ADENOSINE AS A POTENTIAL TARGET FOR CANCER BIOTHERAPY
Abstract
The literature review describes the role of extracellular adenosine in formation of immunosuppressive adenosinergic microenvironment of solid tumors. Hypoxia-induced accumulation of extracellular adenosine in 50–100 μM concentration (cf the normal 10–100 nM) is a pathophysiological indicator of a broad spectrum of human malignant neoplastic diseases. Four types of cell surface receptors for adenosine as the signal molecule have been revealed. Upon activation the receptors cause inhibition of effector functions of cytotoxic T-lymphocytes, native killers and macrophages playing a key part in antitumor immune response. The author of the review proposed the idea to remove the procancer shield from immune attack using adenosine deaminase fused with annexin A5. It was postulated that such chimeric protein injected into the body of cancer patient will bind exclusively with tumor cells and disrupt adenosine protecting them from cancerostatic immune action.
About the Author
A. I. Zinchenko
Institute of Microbiology of the National Academy of Sciences of Belarus
Belarus
D. Sc. (Biol.), Professor, Head of Laboratory
Belarus
D. Sc. (Biol.), Professor, Head of Laboratory
References
1. Blay J. (2012) ‟Adenosine and tumor microenvironment”, Encyclopedia of Cancer, 3nd ed., Springer, Heidelberg, DE, pp. 49-53.
2. Ramakers, B. P., Wever, K. E., Kox, M., van den Broek, P. H., Mbuyi, F., Rongen, G., Masereeuw, R., van der Hoeven, J. G., Smits, P., Riksen, N. P. and Pickkers, P. (2012) ‟How systemic inflammation modulates adenosine metabolism and adenosine receptor expression in humans in vivo”, Critical Care Medicine, vol. 40, no. 9, pp. 2609-2616.
3. Spychala, J. (2000) ‟Tumor-promoting functions of adenosine”, Pharmacology & Therapeutics, vol. 87, no. 2–3, pp. 161-173.
4. Volmer, J. B., Thompson, L. F. and Blackburn, M. R. (2006) ‟Ecto-5′-nucleotidase (CD73)-mediated adenosine production is tissue protective in a model of bleomycin-induced lung injury”, Journal of Immunology, vol. 176, pp. 4449-4458.
5. Grenz, A., Zhang, H., Weingart, J., von Wietersheim, S., Eckle, T., Schnermann, J., Kohle, C., Kloor, D., Gleiter, C. H., Vallon, V., Eltzschig, H. K. and Osswald, H. (2007) ‟Lack of effect of extracellular adenosine generation and signaling on renal erythropoietin secretion during hypoxia”, American Journal of Physiology. Renal Physiology, vol. 293, pp. 1501-1511.
6. Baldwin, S. A., Beal, P. R., Yao, S. Y., King, A. E., сass, C. E. and Young, J. D. (2004) ‟The equilibrative nucleoside transporter family, SLC29”, Pflugers Arch, vol. 447, no. 5, pp. P. 735-743.
7. Busse, M. and Vaupel, P. (1996) ‟Accumulation of purine catabolites in solid tumors exposed to therapeutic hyperthermia”, Experientia, vol. 52, no. 5, pp. 469-473.
8. Hasko, G. and Cronstein, B. N. (2004) ‟Adenosine: an endogenous regulator of innate immunity‟, Trends in Immunology, vol. 25, no. 1, pp. 33-39.
9. Ohta, A., Gorelik, E., Prasad, S. J., Ronchese, F., Lukashev, D., Wong, M., Huang, X., Caldwell, S., Liu, K., Smith, P. Chen, J. F., Jackson, E. K., Apasov, S., Abrams, S. and Sitkovsky, M. (2006) ‟A2A adenosine receptor protects tumors from antitumor T cells”, Proceedings of the National Academy of Sciences, vol. 103, pp. 13132-13137.
10. Vaupel, P. and Mayer, A. (2016) ‟Hypoxia-driven adenosine accumulation: a crucial microenvironmental factor promoting tumor progression”, Advances in Experimental Medicine and Biology, vol. 876, pp. 177-183.
