Yamane K (2008) DNA mismatch repair: molecular mechanism, cancer, and ageing. Mech Ageing Dev 129:391–407

    Article  PubMed  CAS  Google Scholar 

  • Hsu LC, White RL (1998) BRCA1 is associated with the centrosome during mitosis. Proc Natl Acad Sci U S A 95:12983–12988

    Article  PubMed  CAS  Google Scholar 

  • Jeggo P, Löbrich M (2007) DNA double-strand breaks: their cellular and clinical impact? Oncogene 26:7717–7719

    Article  PubMed  CAS  Google Scholar 

  • Kaelin WG (2005) The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer 5:689–698

    Article  PubMed  CAS  Google Scholar 

  • Kinzler KW, Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87:159–170

    Article  PubMed  CAS  Google Scholar 

  • Kitao H, Takata M (2011) Fanconi anemia: a disorder defective in the DNA damage response. Int J Hematol 93:417–424

    Article  PubMed  CAS  Google Scholar 

  • Ko MJ, Murata K, Hwang D-S, Parvin JD (2006) Inhibition of BRCA1 in breast cell lines causes the centrosome duplication cycle to be disconnected from the cell cycle. Oncogene 25:298–303

    Article  PubMed  CAS  Google Scholar 

  • Krämer A, Neben K, Ho A (2002) Centrosome replication, genomic instability and cancer. Leukemia 16:767–775

    Article  PubMed  Google Scholar 

  • Kuhnert VM, Kachnic L, Li L, Purschke M, Gheorghiu L, Lee R, Held KD, Willers H (2009) FANCD2-deficient human fibroblasts are hypersensitive to ionising radiation at oxygen concentrations of 0% and 3% but not under normoxic conditions. Int J Radiat Biol 85:523–531

    Article  PubMed  CAS  Google Scholar 

  • Kumareswaran R, Ludkovski O, Meng A, Sykes J, Pintilie M, Bristow RG (2012) Chronic hypoxia compromises repair of DNA double-strand breaks to drive genetic instability. J Cell Sci 125:189–199

    Article  PubMed  CAS  Google Scholar 

  • Kuzminov A (2001) Single-strand interruptions in replicating chromosomes cause double-strand breaks. Proc Natl Acad Sci U S A 98:8241–8246

    Article  PubMed  CAS  Google Scholar 

  • Luoto K, Kumareswaran R, Bristow RG (2013) Tumor Hypoxia as a Driving Force in Genetic Instability In Press. Genome Integrity

    Google Scholar 

  • Martin S, McCabe N, Mullarkey M, Cummins R, Burgess DJ, Nakabeppu Y, Oka S, Kay E, Lord CJ, Ashworth A (2010) DNA polymerases as potential therapeutic targets for cancers deficient in the DNA mismatch repair proteins MSH2 or MLH1. Cancer Cell 17:235–248

    Article  PubMed  CAS  Google Scholar 

  • Mazzorana M, Montoya G, Mortuza GB (2011) The centrosome: a target for cancer therapy. Curr Cancer Drug Targets 11:600–612

    Article  PubMed  CAS  Google Scholar 

  • McGranahan N, Burrell R, Endesfelder D, Novelli MR, Swanton C (2012) Cancer chromosomal instability: therapeutic and diagnostic challenges. EMBO Rep 13:528–538

    Article  PubMed  CAS  Google Scholar 

  • Meng AX, Jalali F, Cuddihy A, Chan N, Bindra RS, Glazer PM, Bristow RG (2005) Hypoxia down-regulates DNA double strand break repair gene expression in prostate cancer cells. Radiother Oncol J Eur Soc Ther Radiol Oncol 76:168–176

    Article  CAS  Google Scholar 

  • Meng F, Evans JW, Bhupathi D et al (2012) Molecular and cellular pharmacology of the hypoxia-activated prodrug TH-302. Mol Cancer Ther 11:740–751

    Article  PubMed  CAS  Google Scholar 

  • Michor F, Iwasa Y, Vogelstein B, Lengauer C, Nowak M (2005) Can chromosomal instability initiate tumorigenesis? Semin Cancer Biol 15:43–49

