Tumour Hypoxia – Molecular Mechanisms and Clinical Relevance
Authors:
M. Takáčová 1,2; S. Pastoreková 1,2
Authors place of work:
Regionální centrum aplikované molekulární onkologie, Masarykův onkologický ústav, Brno
1; Oddelenie molekulárnej medicíny, Virologický ústav, Slovenská akadémia vied, Bratislava, Slovenská republika
2
Published in the journal:
Klin Onkol 2015; 28(3): 183-190
Category:
Přehledy
doi:
https://doi.org/10.14735/amko2015183
Summary
Oxygen is absolutely essential for correct functioning of living organisms and alterations in its concentration lead to serious consequences. In tumor tissues, oxygen plays an important role in energy production and modulation of red- ox balance. Insufficient oxygen supply within tissues results in hypoxia that is a characteristic feature of the tumor microenvironment. Hypoxia- inducible transcriptional factor represents a key executor of a cellular and molecular response to hypoxia and can activate the expression of more than hundred genes involved in various essential cellular processes. From the clinical point of view, phenotypic alterations caused by hypoxia are serious. Tumor hypoxia has been associated with resistance to therapy, disease progression and recurrence as well as increased mortality. Therefore, intratumoral hypoxia represents a clinically relevant problem, and its detection within tumors is very important for patient stratification for a suitable treatment. Currently available strategies directed towards the detection of hypoxic regions within tumor tissue suffer from numerous limitations e. g. invasiveness, inaccessibility of tumor tissue, low sensibility, inaccurate interpretation etc. On the other hand, the use of an intrinsic endogenous hypoxic marker, which can be detected through immunohistochemistry, is relatively simple, routinely available, and reproducible and can be performed on both prospective and retrospective samples. These include carbonic anhydrase IX (CA IX), one of the most strongly hypoxia-induced proteins and a prominent indicator of chronic hypoxia. Moreover, hypoxia-induced proteins (including CA IX) are also potential targets of anticancer therapy, and their practical application is a subject of intense research.
Key words:
hypoxia – tumor microenvironment – hypoxia- inducible factor – resistance – carbonic anhydrase IX
This study was supported by European Regional Development Fund and the state budget of the Czech Republic for Regional Centre for Applied Molecular Oncology – RECAMO (CZ.1.05/2.1.00/03.0101), the project MEYS – NPS I – LO1413, European Regional Development Fund and the State Budget of the Slovak Republic (ITMS 26240220087) and the Slovak Scientific Grant Agency VEGA 2/0152/12.
The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.
The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.
Submitted:
27. 3. 2015
Accepted:
13. 4. 2015
Zdroje
1. Carreau A, El Hafny- Rahbi B, Matejuk A et al. Why is the partial oxygen pressure of human tissues a crucial parameter? Small molecules and hypoxia. J Cell Mol Med 2011; 15(6): 1239– 1253. doi: 10.1111/ j.1582- 4934.2011.01258.x.
2. Brown JM. The hypoxic cell: a target for selective cancer therapy – eighteenth Bruce F. Cain Memorial Award lecture. Cancer Res 1999; 59(23): 5863– 5870.
3. Wouters BG, van den Beucken T, Magagnin MG et al. Targeting hypoxia tolerance in cancer. Drug Resist Updat 2004; 7(1): 25– 40.
4. Brown JM. Exploiting the hypoxic cancer cell: mechanisms and therapeutic strategies. Mol Med Today 2000; 6(4): 157– 162.
5. Pugh CW, Gleadle J, Maxwell PH. Hypoxia and oxidative stress in breast cancer. Hypoxia signalling pathways. Breast Cancer Res 2001; 3(5): 313– 317.
6. Wang GL, Jiang BH, Rue EA et al. Hypoxia- inducible factor 1 is a basic- helix- loop- helix- PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 1995; 92(12): 5510– 5514.
7. Lando D, Peet DJ, Whelan DA et al. Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science 2002; 295(5556): 858– 861.
8. Huang LE, Gu J, Schau M et al. Regulation of hypoxia- inducible factor 1alpha is mediated by an O2- dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA 1998; 95(14): 7987– 7992.