11. Kobayashi, S., Zimmermann, H. and Millhorn, D. E. (2000) ‟Chronic hypoxia enhances adenosine release in rat PC12 cells by altering adenosine metabolism and membrane transport”, Journal of Neurochemistry, vol. 74, pp. 621-632.
12. Synnestvedt, K., Furuta, G. T., Comerford, K. M., Louis, N., Karhausen, J., Eltzschig, H. K., Hansen, K. R., Thompson, L. F. and Colgan, S. P. (2002) ‟Ecto-5′-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia”, Journal of Clinical Investigation, vol. 110, pp. 993-1002.
13. Decking, U. K., Schlieper, G., Kroll, K. and Schrader, J. (1997) ‟Hypoxia- induced inhibition of adenosine kinase potentiates cardiac adenosine release”, Circulation Research , vol. 81, pp. 154-164.
14. Fredholm, B. B., Izerman, A. P., Jacobson, K. A., Klotz, K. N. and Linden, J. (2001) ‟International union of pharmacology. XXV. Nomenclature and classification of adenosine receptors”, Pharmacological Reviews, vol. 53, pp. 527-552.
15. Linden, J. (2001) ‟Molecular approach to adenosine receptors: receptor-mediated mechanisms of tissue protection”, Annual Review of Pharmacology and Toxicology, vol. 41, pp. 775-787.
16. Nowak, M., Lynch, L., Yue, S., Ohta, A., Sitkovsky, M., Balk, S. P. and Exley, M. A. (2010) ‟The A2aR adenosine receptor controls cytokine production in iNKT cells‟, European Journal of Immunology, vol. 40, no. 3, pp. 682-687.
17. Vaupel, P. and Multhoff, G. (2016) ‟Adenosine can thwart antitumor immune responses elicited by radiotherapy. Therapeutic strategies alleviating protumor ADO activities”, Strahlentherapie und Onkologie, vol. 192, no. 5, pp. 279-287.
18. Ohta, A. (2016) ‟A metabolic immune checkpoint: adenosine in tumor microenvironment”, Frontiers in Immunology, Available at: http://dx. doi. org/10.3389/fimmu.2016.00109.
19. Hasko, G. and Pacher, P. (2012) ‟Regulation of macrophage function by adenosine”, Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 32, pp. 865 -869.20. Morello, S., Pinto, A., Blandizzi, C. and Antonioli, L. (2016) ‟Myeloid cells in the tumor microenvironment: role of adenosine”, Oncoimmunology, Available at: http://dx. doi. org/10.1080/2162402X.2015.1108515.
20. Itoh, K., Tilden, A. B. and Balch, C. M. (1986) ‟Interleukin 2 activation of cytotoxic T-lymphocytes infiltrating into human metastatic melanomas”, Cancer research, vol. 46, pp. 3011-3017.
21. Antonioli, L., Blandizzi, C., Pacher, P. and Hasko, G. (2013) ‟Immunity, inflammation and cancer: a leading role for adenosine”, Nature Reviews Cancer, vol. 13, no. 12, pp. 842-857.
22. Thammavongsa, V., Kern, J. W., Missiakas, D. M. and Schneewind, O. (2009) ‟Staphylococcus aureus synthesizes adenosine to escape host immune responses”, Journal of Experimental Medicine, vol. 206, pp. 2417-2427.
23. Crane, J. K., Olson, R. A., Jones, H. M. and Duffey, M. E. (2002) ‟Release of ATP during host cell killing by enteropathogenic E. coli and its role as a secretory mediator”, American Journal of Physiology – Gastrointestinal and Liver Physiology, vol. 283, pp. G74-G86.
24. Tasca, T., Bonan, C. D., Carli, G. A., Battastini, A. M. and Sarkis, J. J. (2003) ‟Characterization of an ecto-5′-nucleotidase (EC 3.1.3.5) activity in intact cells of Trichomonas vaginalis”, Experimental Parasitology, vol. 105, pp. 167-173.
25. Young, A., Mittal, D., Stagg, J. and Smyth, M. J. (2014) ‟Targeting cancer-derived adenosine: new therapeutic approaches”, Cancer Discovery , vol. 4, no. 8, pp. 879-888.
