Targeting CD73 and downstream adenosine receptor signaling in triple-negative breast cancer

Expert Opinion on Therapeutic Targets

Volumn 18, Issue 8, 2014, Pages 863-881

  Allard, Bertrand ^a   Turcotte, Martin ^a   Stagg, John ^a  

^a CENTRE HOSPITALIER DE L UNIVERSITÉ DE MONTRÉAL   (Canada)

Author keywords

Adenosine receptors; CD73; Immunosuppression; Triple negative breast cancer

Indexed keywords

5' NUCLEOTIDASE; ADENOSINE; ADENOSINE DIPHOSPHATE; ADENOSINE PHOSPHATE; ADENOSINE RECEPTOR; ADENOSINE TRIPHOSPHATE; ALPHA,BETA METHYLENEADENOSINE DIPHOSPHATE; CALCIUM; CD39 ANTIGEN; T LYMPHOCYTE RECEPTOR; ADENOSINE A1 RECEPTOR ANTAGONIST; ADENOSINE A2A RECEPTOR; ADENOSINE A2B RECEPTOR; ANTINEOPLASTIC AGENT; GLYCOSYLPHOSPHATIDYLINOSITOL ANCHORED PROTEIN; NT5E PROTEIN, HUMAN;

AMINO TERMINAL SEQUENCE; ANTIGEN EXPRESSION; BREAST CARCINOGENESIS; CALCIUM TRANSPORT; CANCER GROWTH; CANCER PROGNOSIS; CARBOXY TERMINAL SEQUENCE; CATALYSIS; CD8+ T LYMPHOCYTE; COMPLEX FORMATION; CRYSTAL STRUCTURE; DISEASE ASSOCIATION; ENZYME ACTIVITY; ENZYME STRUCTURE; GLYCOSYLATION; HUMAN; LYMPHOCYTE PROLIFERATION; MOLECULAR WEIGHT; NONHUMAN; PROTEIN FUNCTION; PROTEIN TARGETING; REVIEW; SIGNAL TRANSDUCTION; TRIPLE NEGATIVE BREAST CANCER; TUMOR MICROENVIRONMENT; UPREGULATION; ANIMAL; ANTAGONISTS AND INHIBITORS; DRUG DESIGN; DRUG EFFECTS; FEMALE; GENE EXPRESSION REGULATION; METABOLISM; MOLECULARLY TARGETED THERAPY; PATHOLOGY; TRIPLE NEGATIVE BREAST NEOPLASMS;

5'-NUCLEOTIDASE; ADENOSINE A1 RECEPTOR ANTAGONISTS; ANIMALS; ANTINEOPLASTIC AGENTS; DRUG DESIGN; FEMALE; GENE EXPRESSION REGULATION, NEOPLASTIC; GPI-LINKED PROTEINS; HUMANS; MOLECULAR TARGETED THERAPY; RECEPTOR, ADENOSINE A2A; RECEPTOR, ADENOSINE A2B; SIGNAL TRANSDUCTION; TRIPLE NEGATIVE BREAST NEOPLASMS;

EID: 84904433795     PISSN: 14728222     EISSN: 17447631     Source Type: Journal    
DOI: 10.1517/14728222.2014.915315     Document Type: Review

References (171)