    Article  PubMed  CAS  Google Scholar 

  • Mihaylova VT, Bindra RS, Yuan J, Campisi D, Narayana L, Jensen R, Giordano F, Randall JS, Rockwell S, Glazer PM (2003) Decreased expression of the DNA mismatch repair gene Mlh1 under hypoxic stress in mammalian cells. Mol Cell Biol 23:3265–3273

    Article  PubMed  CAS  Google Scholar 

  • Mills KD, Ferguson DO, Alt FW (2003) The role of DNA breaks in genomic instability and tumorigenesis. Immunol Rev 194:77–95

    Article  PubMed  CAS  Google Scholar 

  • Milosevic M, Chung P, Parker C et al (2007) Androgen withdrawal in patients reduces prostate cancer hypoxia: implications for disease progression and radiation response. Cancer Res 67:6022–6025

    Article  PubMed  CAS  Google Scholar 

  • Milosevic M, Warde P, Ménard C et al (2012) Tumor hypoxia predicts biochemical failure following radiotherapy for clinically localized prostate cancer. Clin Cancer Res 18:2108–2114. doi:10.1158/1078-0432.CCR-11-2711

    Article  PubMed  CAS  Google Scholar 

  • Nakada C, Tsukamoto Y, Matsuura K, Nguyen TL, Hijiya N, Uchida T, Sato F, Mimata H, Seto M, Moriyama M (2011) Overexpression of miR-210, a downstream target of HIF1α, causes centrosome amplification in renal carcinoma cells. J Pathol 224:280–288

    Article  PubMed  CAS  Google Scholar 

  • Nakamura H, Tanimoto K, Hiyama K, Yunokawa M, Kawamoto T, Kato Y, Yoshiga K, Poellinger L, Hiyama E, Nishiyama M (2008) Human mismatch repair gene, MLH1, is transcriptionally repressed by the hypoxia-inducible transcription factors, DEC1 and DEC2. Oncogene 27:4200–4209

    Article  PubMed  CAS  Google Scholar 

  • Nigg EA (2002) Centrsome aberrations: cause or consequence of cancer progression? Nat Rev Cancer 2:1–11

    Article  Google Scholar 

  • Nouspikel T (2009) Nucleotide excision repair: variations on versatility. Cell Mol Life Sci 66:994–1009

    Article  PubMed  CAS  Google Scholar 

  • Pihan GA, Purohit A, Wallace J, Malhotra R, Liotta L, and Doxsey SJ (2001) Centrosome defects can account for cellular and genetic changes that characterize prostate cancer progression. Cancer Res 61:2212–2219

    Google Scholar 

  • Pollack A (2003) Prostate cancer DNA ploidy and response to salvage hormone therapy after radiotherapy with or without short-term total androgen blockade: an analysis of RTOG 8610. J Clin Oncol 21:1238–1248. doi:10.1200/JCO.2003.02.025

    Article  PubMed  CAS  Google Scholar 

  • Pollack A, Zagars GK, El-Naggar AK, Gauwitz MD, Terry NHA (1994a) Near-diploidy: a new prognostic factor for clinically localized prostate cancer treated with external beam radiation therapy. Cancer 73:1895–1903. doi:10.1002/1097-0142(19940401)73:7<1895::AID-CNCR2820730721>3.0.CO;2-0

    Article  PubMed  CAS  Google Scholar 

  • Pollack A, Zagars GK, El-Naggar K, Terry NH (1994b) Relationship of tumor DNA-ploidy to serum prostate-specific antigen doubling time after radiotherapy for prostate cancer. Urology 44:711–718

    Article  PubMed  CAS  Google Scholar 

  • Pretorius ME, Waehre H, Abeler VM, Davidson B, Vlatkovic L, Lothe R, Giercksky K-E, Danielsen HE (2009) Large scale genomic instability as an additive prognostic marker in early prostate cancer. Cell Oncol 31:251–259. doi:10.3233/CLO-2009-0463