26. Sitkovsky, M. V., Hatfield, S., Abbott, R., Belikoff, B., Lukashev, D. and Ohta, A. (2014) ‟Hostile, hypoxia-A2-adenosinergic tumor biology as the next barrier to overcome for tumor immunologists”, Cancer Immunology Research, vol. 2, no. 7, pp. 598-605.
27. Ohta, A. and Sitkovsky, M. (2014) ‟Extracellular adenosine-mediated modulation of regulatory T cells”, Frontiers in Immunology, Available at: http://dx. doi. org/10.3389/fimmu.2014.00304.
28. Antonioli, L., Hasko, G., Fornai, M., Colucci, R. and Blandizzi, C. (2014) ‟Adenosine pathway and cancer: where to go from here?”, Expert Opinion on Therapeutic Targets, vol. 18, no. 9, pp. 973-977.
29. Hausler, S. F., Del Barrio, I. M., Diessner, J., Stein, R. G., Strohschein, J., Honig, A., Dietl, J. and Wischhusen, J. (2014) ‟Anti-CD39 and anti-CD73 antibodies A1 and 7G2 improve targeted therapy in ovarian cancer by blocking adenosine- ependent immune evasion”, American Journal of Translational Research, vol. 6, no. 2, pp. 129-139.
30. Merighi, S., Mirandola, P., Varani, K., Gessi, S., Leung, E., Baraldi, P. G., Tabrizi, M. A. and Borea, P. A. (2003) ‟A glance at adenosine receptors: novel target for antitumor therapy”, Pharmacology & Therapeutics, vol. 100, no. 1, pp. 31- 48.
31. Sitkovsky, M., Lukashev, D., Deaglio, S., Dwyer, K., Robson, S. C. and Ohta, A. (2008) ‟Adenosine A2A receptor antagonists: blockade of adenosinergic effects and T regulatory cells”, British Journal of Pharmacology, vol. 153, suppl. 1, pp. S457–S464.
32. Hatfield, S. M., Kjaergaard, J., Lukashev, D., Schreiber, T. H., Belikoff, B., Abbott, R., Sethumadhavan, S., Philbrook, P., Ko, K., Cannici, R.,Thayer, M., Rodig, S., Kutok, J. L., Jackson, E. K., Karger, B., Podack, E. R., Ohta A. and Sitkovsky, M. V. (2015) ‟Immunological mechanisms of the antitumor effects of supplemental oxygenation”, Science Translational Medicine, vol. 7, no. 277, Available at: http://stm. sciencemag. org/content/7/277/277ra30.
33. Hatfield, S. M. and Sitkovsky, M. (2016) ‟A2A adenosine receptor antagonists to weaken the hypoxia-HIF-1a driven immunosuppression and improve immunotherapies of cancer”, Current Opinion in Pharmacology, vol. 29, no. 1, pp. 90-96.
34. Hatfield, S. M. and Sitkovsky, M. (2015) ‟Oxygenation to improve cancer vaccines, adoptive cell transfer and blockade of immunological negative regulators”, Oncoimmunology, vol. 4, no. 12, Available at: https://dash. harvard. edu/bitstream/ handle/1/25658394/4635883. pdf?sequence=1.36. Sheth, S., Brito, R., Mukherjea, D.,
35. Rybak, L. P. and Ramkumar, V. (2014) ‟Adenosine receptors: expression, function and regulation”, International Journal of Molecular Sciences, vol. 15, no. 2, pp. 2024- 2052.
36. Cekic, C. and Linden, J. (2014) ‟Adenosine A2A receptors intrinsically regulate CD8+ T cells in the tumor microenvironment”, Cancer Research, vol. 74, pp. 7239-7249.
37. Allard, B., Pommey, S., Smyth, M. J. and Stagg, J. (2013) ‟Targeting CD73 enhances the anti-tumor activity of anti- PD-1 and anti-CTLA-4 mAbs”, Clinical Cancer Research, vol. 19, pp. 5626-5635.
38. Beavis, P. A., Milenkovski, N., Henderson, M. A., John, L. B., Allard, B., Loi, S., Kershaw, M. H., Stagg, J. and Darcy, P. K. (2015) ‟Adenosine receptor 2A blockade increases the efficacy of anti-PD-1 through enhanced antitumor T-cell responses”, Cancer Immunology Research, vol. 3, pp. 506-517.
