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Strahlentherapie und Onkologie

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01.07.2012 | Short communication

Acute versus chronic hypoxia in tumors

Controversial data concerning time frames and biological consequences

verfasst von: C. Bayer, Ph.D., P. Vaupel

Erschienen in: Strahlentherapie und Onkologie | Ausgabe 7/2012

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Abstract

Background

Many tumors contain hypoxic regions. Hypoxia, in turn, is known to increase aggressiveness and to be associated with treatment resistance. The two most frequently described and investigated subtypes of tumor hypoxia are acute and chronic. These two subtypes can lead to completely different hypoxia-related responses within the tumor, which could have a direct effect on tumor development and response to treatment. In order to accurately assess the specific biological consequences, it is important to understand which time frames best define acute and chronic hypoxia.

Materials and methods

This article provides an overview of the kinetics of in vitro and in vivo acute and chronic tumor hypoxia. Special attention was paid to differentiate between methods to detect spontaneous in vivo hypoxia and to describe the biological effects of experimental in vitro and in vivo acute and chronic tumor hypoxia.

Results and conclusions

There are large variations in reported spontaneous fluctuations in acute hypoxia that are dependent on the cell lines investigated and the detection method used. In addition to differing hypoxia levels, exposure times used to induce in vitro and in vivo experimental acute and chronic hypoxia range from 30 min to several weeks with no clear boundaries separating the two. Evaluation of the biological consequences of each hypoxia subtype revealed a general trend that acute hypoxia leads to a more aggressive phenotype. Importantly, more information on the occurrence of acute and chronic hypoxia in human tumors is needed to help our understanding of the clinical consequences.

Aguilera A, Gomez-Gonzalez B (2008) Genomic instability: a mechanistic view of its causes and consequences. Nat Rev Genet 9:204–217PubMedCrossRef

Alqawi O, Wand HP, Espiritu M, Singh G (2007) Chronic hypoxia promotes an aggressive phenotype in rat prostate cancer cells. Free Radic Res 41:788–797PubMedCrossRef

Bayer C, Shi K, Astner ST et al (2011) Acute versus chronic hypoxia: why a simplified classification is simply not enough. Int J Radiat Oncol Biol Phys 80:965–968PubMedCrossRef

Bayer C, Shi K, Maftei CA et al (2011) Assessment of chronic and acute hypoxia in head and neck cancer using microscopic and macroscopic imaging approaches. Strahlenther Onkol 187:602

Bindra RS, Crosby ME, Glazer PM (2007) Regulation of DNA repair in hypoxic cancer cells. Cancer Metastasis Rev 26:249–260PubMedCrossRef

Bennewith KL, Durand RE (2004) Quantifying transient hypoxia in human tumor xenografts by flow cytometry. Cancer Res 64:6183–6189PubMedCrossRef

Braun RD, Lanzen JL, Dewhirst MW (1999) Fourier analysis of fluctuations of oxygen tension and blood flow in R3230Ac tumors and muscle in rats. Am J Physiol Heart Circ Physiol 277:H551–H568

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

Brown JM (1979) Evidence of acutely hypoxic cells in mouse tumours, and a possible mechanism of reoxygenation. Br J Radiol 52:650–656PubMedCrossRef

10.

Brurberg KG, Graff BA, Rofstad EK (2003) Temporal heterogeneity in oxygen tension in human melanoma xenografts. Br J Cancer 89:350–356PubMedCrossRef

11.

Brurberg KG, Graff BA, Olsen DR, Rofstad EK (2004) Tumor-line specific pO₂ fluctuations in human melanoma xenografts. Int J Radiat Biol Phys 58:403–409CrossRef

12.

Cairns R, Kalliomaki T, Hill RP (2001) Acute (cyclic) hypoxia enhances spontaneous metastasis of KHT murine tumors. Cancer Res 61:8903–8908PubMed

13.