    PubMed  CAS  Google Scholar 

  • Rai R, Dai H, Multani AS et al (2006) BRIT1 regulates early DNA damage response, chromosomal integrity, and cancer. Cancer Cell 10:145–157

    Article  PubMed  CAS  Google Scholar 

  • Rai R, Phadnis A, Haralkar S, Badwe R, Dai H, Li K, Lin S-Y (2008) Differential regulation of centrosome integrity by DNA damage response proteins. Cell Cycle 7:2225–2233

    Article  PubMed  CAS  Google Scholar 

  • Rezvani HR, Mahfouf W, Ali N, Chemin C, Ged C, Kim AL, De Verneuil H, Taïeb A, Bickers DR, Mazurier F (2010) Hypoxia-inducible factor-1alpha regulates the expression of nucleotide excision repair proteins in keratinocytes. Nucl Acids Res 38:797–809

    Article  PubMed  CAS  Google Scholar 

  • Ross JS, Figge H, Bui HX, Del Rosario D, Jennings T, Rifkin MD, Fisher H (1994) Prediction of pathologic stage and postprostatectomy disease recurrence by DNA ploidy analysis of initial needle biopsy specimens of prostate cancer. Cancer 74:2811–2818

    Article  PubMed  CAS  Google Scholar 

  • Rothkamm K, Krüger I, Thompson LH, Kru I, Lo M (2003) Pathways of DNA double-strand break repair during the mammalian cell cycle pathways of DNA double-strand break repair during the mammalian cell cycle. Mol Cell Biol. doi:10.1128/MCB.23.16.5706

    PubMed  Google Scholar 

  • Saladino C, Bourke E, Conroy PC, Morrison CG (2009) Centriole separation in DNA damage-induced centrosome amplification. Environ Mol Mutagen 50:725–732. doi:10.1002/em

    Article  PubMed  CAS  Google Scholar 

  • Schwartz M, Zlotorynski E, Goldberg M, Ozeri E, Rahat A, Sage C, Chen BPC, Chen DJ, Agami R, Kerem B (2005) Homologous recombination and nonhomologous end-joining repair pathways regulate fragile site stability. Genes Dev 19:2715–2726

    Article  PubMed  CAS  Google Scholar 

  • Semenza GL (2012) Hypoxia-inducible factors in physiology and medicine. Cell 148:399–408

    Article  PubMed  CAS  Google Scholar 

  • Shahrzad S, Quayle L, Stone C, Plumb C, Shirasawa S, Rak JW, Coomber BL (2005) Ischemia-induced K-ras mutations in human colorectal cancer cells: role of microenvironmental regulation of MSH2 expression. Cancer Res 65:8134–8141

    Article  PubMed  CAS  Google Scholar 

  • Shimada M, Kobayashi J, Hirayama R, Komatsu K (2010) Differential role of repair proteins, BRCA1/NBS1 and Ku70/DNA-PKcs, in radiation-induced centrosome overduplication. Cancer Sci 101:2531–2537. doi:10.1111/j.1349-7006.2010.01702.x

    Article  PubMed  CAS  Google Scholar 

  • Smith M, Fornance A (1995) Genomic instability and the role of p53 mutations in cancer cells. Curr Opin Oncol 7:69–75

    PubMed  CAS  Google Scholar 

  • Song J, Cheng WS, Cupps RE, Earle JD (1992) Nuclear deoxyribonucleic acid content measured by static cytometry: important prognostic association for patients with clinically localized prostate carcinoma treated by external beam radiotherapy. J Urol 147:794–797

    PubMed  CAS  Google Scholar 

  • Sprong D, Janssen HL, Vens C, Begg AC (2006) Resistance of hypoxic cells to ionizing radiation is influenced by homologous recombination status. Int J Radiat Oncol Biol Phys 64:562–572

    Article  PubMed  CAS  Google Scholar 

  • Thompson SL, Bakhoum SF, Compton D (2010) Mechanisms of chromosomal instability. Curr Biol 20:R285–R295