1. Stagg J, Allard B. Immunotherapeutic approaches in triple-negative breast cancer: Latest research and clinical prospects. Ther Adv Med Oncol 2013;5:169-81
2. Bauer KR, Brown M, Cress RD, et al. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype. Cancer 2007;109:1721-8 (Pubitemid 46668532)
3. Dent R, Trudeau M, Pritchard KI, et al. Triple-negative breast cancer: Clinical features and patterns of recurrence. Clin Cancer Res 2007;13:4429-34. (Pubitemid 47219710)
4. Anders CK, Deal AM, Miller CR, et al. The prognostic contribution of clinical breast cancer subtype, age, and race among patients with breast cancer brain metastases. Cancer 2011;117:1602-11
5. Lund M, Trivers K, Porter P, et al. Race and triple negative threats to breast cancer survival: A population-based study in Atlanta, GA. Breast Cancer Res Treat 2009;113:357-70
6. Perou CM, Sørlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature 2000;406:747-52.
7. Nielsen TO, Hsu FD, Jensen K, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 2004;10:5367-74 (Pubitemid 39100473)
8. Carey LA. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 2006;295:2492-502 (Pubitemid 43854964)
9. Liedtke C, Mazouni C, Hess KR, et al. Response to neoadjuvant therapy and long-term survival in patients with triplenegative breast cancer. J Clin Oncol 2008;26:1275-81.
10. Dent R, Hanna WM, Trudeau M, et al. Pattern of metastatic spread in triplenegative breast cancer. Breast Cancer Res Treat 2009;115:423-8
11. Cancello G, Maisonneuve P, Rotmensz N, et al. Prognosis and adjuvant treatment effects in selected breast cancer subtypes of very young women (35 years) with operable breast cancer. Ann Oncol, 2010, 21, 1974-81
12. Metzger O, de Azambuja E, Quinaux E, et al. Lymph node ratio is an independent risk classifier in node positive breast cancer patients: Results of the phase III BIG 02-98 trial. Eur J Cancer Suppl 2010;8:61
13. Prat A, Adamo B, Cheang MCU, et al. Molecular characterization of basal-like and non-basal-like triple-negative breast cancer. Oncologist 2013;18:123-33
14. Hugh J, Hanson J, Cheang MCU, et al. Breast cancer subtypes and response to docetaxel in node-positive breast cancer: Use of an immunohistochemical definition in the BCIRG 001 trial. J Clin Oncol 2009;27:1168-76
15. Fulford LG, Reis-Filho JS, Ryder K, et al. Basal-like grade III invasive ductal carcinoma of the breast: Patterns of metastasis and long-term survival. Breast Cancer Res 2007;9:R4
16. Thike AA, Iqbal J, Cheok PY, et al. Triple negative breast cancer: Outcome correlation with immunohistochemical detection of basal markers. Am J Surg Pathol 2010;34:956-64
17. O'Toole SA, Beith JM, Millar EKA, et al. Therapeutic targets in triple negative breast cancer. J Clin Pathol 2013;66:530-42
18. Plummer R. Poly(ADP-ribose) polymerase inhibition: A new direction for BRCA and triple-negative breast cancer? Breast Cancer Res 2011;13:218
19. Lehmann BD, Bauer JA, Chen X, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 2011;121:2750-67.
20. Prat A, Parker J, Karginova O, et al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res 2010;12:1-18
21. Farmer P, Bonnefoi H, Becette V, et al. Identification of molecular apocrine breast tumours by microarray analysis. Breast Cancer Res 2005;7:1
22. Bertucci F, Finetti P, Cervera N, et al. Gene expression profiling shows medullary breast cancer is a subgroup of basal breast cancers. Cancer Res 2006;66:4636-44