Cairns R, Hill RP (2004) Acute hypoxia enhances spontaneous lymph node metastasis in an orthotopic murine model of human cervical carcinoma. Cancer Res 64:2054–2061PubMedCrossRef

14.

Cárdenas-Navia LI, Mace D, Richardson RA et al (2008) The pervasive presence of fluctuating oxygenation in tumors. Cancer Res 68:5812–5819PubMedCrossRef

15.

Chan N, Koritzinsky M, Zhao H et al (2008) Chronic hypoxia decreases synthesis of homologous recombination proteins to offset chemoresistance and radioresistance. Cancer Res 68:605–614PubMedCrossRef

16.

Chaplin DJ, Durand RE, Olive PL (1986) Acute hypoxia in tumors: Implications for modifiers of radiation effects. Int J Radiat Oncol Biol Phys 12:1279–1282PubMedCrossRef

17.

Chaplin DJ, Olive PL, Durand RE (1987) Intermittent blood flow in a murine tumor: radiobiological effects. Cancer Res 47:597–601PubMed

18.

Chaplin DJ, Hill SA (1995) Temporal heterogeneity in microregional erythrocyte flux in experimental solid tumors. Br J Cancer 71:1210–1213PubMedCrossRef

19.

Chaudary N, Hill RP (2007) Hypoxia and metastasis. Clin Cancer Res 13:1947–1949PubMedCrossRef

20.

Dai Y, Bae K, Siemann DW (2011) Impact of hypoxia on the metastatic potential of human prostate cancer cells. Int J Radiat Oncol Biol Phys 81:521–528PubMedCrossRef

21.

Dewhirst MW, Kimura H, Rehmus SW et al (1996) Microvascular studies on the origins of perfusion-limited hypoxia. Br J Cancer Suppl 27:S247–S251PubMed

22.

Dewhirst MW (2009) Relationships between cycling hypoxia, HIF-1, angiogenesis and oxidative stress. Radiat Res 172:653–665PubMedCrossRef

23.

Durand RE, LePard NE (1995) Contribution of transient blood flow to tumor hypoxia in mice. Acta Oncol 34:317–323PubMedCrossRef

24.

Durand RE, Aquino-Parsons C (2001) Clinical relevance of intermittent tumour blood flow. Acta Oncol 40:929–936PubMedCrossRef

25.

Endrich B, Intaglietta M, Reinhold HS, Gross JF (1979) Hemodynamic characteristics in microcirculatory blood channels during early tumor growth. Cancer Res 39:17–23PubMed

26.

Goethals L, Debucquoy A, Perneel C et al (2006) Hypoxia in human colorectal adenocarcinoma: comparison between extrinsic and potential intrinsic hypoxia markers. Int J Radiat Biol Phys 65:246–254CrossRef

27.

Gulliksrud K, Vestvik IK, Galappathi K et al (2008) Detection of different hypoxic cell subpopulations in human melanoma xenografts by pimonidazole immunohistochemistry. Radiat Res 170:638–650PubMedCrossRef

28.

Hall EJ, Giacca AJ (2006) Oxygen effect and reoxygenation. In: Hall EJ, Giacca AJ (eds) Radiobiology for the Radiologist, 6th edn. Lippincott Williams & Wilkins, Philadelphia, PA, pp. 85–105

29.

Henze AT, Acker T (2010) Feedback regulators of hypoxia-inducible factors and their role in cancer biology. Cell Cycle 9:2749–2763PubMedCrossRef

30.

Hill SA, Pigott KH, Saunders MI et al (1996) Microregional blood flow in murine and human tumours assessed using laser Doppler microprobes. Br J Cancer 74(Suppl XXVII):S260–S263

31.

Höckel M, Knoop C, Schlenger K et al (1993) Intratumoral pO₂ predicts survival in advanced cancer of the uterine cervix. Radiother Oncol 26:45–50PubMedCrossRef

32.

Höckel M, Schlenger K, Aral B et al (1996) Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 56:4509–4515PubMed

33.