9. Ivan M, Kondo K, Yang H et al. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 2001; 292(5516): 464– 468.
10. Jaakkola P, Mole DR, Tian YM et al. Targeting of HIF-alpha to the von Hippel- Lindau ubiquitylation complex by O2- regulated prolyl hydroxylation. Science 2001; 292(5516): 468– 472.
11. Schofield CJ, Ratcliffe PJ. Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol 2004; 5(5): 343– 354.
12. Berra E, Benizri E, Ginouves A et al. HIF prolyl- hydroxylase 2 is the key oxygen sensor setting low steady- state levels of HIF- 1alpha in normoxia. EMBO J 2003; 22(16): 4082– 4090.
13. Appelhoff RJ, Tian YM, Raval RR et al. Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia- inducible factor. J Biol Chem 2004; 279(37): 38458– 38465.
14. Iwai K, Yamanaka K, Kamura T et al. Identification of the von Hippel-lindau tumor- suppressor protein as part of an active E3 ubiquitin ligase complex. Proc Natl Acad Sci USA 1999; 96(22): 12436– 12441.
15. Jiang BH, Zheng JZ, Leung SW et al. Transactivation and inhibitory domains of hypoxia- inducible factor 1alpha. Modulation of transcriptional activity by oxygen tension. J Biol Chem 1997; 272(31): 19253– 19260.
16. Lando D, Peet DJ, Gorman JJ et al. FIH- 1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia- inducible factor. Genes Dev 2002; 16(12): 1466– 1471.
17. Semenza GL. Hypoxia- inducible factor 1: control of oxygen homeostasis in health and disease. Pediatr Res 2001; 49(5): 614– 617.
18. Wenger RH. Cellular adaptation to hypoxia: O2- sensing protein hydroxylases, hypoxia- inducible transcription factors, and O2- regulated gene expression. FASEB J 2002; 16(10): 1151– 1162.
19. Richard DE, Berra E, Gothié E et al. p42/ p44 mitogen-activated protein kinases phosphorylate hypoxia- inducible factor 1alpha (HIF- 1alpha) and enhance the transcriptional activity of HIF- 1. J Biol Chem 1999; 274(46): 32631– 32637.
20. Suzuki H, Tomida A, Tsuruo T. Dephosphorylated hypoxia- inducible factor 1alpha as a mediator of p53- dependent apoptosis during hypoxia. Oncogene 2001; 20(41): 5779– 5788.
21. Lancaster DE, McNeill LA, McDonough MA et al. Disruption of dimerization and substrate phosphorylation inhibit factor inhibiting hypoxia- inducible factor (FIH) activity. Biochem J 2004; 383(3): 429– 437.
22. Jeong JW, Bae MK, Ahn MY et al. Regulation and destabilization of HIF- 1alpha by ARD1- mediated acetylation. Cell 2002; 111(5): 709– 720.
23. Li F, Sonveaux P, Rabbani ZN et al. Regulation of HIF- 1alpha stability through S- nitrosylation. Mol Cell 2007; 26(1): 63– 74.
24. Cheng J, Kang X, Zhang S et al. SUMO- specific protease 1 is essential for stabilization of HIF1alpha during hypoxia. Cell 2007; 131(3): 584– 595.
25. Kewley RJ, Whitelaw ML, Chapman- Smith A. The mammalian basic helix- loop- helix/ PAS family of transcriptional regulators. Int J Biochem Cell Biol 2004; 36(2): 189– 204.
26. Gu YZ, Moran SM, Hogenesch JB et al. Molecular characterization and chromosomal localization of a third alpha- class hypoxia inducible factor subunit, HIF3alpha. Gene Expr 1998; 7(3): 205– 213.
27. Makino Y, Cao R, Svensson K et al. Inhibitory PAS domain protein is a negative regulator of hypoxia- inducible gene expression. Nature 2001; 414(6863): 550– 554.
28. Wenger RH. Mammalian oxygen sensing, signalling and gene regulation. J Exp Biol 2000; 203(8): 1253– 1263.
29. Semenza GL. Angiogenesis in ischemic and neoplastic disorders. Annu Rev Med 2003; 54: 17– 28.
30. Wang GL, Semenza GL. General involvement of hypoxia- inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci USA 1993; 90(9): 4304– 4308.