23. Von Minckwitz G, Untch M, Blohmer J-U, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 2012;30:1796-804
24. Frasci G, Comella P, Rinaldo M, et al. Preoperative weekly cisplatin-epirubicin-paclitaxel with GCSF support in triple-negative large operable breast cancer. Ann Oncol 2009;20:1185-92
25. Antonioli L, Pacher P, Vizi ES, Haskó G. CD39 and CD73 in immunity and inflammation. Trends Mol Med 2013;19:355-67.
26. Stagg J, Divisekera U, McLaughlin N, et al. Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis. Proc Natl Acad Sci USA 2010;107:1547-52.
27. Lois S, Pommey S, Haibe-Kains B, et al. CD73 is associated with poor prognosis and anthracycline resistance in triple negative breast cancer. Proc Natl Acad Sci USA 2013;110(27):11091-6.
28. Rust S, Guillard S, Sachsenmeier K, et al. Combining phenotypic and proteomic approaches to identify membrane targets in a "triple negative" breast cancer cell type. Mol Cancer 2013;12:11.
29. Terp MG, Olesen KA, Arnspang EC, et al. Anti-human CD73 monoclonal antibody inhibits metastasis formation in human breast cancer by inducing clustering and internalization of CD73 expressed on the surface of cancer cells. J Immunol 2013;191:4165-73.
30. Misumi Y, Ogata S, Ohkubo K, et al. Primary structure of human placental 5'-nucleotidase and identification of the glycolipid anchor in the mature form. Eur J Biochem 1990;191:563-9
31. Misumi Y, Ogata S, Hirose S, Ikehara Y. Primary structure of rat liver 5'-nucleotidase deduced from the cDNA. Presence of the COOH-terminal hydrophobic domain for possible posttranslational modification by glycophospholipid. J Biol Chem 1990;265:2178-83
32. Volknandt W, Vogel M, Pevsner J, et al. 5'-nucleotidase from the electric ray electric lobe. Primary structure and relation to mammalian and procaryotic enzymes. Eur J Biochem 1991;202:855-61
33. Klemens MR, Sherman WR, Holmberg NJ, et al. Characterization of soluble vs membrane-bound human placental 5'-nucleotidase. Biochem Biophys Res Commun 1990;172:1371-7
34. Fini C, Talamo F, Cherri S, et al. Biochemical and mass spectrometric characterization of soluble ecto-5'-nucleotidase from bull seminal plasma. Biochem J 2003;372:443-51 (Pubitemid 36723890)
35. Vogel M, Kowalewski H, Zimmermann H, et al. Soluble low-Km 5'-nucleotidase from electric-ray (Torpedo marmorata) electric organ and bovine cerebral cortex is derived from the glycosyl-phosphatidylinositol-anchored ectoenzyme by phospholipase C cleavage. Biochem J 1992;284(Pt 3):621-624
36. Chuang NN, Newby AC, Luzio JP. Characterization of different molecular forms of 5'-nucleotidase in normal serum and in serum from cholestatic patients and bile-duct-ligated rats. Biochem J 1984;224:689-95 (Pubitemid 15155691)
37. Johnson SM, Patel S, Bruckner FE, Collins DA. 5'-Nucleotidase as a marker of both general and local inflammation in rheumatoid arthritis patients. Rheumatology (Oxford) 1999;38:391-6 (Pubitemid 29507120)
38. Buschette-Brambrink S, Gutensohn W. Human placental ecto-5'-nucleotidase: Isoforms and chemical crosslinking products of the membrane-bound and isolated enzyme. Biol Chem Hoppe Seyler 1989;370:67-74 (Pubitemid 19043070)
39. Bailyes EM, Soos M, Jackson P, et al. The existence and properties of two dimers of rat liver ecto-5'-nucleotidase. Biochem J 1984;221:369-77
40. Mart́nez-Mart́nez A, Muñoz-Delgado E, Campoy FJ, et al. The ecto-5'-nucleotidase subunits in dimers are not linked by disulfide bridges but by non-covalent bonds. Biochim Biophys Acta 2000;1478:300-8