Höckel M, Schlenger K, Höckel S et al (1999) Hypoxic cervical cancers with low apoptotic index are highly aggressive. Cancer Res 59:4525–4528PubMed

34.

Höckel M, Vaupel P (2001) Tumor hypoxia: Definitions and current clinical, biological and molecular aspects. J Natl Cancer Inst 93:266–276PubMedCrossRef

35.

Holmquist L, Jögi A, Pahlman S (2005) Phenotypic persistence after reoxygenation of hypoxic neuroblastoma cells. Int J Cancer 116:218–225PubMedCrossRef

36.

Homquist-Mengelbier L, Fredlund E, Löfstedt T et al (2006) Recruitment of HIF-1α and HIF-2α to common target genes is differentially regulated in neuroblastoma: HIF-2α promotes an aggressive phenotype. Cancer Cell 10:413–423CrossRef

37.

Hsieh CH, Lee CH, Liang JA et al (2010) Cycling hypoxia increases U87 glioma cell radioresistance via ROS induced higher and long-term HIF-1 signal transduction activity. Oncol Rep 24:1629–1636PubMedCrossRef

38.

Hsieh CH, Shyu WC, Chiang CY et al (2011) NADPH oxidase subunit 4-mediated reactive oxygen species contribute to cycling hypoxia-promoted tumor progression in glioblastoma multiforme. PloS One 6:e23945PubMedCrossRef

39.

Hsieh CH, Chang HT, Shen WC et al (2011) Imaging the impact of Nox4 in cycling hypoxia-mediated U87 glioblastoma invasion and infiltration. Mol Imaging Biol, doi:10.1007/s11307-011-0516-0

40.

Janssen HLK, Haustermans KMG, Sprong D et al (2002) HIF-1α, pimonidazole, and iododeoxyuridine to estimate hypoxia and perfusion in human head-and-neck tumors. Int J Radiat Oncol Biol Phys 54:1537–1549PubMedCrossRef

41.

Jiang BH, Semenza GL, Bauer C, Marti HH (1996) Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am J Physiol Cell Physiol 271:C1172–C1180

42.

Kalliomäki TM, McCallum G, Wells PG, Hill RP (2009) Progression and metastasis in a transgenic mouse breast cancer model: effects of exposure to in vivo hypoxia. Cancer Lett 282:98–108PubMedCrossRef

43.

Kato Y, Yashiro M, Fuyuhiro Y et al (2011) Effects of acute and chronic hypoxia on the radiosensitivity of gastric and esophageal cancer cells. Anticancer Res 31:3369–3376PubMed

44.

Kimura H, Braun RD, Ong ET et al (1996) Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma. Cancer Res 56:5522–5528PubMed

45.

Koh MY, Lemos R, Liu X, Powis G (2011) The hypoxia-associated factor switches cells from HIF-1α- to HIF-2α-dependent signaling promoting stem cell characteristics, aggressive tumor growth and invasion. Cancer Res 71:4015–4027PubMedCrossRef

46.

Koritzinsky M, Magagnin MG, van der Beucken T et al (2006) Gene expression during acute and prolonged hypoxia is regulated by distinct mechanisms of translational control. EMBO J 25:1114–1125PubMedCrossRef

47.

Lanzen J, Brown RD, Klitzman B et al (2006) Direct demonstration of instabilities in oxygen concentrations within the extravascular compartment of an experimental tumor. Cancer Res 66:2219–2223PubMedCrossRef

48.

Lin Q, Cong X, Yun Z (2011) Differential hypoxic regulation of hypoxia-inducible factors 1α and 2α. Mol Cancer Res 9:757–765PubMedCrossRef

49.

Louie E, Nik S, Chen JS et al (2010) Identification of a stem-like cell population by exposing metastatic breast cancer cell lines to repetitive cycles of hypoxia and reoxygenation. Breast Cancer Res 12:R94PubMedCrossRef

50.