39. Allard, B., Beavis, P. A., Darcy, P. K. and Stagg, J. (2016) ‟Immunosuppressive activities of adenosine in cancer”, Current Opinion in Pharmacology, vol. 29, pp. 7-16.
40. Hellstrom, I., Hellstrom, K. E., Pierce, G. E. and Yang, J. P. (1968) ‟Cellular and humoral immunity to different types of human neoplasms”, Nature, vol. 220, pp. 1352-1354.
41. Lukashev, D., Sitkovsky, M. and Ohta, A. (2007) ‟From “Hellstrom Paradox” to anti-adenosinergic cancer immunotherapy”, Purinergic Signalling, vol. 3, pp. 129-134.
42. Malhotra, V. and Perry, M. C. (2003) ‟Classical chemotherapy: mechanisms, toxicities and the therapeutic window”, Cancer Biology & Therapy, vol. 2, suppl. 1, pp. S2–S4.
43. Corrie, P. G. (2011) ‟Cytotoxic chemotherapy: clinical aspects”, Medicine, vol. 39, pp. 717-722.
44. Vinay, D. S., Ryan, E. P., Pawelec, G., Talib, W. H., Stagg, J., Elkord, E., Lichtor, T., Decker, W. K., Whelan, R. L. and Kumara, H. M. (2015) ‟Immune evasion in cancer: mechanistic basis and therapeuticstrategies”, Seminars in Cancer Biology, vol. 35, pp. 185–198.
45. Utsugi, T., Schroit, A. J., Connor, J., Bucana, C. D. and Fidler, I. J. (1991) ‟Elevated expression of phosphatidylserine in the outer membrane leaflet of human tumor cells and recognition by activated human bloodmonocytes”, Cancer Research, 1991, vol. 51, pp. 3062-3066.
46. Ran, S., Downes, A. and Thorpe, P. E. (2002) ‟Increased exposure of anionic phospholipids on the surface of tumor blood vessels”, Cancer Research, vol. 62, no. 21, pp. 6132-6140.48. Birge, R. B., Boeltz, S., Kumar, S., Carlson, J., Wanderley, J., Calianese, D., Barcinski, M., Brekken, R. A., Huang, X., Hutchins, J. T. and Freimark, B. (2016) ‟Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer”, Cell Death Differ, vol. 23, no. 6, pp. 962-978.
47. Zwaal, R. F. and Schroit, A. J. (1997) ‟Pathophysiologic implications of membrane phospholipid asymmetry in blood cells”, Blood, vol. 89, pp. 1121-1132.
48. Bevers, E. M., Comfurius, P., Dekkers, D. W., Harmsma, M. and Zwaal, R. F. (1998) ‟Regulatory mechanisms of transmembrane phospholipid distributions and pathophysiological implications of transbilayer lipid scrambling”, Lupus, vol. 7, suppl. 2, pp. 126-131.
49. Vallabhapurapu, S. D., Blanco, V. M., Sulaiman, M. K., Vallabhapurapu, S. L., Chu, Z., Franco, R. S. and Qi, X. (2015) ‟Variation in human cancer cell external phosphatidylserine is regulated by flippase activity and intracellular calcium”, Oncotarget, vol. 6, no. 33, pp. 34375-34388.
50. Ganta, S., Devalapally, H., Shahiwala, A. and Amiji, M. (2008) ‟A review of stimuli-responsive nanocarriers for drug and gene delivery”, Journal of Controlled Release, vol. 126, no. 3, pp. 187-204.
51. Zweytick, D., Riedl, S., Rinner, B., Asslaber, M., Schaider, H., Walzer, S., Novak, A. and Lohner, K. (2011) ‟In search of new targets – the membrane lipid phosphatidylserine – the underestimated Achilles’ Heel of cancer cells”, Annals of Oncology, vol. 22, suppl. 3, p. 43.
52. Schick, P. K., Kurica, K. B. and Chacko, G. K. (1976) ‟Location of phosphatidylethanolamine and phosphatidylserine in the human platelet plasma membrane”, Journal of Clinical Investigation, vol. 57, pp. 1221-1226.