    Article  PubMed  CAS  Google Scholar 

  • Thoms JW, Dal Pra A, Anborgh PH et al (2012) Plasma osteopontin as a biomarker of prostate cancer aggression: relationship to risk category and treatment response. Brit J Cancer 107:840–846. doi:10.1038/bjc.2012.345

    Article  PubMed  CAS  Google Scholar 

  • Turaka A, Buyyounouski MK, Hanlon AL, Horwitz EM, Greenberg RE, Movsas B (2012) Hypoxic prostate/muscle PO2 ratio predicts for outcome in patients with localized prostate cancer: long-term results. Int J Radiat Oncol Biol Phys 82:e433–e439. doi:10.1016/j.ijrobp.2011.05.037

    Article  PubMed  Google Scholar 

  • Vergis R, Corbishley CM, Norman AR et al (2008) Intrinsic markers of tumour hypoxia and angiogenesis in localised prostate cancer and outcome of radical treatment: a retrospective analysis of two randomised radiotherapy trials and one surgical cohort study. Lancet Oncol 9:342–351. doi:10.1016/S1470-2045(08)70076-7

    Article  PubMed  Google Scholar 

  • Weber DC, Tille J-C, Combescure C, Egger J-F, Laouiti M, Hammad K, Granger P, Rubbia-Brandt L, Miralbell R (2012) The prognostic value of expression of HIF1α, EGFR and VEGF-A, in localized prostate cancer for intermediate- and high-risk patients treated with radiation therapy with or without androgen deprivation therapy. Radiat Oncol (London, England) 7:66. doi:10.1186/1748-717X-7-66

    Article  Google Scholar 

  • Wilson W, Hay M (2011) Targeting hypoxia in cancer therapy. Nat Rev Cancer 11:393–410

    Article  PubMed  CAS  Google Scholar 

  • Wirth M, Muller H, Manseck A, Muller J, Frohmuler H (1991) Value of nuclear DNA ploidy patterns in patients with prostate cancer after radical prostatectomy. Eur Urol 20:248–252

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was financially supported in part by the Ontario Ministry of Health and Long Term Care, The Terry Fox Foundation/Research Institute (New Frontiers Research Program PPG09-020005 to R.G.B.), the Ontario Institute for Cancer Research and the Canadian Foundation for Innovation. R.G.B. is a Canadian Cancer Society Research Scientist Prostate Cancer Canada (CPC-GENE project; with monies from the Movember Foundation), and A.D. was awarded a Canadian Urology Oncology Group fellowship. The views expressed in this chapter do not necessarily reflect those of the Ontario Ministry of Health and Long Term Care.

Author information

Authors and Affiliations

  1. Departments of Radiation Oncology and Medical Biophysics, University of Toronto, Toronto, ON, Canada

    Daria Taiakina, Alan Dal Pra M.D. & Robert G. Bristow M.D., Ph.D., FRCPSC

  2. Radiation Medicine Program, Ontario Cancer Institute/Princess Margaret Cancer Center, 610 University Avenue, Toronto, ON, M5G 2M9, Canada

    Robert G. Bristow M.D., Ph.D., FRCPSC

Authors
  1. Daria Taiakina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alan Dal Pra M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert G. Bristow M.D., Ph.D., FRCPSC
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Daria Taiakina or Robert G. Bristow M.D., Ph.D., FRCPSC .

Editor information

Editors and Affiliations

  1. Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA

    Constantinos Koumenis

  2. Cancer Research, Gray Institute for Radiation Oncology, Oxford, United Kingdom

    Ester Hammond

  3. Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California, USA

    Amato Giaccia

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this paper

Cite this paper

Taiakina, D., Pra, A.D., Bristow, R.G. (2014). Intratumoral Hypoxia as the Genesis of Genetic Instability and Clinical Prognosis in Prostate Cancer. In: Koumenis, C., Hammond, E., Giaccia, A. (eds) Tumor Microenvironment and Cellular Stress. Advances in Experimental Medicine and Biology, vol 772. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5915-6_9

Download citation

Publish with us

Policies and ethics

Search

Navigation