Magat J, Jordan BF, Cron GO, Gallez B (2010) Noninvasive mapping of spontaneous fluctuations in tumor oxygenation using ¹⁹F MRI. Med Phys 37:5434–5441PubMedCrossRef

51.

Maftei CA, Bayer C, Shi K et al (2011) Quantitative assessment of hypoxia subtypes in microcirculatory supply units of malignant tumors using (immuno-)fluorescence techniques. Strahlenther Onkol 187:260–266PubMedCrossRef

52.

Maftei CA, Bayer C, Astner ST et al (2011) Monitoring the fraction of total hypoxia and hypoxia subtypes in human squamous cell carcinomas during fractionated irradiation: evaluation using pattern recognition in microcirculatory supply units. Strahlenther Onkol 187(Suppl 1):25CrossRef

53.

Maftei CA, Bayer C, Shi K et al (2011) Changes in the fraction of total hypoxia and hypoxia subtypes in human squamous cell carcinomas upon fractionated irradiation: evaluation using pattern recognition in microcirculatory supply units. Radiother Oncol 101:209–216PubMedCrossRef

54.

Maftei CA, Shi K, Bayer C et al (2011) Comparison of (immuno-)fluorescence data with serial [¹⁸F]Fmiso PET/CT imaging for assessment of chronic and acute hypoxia in head and neck cancers. Radiother Oncol 99:412–417PubMedCrossRef

55.

Martinive P, Defresne F, Bouzin C et al (2006) Preconditioning of the tumor vasculature and tumor cells by intermittent hypoxia: Implications for anticancer therapies. Cancer Res 66:11736–11744PubMedCrossRef

56.

Matsumoto S, Batra S, Saito K et al (2011) Anti-angiogenic agent sunitib transiently increases tumor oxygenation and suppresses cycling hypoxia. Cancer Res 71:6350–6359PubMedCrossRef

57.

Minchinton AI, Durand RE, Chaplin DJ (1990) Intermittent blood flow in the KHT sarcoma-flow cytometry studies using Hoechst 33342. Br J Cancer 62:195–200PubMedCrossRef

58.

Mottet D, Dumont V, Deccache Y et al (2003) Regulation of hypoxia-inducible factor-1α protein level during hypoxic conditions by the phosphatidylinositol 3-kinase/akt/glycogen synthase kinase 3β pathway in HepG2 cells. J Biol Chem 33:31277–31285CrossRef

59.

Pettersen EO, Wang H (1996) Radiation-modifying effect of oxygen in synchronized cells pre-treated with acute or prolonged hypoxia. Int J Radiat Biol 70:319–326PubMedCrossRef

60.

Pigott KH, Hill SA, Chaplin DJ, Saunders MI (1996) Microregional fluctuations in perfusion within human tumours detected using laser Doppler flowmetry. Radiother Oncol 40:45–50PubMedCrossRef

61.

Pires IM, Bencokova Z, Milani M et al (2010) Effects of acute versus chronic hypoxia on DNA damage responses and genomic instability. Cancer Res 70:925–935PubMedCrossRef

62.

Quero L, Dubois L, Lieuwes NG et al (2011) miR-210 as a marker of chronic hypoxia, but not a therapeutic target in prostate cancer. Radiother Oncol 101:203–208PubMedCrossRef

63.

Ragan DMS, Schmidt EE, Macdonald IC et al (1988) Spontaneous cyclic contractions of the capillary wall in vivo, impeding red cell flow: a quantitative analysis. Evidence for endothelial cell contractility. Microvascular Res 36:13–30CrossRef

64.

Reinhold HS, Blachiwiecz B, Blok A (1977) Oxygenation and reoxygenation in ‘sandwich’ tumours. Bibl Anat 15:270–272PubMed

65.

Reinhold HS, Berg-Blok AE van den, Berg AP van den (1991) Variations in oxygenation of tumours as derived from NAD(H) measurements. Int J Radiat Biol 60:175–178PubMedCrossRef

66.