41. Fini C, Palmerini CA, Damiani P, et al. 5'-nucleotidase from bull seminal plasma, chicken gizzard and snake venom is a zinc metalloprotein. Biochim Biophys Acta 1990;1038:18-22 (Pubitemid 20086739)
42. Zimmermann H. 5'-Nucleotidase: Molecular structure and functional aspects. Biochem J 1992;285:345-65.
43. Zimmermann H, Zebisch M, Sträter N. Cellular function and molecular structure of ecto-nucleotidases. Purinergic Signal 2012;8:437-502.
44. Yegutkin GG, Henttinen T, Jalkanen S. Extracellular ATP formation on vascular endothelial cells is mediated by ectonucleotide kinase activities via phosphotransfer reactions. FASEB J 2001;15:251-60 (Pubitemid 32063205)
45. Neu HC. The 5'-Nucleotidase of Escherichia coli I. Purification and properties. J Biol Chem 1967;242:3896-904
46. El-Tayeb A, Iqbal J, Behrenswerth A, et al. Nucleoside-5'-monophosphates as prodrugs of adenosine A2A receptor agonists activated by ecto-5'- nucleotidase. J Med Chem 2009;52:7669-77
47. Garavaglia S, Bruzzone S, Cassani C, et al. The high-resolution crystal structure of periplasmic Haemophilus influenzae NAD nucleotidase reveals a novel enzymatic function of human CD73 related to NAD metabolism. Biochem J 2012;441:131-41
48. Knofel T, Sträter N. X-ray structure of the Escherichia coli periplasmic 5'-nucleotidase containing a dimetal catalytic site. Nat Struct Biol 1999;6:448-53
49. Knofel T, Sträter N. E. coli 5'-nucleotidase undergoes a hinge-bending domain rotation resembling a ball-and-socket motion. J Mol Biol 2001;309:255-66 (Pubitemid 32553522)
50. Knofel T, Sträter N. Mechanism of hydrolysis of phosphate esters by the dimetal center of 5'-nucleotidase based on crystal structures. J Mol Biol 2001;309:239-54
51. Heuts DPHM, Weissenborn MJ, Olkhov RV, et al. Crystal structure of a soluble form of human CD73 with ecto-5'-nucleotidase activity. Chembiochem Eur J Chem Biol 2012;13:2384-91.
52. Knapp K, Zebisch M, Pippel J, et al. Crystal structure of the human ecto-5¢-nucleotidase (CD73): Insights into the regulation of purinergic signaling. Structure 2012;20:2161-73.
53. Hilaire C, Ziegler SG, Markello TC, et al. NT5E mutations and arterial calcifications. N Engl J Med 2011;364:432-42.
54. Yegutkin GG. Nucleotide-and nucleoside-converting ectoenzymes: Important modulators of purinergic signalling cascade. Biochim Biophys Acta 2008;1783:673-94
55. Antonioli L, Blandizzi C, Pacher P, Haskó G. Immunity, inflammation and cancer: A leading role for adenosine. Nat Rev Cancer 2013;13:842-57.
56. Eltzschig HK, Sitkovsky MV, Robson SC. Purinergic signaling during inflammation. N Engl J Med 2012;367:2322-33
57. Resta R, Yamashita Y, Thompson LF. Ecto-enzyme and signaling functions of lymphocyte CD 7.Immunol Rev 1998;161:95-109
58. Beavis PA, Stagg J, Darcy PK, Smyth MJ. CD73: A potent suppressor of antitumor immune responses. Trends Immunol 2012;33:231-7.
59. Decking UK, Schlieper G, Kroll K, Schrader J. Hypoxia-induced inhibition of adenosine kinase potentiates cardiac adenosine release. Circ Res 1997;81:154-64 (Pubitemid 27342482)
60. Morote-Garcia JC, Rosenberger P, Kuhlicke J, Eltzschig HK. HIF-1-dependent repression of adenosine kinase attenuates hypoxia-induced vascular leak. Blood 2008;111:5571-80
61. Sitkovsky MV. Damage control by hypoxia-inhibited AK. Blood 2008;111:5424-5