31. Semenza GL. Surviving ischemia: adaptive responses mediated by hypoxia- inducible factor 1. J Clin Invest 2000; 106(7): 809– 812.
32. Maxwell PH. Hypoxia- inducible factor as a physiological regulator. Exp Physiol 2005; 90(6): 791– 797.
33. Hockel M, Vaupel P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 2001; 93(4): 266– 276.
34. Brown JM, Giaccia AJ. The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res 1998; 58(7): 1408– 1416.
35. Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 2004; 4(6): 437– 447.
36. Comerford KM, Wallace TJ, Karhausen J et al. Hypoxia- inducible factor- 1- dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res 2002; 62(12): 3387– 3394.
37. Thomlinson RH, Gray LH. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 1955; 9(4): 539– 549.
38. Harada H. How can we overcome tumor hypoxia in radiation therapy? J Radiat Res 2011; 52(5): 545– 556.
39. Scharovsky OG, Mainetti LE, Rozados VR. Metronomic chemotherapy: changing the paradigm that more is better. Curr Oncol 2009; 16(2): 7– 15.
40. Heddleston JM, Li Z, Lathia JD et al. Hypoxia inducible factors in cancer stem cells. Br J Cancer 2010; 102(5): 789– 795. doi: 10.1038/ sj.bjc.6605551.
41. Gustafsson MV, Zheng X, Pereira T et al. Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev Cell 2005; 9(5): 617– 628.
42. Li Y, Laterra J. Cancer stem cells: distinct entities or dynamically regulated phenotypes? Cancer Res 2012; 72(3): 576– 580. doi: 10.1158/ 0008- 5472.CAN- 11- 3070.
43. Holcakova J, Nekulova M, Orzol P et al. Mechanisms of drug resistance and cancer stem cells. Klin Onkol 2014; 27 (Suppl 1): S34– S41.
44. Vaupel P, Schlenger K, Knoop C et al. Oxygenation of human tumors: evaluation of tissue oxygen distribution in breast cancers by computerized O2 tension measurements. Cancer Res 1991; 51(12): 3316– 3322.
45. Varia MA, Calkins- Adams DP, Rinker LH et al. Pimonidazole: a novel hypoxia marker for complementary study of tumor hypoxia and cell proliferation in cervical carcinoma. Gynecol Oncol 1998; 71(2): 270– 277.
46. Janssens GO, Rademakers SE, Terhaard CH et al. Accelerated radiotherapy with carbogen and nicotinamide for laryngeal cancer: results of a phase III randomized trial. J Clin Oncol 2012; 30(15): 1777– 1783. doi: 10.1200/ JCO.2011.35.9315.
47. Lee ST, Scott AM. Hypoxia positron emission tomography imaging with 18f- fluoromisonidazole. Semin Nucl Med 2007; 37(6): 451– 461.
48. Holland JP, Lewis JS, Dehdashti F. Assessing tumor hypoxia by positron emission tomography with Cu- ATSM. Q J Nucl Med Mol Imaging 2009; 53(2): 193– 200.
49. Laforest R, Dehdashti F, Lewis JS et al. Dosimetry of 60/ 61/ 62/ 64Cu- ATSM: a hypoxia imaging agent for PET. Eur J Nucl Med Mol Imaging 2005; 32(7): 764– 770.
50. Ogawa S, Menon RS, Tank DW et al. Functional brain mapping by blood oxygenation level- dependent contrast magnetic resonance imaging. A comparison of signal characteristics with a biophysical model. Biophys J 1993; 64(3): 803– 812.
51. Pastorekova S, Zavadova Z, Kostal M et al. A novel quasi- viral agent, MaTu, is a two-component system. Virology 1992; 187(2): 620– 626.
52. Pastorek J, Pastorekova S, Callebaut I et al. Cloning and characterization of MN, a human tumor-associated protein with a domain homologous to carbonic anhydrase and a putative helix- loop- helix DNA binding segment. Oncogene 1994; 9(10): 2877– 2888.
53. Opavsky R, Pastorekova S, Zelnik V et al. Human MN/ CA9 gene, a novel member of the carbonic anhydrase family: structure and exon to protein domain relationships. Genomics 1996; 33(3): 480– 487.