Reynolds TY, Rockwell S, Glazer PM (1996) Genetic instability induced by the tumor microenvironment. Cancer Res 56:5754–5757PubMed

67.

Rofstad EK, Maseide K (1999) Radiobiological and immunohistochemical assessment of hypoxia in human melanoma xenografts: acute and chronic hypoxia in individual tumors. Int J Radiat Biol 75:1377–1393PubMedCrossRef

68.

Rofstad EK, Galappathi K, Mathiesen B et al (2007) Fluctuating and diffusion-limited hypoxia in hypoxia-induced metastasis. Clin Cancer Res 13:1971–1978PubMedCrossRef

69.

Rofstad EK, Gaustad JV, Egeland TAM et al (2010) Tumors exposed to acute cyclic hypoxic stress show enhanced angiogenesis, perfusion and metastatic dissemination. Int J Cancer 127:1535–1546PubMedCrossRef

70.

Rouschop KM, Ramaekers CH, Schaaf MB et al (2009) Autophagy is required during cycling hypoxia to lower production of reactive oxygen species. Radiother Oncol 92:411–416PubMedCrossRef

71.

Ruggieri P (2004) Hypofractionation in non-small cell lung cancer (NSCLC): suggestions from modelling both acute and chronic hypoxia. Phys Med Biol 49:4811–4823PubMedCrossRef

72.

Russel J, Carlin S, Burke SA et al (2009) Immunohistochemical detection of changes in tumor hypoxia. Int J Radiat Oncol Biol Phys 73:1177–1186CrossRef

73.

Semenza GL (2010) Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29:625–634PubMedCrossRef

74.

Shrieve DC, Harris JW (1985) The in vitro sensitivity of chronically hypoxic EMT6/SF cells to X-radiation and hypoxic cell radiosensitizers. Int J Radiat Biol 48:127–138CrossRef

75.

Silvia P, Homer JJ, Slevin NJ et al (2007) Clinical and biological factors affecting response to radiotherapy in patients with head and neck cancer: a review. Clin Otolaryngology 32:337–345CrossRef

76.

Stewart GD, Nanda J, Katz E et al (2011) DNA strand breaks and hypoxia response inhibition mediate the radiosensitization effect of nitric oxide donors on prostate cancer under varying oxygen conditions. Biochem Pharmacol 81:203–210PubMedCrossRef

77.

Sweet R, Paul A, Zastre J (2010) Hypoxia induced upregulation and function of the thiamine transporter, SLC19A3 in a breast cancer cell line. Cancer Biol Ther 10:1101–1111PubMedCrossRef

78.

Terraneo L, Bianciardi P, Caretti A et al (2010) Chronic systemic hypoxia promotes LNCaP prostate cancer growth in vivo. Prostate 70:1243–1254PubMedCrossRef

79.

Thews O, Wolloscheck T, Dillenburg W et al (2004) Microenvironmental adaptation of experimental tumours to chronic vs. acute hypoxia. Br J Cancer 91:1181–1189PubMed

80.

Thomlinson RH, Gray LH (1955) The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 9:539–549PubMedCrossRef

81.

Trotter MJ, Chaplin DJ, Durand RE, Olive PL (1989) The use of fluorescent probes to identify regions of transient perfusion in murine tumors. Int J Radiat Oncol Biol Phys 16:931–934PubMedCrossRef

82.

Trotter MJ, Chaplin DJ, Olive PL (1991) Possible mechanisms for intermittent blood flow in the murine SCCVII carcinoma. Int J Radiat Biol 60:139–146PubMedCrossRef

83.

Tufto I, Rofstad EK (1995) Transient perfusion in human melanoma xenografts. Br J Cancer 71:789–793PubMedCrossRef

84.

Van Malenstein H, Gevaert O, Libbrecht L et al (2010) A seven-gene set associated with chronic hypoxia of prognostic importance in hepatocellular carcinoma. Clin Cancer Res 16:4278–4288CrossRef

85.