62. Fredholm BB, IJzerman AP, Jacobson KA, et al. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 2001;53:527-52. (Pubitemid 33136237)
63. Fredholm BB, IJzerman AP, Jacobson KA, et al. International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and Classification of Adenosine Receptors-An Update. Pharmacol Rev 2011;63:1-34
64. Koeppen M, Eckle T, Eltzschig HK. Interplay of hypoxia and A2B adenosine receptors in tissue protection. Adv Pharmacol 2011;61:145-86
65. Klinger M, Freissmuth M, Nanoff C. Adenosine receptors: G protein-mediated signalling and the role of accessory proteins. Cell Signal 2002;14:99-108 (Pubitemid 34056581)
66. Aherne CM, Kewley EM, Eltzschig HK. The resurgence of A2B adenosine receptor signaling. Biochim Biophys Acta 2011;1808:1329-39
67. Antonioli L, Colucci R, La Motta C, et al. Adenosine deaminase in the modulation of immune system and its potential as a novel target for treatment of inflammatory disorders. Curr Drug Targets 2012;13:842-62
68. Colgan SP, Eltzschig HK, Eckle T, Thompson LF. Physiological roles for ecto-5'-nucleotidase (CD73). Purinergic Signal 2006;2:351-60
69. Thompson LF, Eltzschig HK, Ibla JC, et al. Crucial role for ecto-5¢-nucleotidase (CD73) in vascular leakage during hypoxia. J Exp Med 2004;200:1395-405 (Pubitemid 39657287)
70. Castrop H, Huang Y, Hashimoto S, et al. Impairment of tubuloglomerular feedback regulation of GFR in ecto-5¢-nucleotidase/CD73-deficient mice. J Clin Invest 2004;114:634-42 (Pubitemid 39578753)
71. Koszalka P, Ozüyaman B, Huo Y, et al. Targeted disruption of cd73/ecto-5'-nucleotidase alters thromboregulation and augments vascular inflammatory response. Circ Res 2004;95:814-21 (Pubitemid 39390584)
72. Blume C, Felix A, Shushakova N, et al. Autoimmunity in CD73/Ecto-5'-nucleotidase deficient mice induces renal injury. PloS One 2012;7:e37100
73. Lennon PF, Taylor CT, Stahl GL, Colgan SP. Neutrophil-derived 5'-adenosine monophosphate promotes endothelial barrier function via CD73-mediated conversion to adenosine and endothelial A2B receptor activation. J Exp Med 1998;188:1433-43 (Pubitemid 28489580)
74. Giron MC, Bin A, Brun P, et al. Cyclic AMP in rat ileum: Evidence for the presence of an extracellular cyclic AMPadenosine pathway. Gastroenterology 2008;134:1116-26 (Pubitemid 351451977)
75. Antonioli L, Fornai M, Colucci R, et al. Differential recruitment of high affinity A1 and A2A adenosine receptors in the control of colonic neuromuscular function in experimental colitis. Eur J Pharmacol 2011;650:639-49
76. Synnestvedt K, Furuta GT, Comerford KM, et al. Ecto-5-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia. J Clin Invest 2002;110:993-1002
77. A ° lgars A, Karikoski M, Yegutkin GG, et al. Different role of CD73 in leukocyte trafficking via blood and lymph vessels. Blood 2011;117:4387-93
78. Mills JH, Thompson LF, Mueller C, et al. CD73 is required for efficient entry of lymphocytes into the central nervous system during experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 2008;105:9325-30
79. Eckle T, Krahn T, Grenz A, et al. Cardioprotection by ecto-5¢-nucleotidase (CD73) and A2B adenosine receptors. Circulation 2007;115:1581-90 (Pubitemid 46648643)
80. Grenz A, Zhang H, Eckle T, et al. Protective role of ecto-5'-nucleotidase (CD73) in renal ischemia. J Am Soc Nephrol 2007;18:833-45 (Pubitemid 46434500)