54. Pastorekova S, Parkkila S, Parkkila AK et al. Carbonic anhydrase IX, MN/ CA IX: analysis of stomach complementary DNA sequence and expression in human and rat alimentary tracts. Gastroenterology 1997; 112(2): 398– 408.
55. Liao SY, Aurelio ON, Jan K et al. Identification of the MN/ CA9 protein as a reliable diagnostic biomarker of clear cell carcinoma of the kidney. Cancer Res 1997; 57(14): 2827– 2831.
56. McKiernan JM, Buttyan R, Bander NH et al. Expression of the tumor-associated gene MN: a potential biomarker for human renal cell carcinoma. Cancer Res 1997; 57(12): 2362– 2365.
57. Turner JR, Odze RD, Crum CP et al. MN antigen expression in normal, preneoplastic, and neoplastic esophagus: a clinicopathological study of a new cancer-associated biomarker. Hum Pathol 1997; 28(6): 740– 744.
58. Saarnio J, Parkkila S, Parkkila AK et al. Immunohistochemical study of colorectal tumors for expression of a novel transmembrane carbonic anhydrase, MN/ CA IX, with potential value as a marker of cell proliferation. Am J Pathol 1998; 153(1): 279– 285.
59. Vermylen P, Roufosse C, Burny A et al. Carbonic anhydrase IX antigen differentiates between preneoplastic malignant lesions in non-small cell lung carcinoma. Eur Respir J 1999; 14(4): 806– 811.
60. Kivela AJ, Parkkila S, Saarnio J et al. Expression of transmembrane carbonic anhydrase isoenzymes IX and XII in normal human pancreas and pancreatic tumours. Histochem Cell Biol 2000; 114(3): 197– 204.
61. Ivanov S, Liao SY, Ivanova A et al. Expression of hypoxia- inducible cell- surface transmembrane carbonic anhydrases in human cancer. Am J Pathol 2001; 158(3): 905– 919.
62. Haapasalo JA, Nordfors KM, Hilvo M et al. Expression of carbonic anhydrase IX in astrocytic tumors predicts poor prognosis. Clin Cancer Res 2006; 12(2): 473– 477.
63. Kowalewska M, Radziszewski J, Kulik J et al. Detection of carbonic anhydrase 9- expressing tumor cells in the lymph nodes of vulvar carcinoma patients by RT-PCR. Int J Cancer 2005; 116(6): 957– 962.
64. Niemela AM, Hynninen P, Mecklin JP et al. Carbonic anhydrase IX is highly expressed in hereditary nonpolyposis colorectal cancer. Cancer Epidemiol Biomarkers Prev 2007; 16(9): 1760– 1766.
65. Jarvela S, Parkkila S, Bragge H et al. Carbonic anhydrase IX in oligodendroglial brain tumors. BMC Cancer 2008; 8: 1. doi: 10.1186/ 1471- 2407- 8- 1.
66. Takacova M, Bullova P, Simko V et al. Expression pattern of carbonic anhydrase IX in Medullary thyroid carcinoma supports a role for RET- mediated activation of the HIF pathway. Am J Pathol 2014; 184(4): 953– 965. doi: 10.1016/ j.ajpath.2014.01.002.
67. Rosenberg V, Pastorekova S, Zatovicova M et al. Relation between carbonic anhydrase IX serum level, hypoxia and radiation resistance of head and neck cancers. Klin Onkol 2014; 27(4): 269– 275.
68. Wykoff CC, Beasley NJ, Watson PH et al. Hypoxia- inducible expression of tumor-associated carbonic anhydrases. Cancer Res 2000; 60(24): 7075– 7083.
69. Wiesener MS, Munchenhagen PM, Berger I et al. Constitutive activation of hypoxia- inducible genes related to overexpression of hypoxia- inducible factor- 1alpha in clear cell renal carcinomas. Cancer Res 2001; 61(13): 5215– 5222.
70. Svastova E, Hulikova A, Rafajova M et al. Hypoxia activates the capacity of tumor-associated carbonic anhydrase IX to acidify extracellular pH. FEBS Lett 2004; 577(3): 439– 445.
71. Svastova E, Witarski W, Csaderova L et al. Carbonic anhydrase IX interacts with bicarbonate transporters in lamellipodia and increases cell migration via its catalytic domain. J Biol Chem 2012; 287(5): 3392– 3402. doi: 10.1074/ jbc.M111.286062.