53. Andree, H. A., Reutelingsperger, C. P., Hauptmann, R., Hemker, H. C., Hermens, W. T. and Willems, G. M. (1990) ‟Binding of vascular anticoagul ant alpha (VAC alpha) to planar phospholipid bilayers”, Journal of Biological Chemistry, vol. 265, pp. 4923-4928.
54. Krais, J. J., De Crescenzo, O. and Harrison, R. G. (2013) ‟Purine nucleoside phosphorylase targeted by Annexin V to breast cancer vasculature for enzyme prodrug therapy”, Public Library of Science ONE, vol. 8, no. 10.
55. Burko, D. V., Eroshevskaya, L. A., Kvach, S. V., Shakhbazau, A. V., Kartel, N. A. and Zinchenko, A. I. (2010) ‟Application of recombinant enzymes for the synthesis of pharmaceutically valuable nucleosides and nucleotides”, Biotechnology in Medicine, Biocatalysis, Environment and Biogeotechnology, Nova Science Publishers, New York, US, pp. 1-13.
56. Korovashkina, A. S., Rymko, A. N., Kvach, S. V. and Zinchenko, A. I. (2013) ‟Enzymatic synthesis of c-di-GMP using inclusion bodies of Thermotoga maritima full-length diguanylate cyclase”, Journal of Biotechnology, vol. 164, no. 2, pp. 276-280.
57. Rymko, A. N., Kvach, S. V. and Zinchenko, A. I. (2013) ‟Creation of Escherichia coli strain producing deoxynucleoside kinase of Drosophila melanogaster”, Vestsі Natsyyanal’nai akademіі navuk Belarusі. Seryya bіyalagіchnykh navuk [Proceedings of the National academy of sciences of Belarus, biological series], no. 2, pp. 87-90.
58. Mishura, A. A., Rymko, A. N. and Zinchenko, A. I. (2016) ‟Construction of chimeric proteins producing strains containing in their structure chitin-binding domain”, Sakharovskie chteniya 2016 g.: ekologicheskie problemy XXI veka: materialy 15-i mezhdunarodnoi nauchnoi konferentsii, Minsk, 19–20 maya 2016 g., MGEI im. A. D. Sakharova BGU [Proc. 15th Int. Conf. “Sakharov readings 2016: environmental problems of the 21st century”], Minsk, 19–20 Маy 2016, Minsk, BY, p. 85.
59. Kvach, S. V., Eroshevskaya, L. A. and Zinchenko, A. I. (2008) ‟Optimization of expression conditions of the strain-superproducer of Escherichia coli adenosine deaminase”, Dinamika izsledovaniya–2008: materiali za IV Mezhdunar. nauch.- prakt. konf., Sofiya, 16–31 yuli 2008 g. [Proceed. 4th Int. Scientific and Practical Conf. ‟Dynamics of a Research-2008”], Sofia, July 16–31 2008, Sofia, BG, vol. 22, pp. 26– 29.
60. Eroshevskaya, L. A., Kvach, S. V. and Zinchenko, A. I. (2009) ‟Construction and use of genetically engineered Escherichia coli adenosine deaminase”, Sovremennye problemy fiziologii, ekologii i biotekhnologii mikroorganizmov: materialy Vserossiiskogo simpoziuma s mezhdunarodnym uchastiem, Moskva, MGU, 24–27 dek. 2009 g. [Proceedings All-Russian Symposium with the International Participation ‟Modern problems of physiology, ecology and biotechnology of microorganisms”], Moscow, December 24–27 2009, Moscow, RU, p. 61.
61. Beresnev, А. I., Kvach, S. V., Sivets, G. G. and Zinchenko, A. I. (2013) ‟Synthesis of purine 3′-α-fluornucleosides with application of Thermus thermophilus pyrimidine nucleoside phosphorylase and Esherichia coli purine nucleoside phosphorylase”, Vestsі Natsyyanal’nai akademіі navuk Belarusі. Seryya bіyalagіchnykh navuk [Proceedings of the National Academy of Sciences of Belarus, biological series], no. 4, pp. 71-76.
Review
Views:
978
Email this article 