Vaupel P, Kluge M, Ambroz MC (1988) Laser Doppler flowmetry in subepidermal tumours and in normal skin of rats during localized ultrasound hyperthermia. Int J Hyperthermia 4:307–321PubMedCrossRef

86.

Vaupel P, Kelleher DK, Höckel M (2001) Oxygenation status of malignant tumors: pathogenesis of hypoxia and significance for tumor therapy. Semin Oncol 28:29–35PubMedCrossRef

87.

Vaupel P, Harrison PL (2004) Tumor hypoxia: causative factors, compensatory mechanisms, and cellular response. Oncologist 9(Suppl 5):4–9PubMedCrossRef

88.

Vaupel P (2004) Tumor microenvironmental physiology and its implications for radiation oncology. Semin Radiat Oncol 14:198–206PubMedCrossRef

89.

Vaupel P, Mayer A, Höckel M (2004) Tumor hypoxia and malignant progression. Methods Enzymol 381:335–354PubMedCrossRef

90.

Vaupel P, Höckel M, Mayer A (2007) Detection and characterization of tumor hypoxia using pO₂ histography. Antioxid Redox Signal 9:1221–1235PubMedCrossRef

91.

Vaupel P, Mayer A (2007) Hypoxia in cancer: Significance and impact on clinical outcome. Cancer Metastasis Rev 26:225–239PubMedCrossRef

92.

Vaupel P (2008) Hypoxia and aggressive tumor phenotype: implications for therapy and prognosis. Oncologist 13(Suppl 3):21–26PubMedCrossRef

93.

Vaupel P (2009) Pathophysiology of solid tumors. In: Molls M, Vaupel P, Nieder C et al (eds) The impact of tumor biology on cancer treatment and multidisciplinary strategies. Springer, Berlin-Heidelberg, pp 51–92

94.

Vaupel P (2009) Physiological mechanisms of treatment resistance. In: Molls M, Vaupel P, Nieder C et al (eds) The impact of tumor biology on cancer treatment and multidisciplinary strategies. Springer, Berlin-Heidelberg, pp. 273–290

95.

Vaupel P (2011) Acute and chronic hypoxia in the clinical setting: merely an academic discussion or do we need to distinguish between the two? Strahlenther Onkol 187:601

96.

Vordermark D, Menke DR, Brown JM (2003) Similar radiation sensitivities of acutely and chronically hypoxic HT fibrosarcoma xenografts. Radiat Res 159:94–101PubMedCrossRef

97.

Yasui H, Matsumoto S, Devasahayam N et al (2010) Low-field magnetic resonance imaging to visualize chronic and cycling hypoxia in tumor-bearing mice. Cancer Res 70:6427–6436PubMedCrossRef

98.

Yu L, Hales CA (2011) Long-term exposure to hypoxia inhibits tumor progression of lung cancer in rats and mice. BMC Cancer 11:331PubMedCrossRef

99.

Wang K, Yorke E, Nehmeh SA et al (2009) Modeling acute and chronic hypoxia using serial images of ¹⁸F-FMISO PET. Med Phys 36:4400–4408PubMedCrossRef

100.

Zölzer F, Streffer C (2002) Increased radiosensitivity with chronic hypoxia in four human tumor cell lines. Int J Radiat Biol Phys 54:910–920CrossRef

Titel: Acute versus chronic hypoxia in tumors
Controversial data concerning time frames and biological consequences
verfasst von: C. Bayer, Ph.D.
P. Vaupel
Publikationsdatum: 01.07.2012
Verlag: Springer-Verlag
Erschienen in: Strahlentherapie und Onkologie / Ausgabe 7/2012
Print ISSN: 0179-7158
Elektronische ISSN: 1439-099X
DOI: https://doi.org/10.1007/s00066-012-0085-4

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Springer Medizin

Acute versus chronic hypoxia in tumors

Controversial data concerning time frames and biological consequences

Abstract

Background

Materials and methods

Results and conclusions

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Abstract

Background

Materials and methods

Results and conclusions

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