72. Loncaster JA, Harris AL, Davidson SE et al. Carbonic anhydrase (CA IX) expression, a potential new intrinsic marker of hypoxia: correlations with tumor oxygen measurements and prognosis in locally advanced carcinoma of the cervix. Cancer Res 2001; 61(17): 6394– 6399.
73. Olive PL, Aquino- Parsons C, MacPhail SH et al. Carbonic anhydrase 9 as an endogenous marker for hypoxic cells in cervical cancer. Cancer Res 2001; 61(24): 8924– 8929.
74. Airley RE, Loncaster J, Raleigh JA et al. GLUT- 1 and CAIX as intrinsic markers of hypoxia in carcinoma of the cervix: relationship to pimonidazole binding. Int J Cancer 2003; 104(1): 85– 91.
75. Iakovlev VV, Pintilie M, Morrison A et al. Effect of distributional heterogeneity on the analysis of tumor hypoxia based on carbonic anhydrase IX. Lab Invest 2007; 87(12): 1206– 1217.
76. Giatromanolaki A, Koukourakis MI, Sivridis E et al. Expression of hypoxia- inducible carbonic anhydrase- 9 relates to angiogenic pathways and independently to poor outcome in non-small cell lung cancer. Cancer Res 2001; 61(21): 7992– 7998.
77. Tomes L, Emberley E, Niu Y et al. Necrosis and hypoxia in invasive breast carcinoma. Breast Cancer Res Treat 2003; 81(1): 61– 69.
78. Rafajova M, Zatovicova M, Kettmann R et al. Induction by hypoxia combined with low glucose or low bicarbonate and high posttranslational stability upon reoxygenation contribute to carbonic anhydrase IX expression in cancer cells. Int J Oncol 2004; 24(4): 995– 1004.
79. Kim SJ, Rabbani ZN, Dewhirst MW et al. Expression of HIF- 1alpha, CA IX, VEGF, and MMP- 9 in surgically resected non-small cell lung cancer. Lung Cancer 2005; 49(3): 325– 335.
80. Winter SC, Buffa FM, Silva P et al. Relation of a hypoxia metagene derived from head and neck cancer to prognosis of multiple cancers. Cancer Res 2007; 67(7): 3441– 3449.
81. Buffa FM, Harris AL, West CM et al. Large meta-analysis of multiple cancers reveals a common, compact and highly prognostic hypoxia metagene. Br J Cancer 2010; 102(2): 428– 435.
82. Toustrup K, Sorensen BS, Alsner J et al. Hypoxia gene expression signatures as prognostic and predictive markers in head and neck radiotherapy. Semin Radiat Oncol 2012; 22(2): 119– 127. doi: 10.1016/ j.semradonc.2011.12.006.
83. Pastorek J, Pastorekova S. Hypoxia-induced carbonic anhydrase IX as a target for cancer therapy: from biology to clinical use. Semin Cancer Biol 2015; 31: 52– 64. doi: 10.1016/ j.semcancer.2014.08.002.
Štítky
Detská onkológia Chirurgia všeobecná OnkológiaČlánok vyšiel v časopise
Klinická onkologie
![Číslo 3](https://www.prelekara.sk/media/cache/resolve/journal_issue/media/image_pdf/5d3c847a13fe48d87962583ec9c5a17c.jpeg)
2015 Číslo 3
- Metamizol jako analgetikum první volby: kdy, pro koho, jak a proč?
- Nejasný stín na plicích – kazuistika
- Tramadol a paracetamol v tlumení poextrakční bolesti
- Fixní kombinace paracetamol/kodein nabízí synergické analgetické účinky
- Je použití metamizolu během prvního trimestru gravidity bezpečné?
Najčítanejšie v tomto čísle
- Nové poznatky ve farmakologii methotrexátu – diagnostické možnosti a klinický význam
- Podávání kontinuálních infuzí cytostatik pomocí elastomerických infuzorů
- Nádorová hypoxia – molekulárne mechanizmy a klinický význam
- Časná integrace paliativní péče do standardní onkologické péče – benefit, limitace, bariéry a druhy paliativní péče