81. Peng Z, Fernandez P, Wilder T, et al. Ecto-5'-nucleotidase (CD73)-mediated extracellular adenosine production plays a critical role in hepatic fibrosis. FASEB 2008;22:2263-72 (Pubitemid 351948645)
82. Muller G, Jung C, Wied S, et al. Transfer of the glycosylphosphatidylinositol-anchored 5'-nucleotidase CD73 from adiposomes into rat adipocytes stimulates lipid synthesis. Br J Pharmacol 2010;160:878-91
83. Kulesskaya N, Voikar V, Peltola M, et al. CD73 is a major regulator of adenosinergic signalling in mouse brain. PLoS One 2013;8(6):e66896
84. Deaglio S, Dwyer KM, Gao W, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 2007;204:1257-65. (Pubitemid 46919862)
85. Hasko G, Pacher P, Vizi ES, Illes P. Adenosine receptor signaling in the brain immune system. Trends Pharmacol Sci 2005;26:511-16 (Pubitemid 41338561)
86. Stagg J, Divisekera U, Duret H, et al. CD73-Deficient Mice Have Increased Antitumor Immunity and Are Resistant to Experimental Metastasis. Cancer Res 2011;71:2892-900.
87. Richard E, Arredondo-Vega FX, Santisteban I, et al. The binding site of human adenosine deaminase for Cd26/dipeptidyl peptidase IV the Arg142gln mutation impairs binding to Cd26 but does not cause immune deficiency. J Exp Med 2000;192:1223-36
88. Airas L, Hellman J, Salmi M, et al. CD73 is involved in lymphocyte binding to the endothelium: Characterization of lymphocyte-vascular adhesion protein 2 identifies it as CD73. J Exp Med 1995;182:1603-8
89. Airas L, Niemelä J, Jalkanen S. CD73 engagement promotes lymphocyte binding to endothelial cells via a lymphocyte function-associated antigen-1-dependent mechanism. J Immunol 2000;165:5411-17
90. Airas L, Jalkanen S. CD73 mediates adhesion of B cells to follicular dendritic cells. Blood 1996;88:1755-64 (Pubitemid 26307072)
91. Olmo N, Turnay J, Risse G, et al. Modulation of 5'-nucleotidase activity in plasma membranes and intact cells by the extracellular matrix proteins laminin and fibronectin. Biochem J 1992;282(Pt 1):181-8
92. Flocke K, Lesch G, Elsässer HP, et al. Monoclonal antibodies against 5'-nucleotidase from a human pancreatic tumor cell line: Their characterization and inhibitory capacity on tumor cell adhesion to fibronectin substratum. Eur J Cell Biol 1992;58:62-70
93. Sadej R, Inai K, Rajfur Z, et al. Tenascin C interacts with Ecto-5¢-nucleotidase (eN) and regulates adenosine generation in cancer cells. Biochim Biophys Acta 2008;1782:35-40
94. Sadej R, Spychala J, Skladanowski AC. Expression of ecto-5'-nucleotidase (eN, CD73) in cell lines from various stages of human melanoma. Melanoma Res 2006;16:213-22 (Pubitemid 44085095)
95. Sadej R, Skladanowski AC. Dual, enzymatic and non-enzymatic, function of ecto-5'-nucleotidase (eN, CD73) in migration and invasion of A375 melanoma cells. Acta Biochim Pol 2011;59:647-52
96. Thompson LF, Ruedi JM, Glass A, et al. Antibodies to 5'-nucleotidase (CD73), a glycosyl-phosphatidylinositol-anchored protein, cause human peripheral blood T cells to proliferate. J Immunol 1989;143:1815-21 (Pubitemid 19241192)
97. Dianzani U, Redoglia V, Bragardo M, et al. Co-stimulatory signal delivered by CD73 molecule to human CD45RAhiCD45ROlo (naive) CD8+ T lymphocytes. J Immunol 1993;151:3961-70 (Pubitemid 23298729)
98. Massaia M, Perrin L, Bianchi A, et al. Human T cell activation. Synergy between CD73 (ecto-5'-nucleotidase) and signals delivered through CD3 and CD2 molecules. J Immunol 1990;145:1664-74 (Pubitemid 20336727)
99. Gutensohn W, Resta R, Misumi Y, et al. Ecto-5'-nucleotidase activity is not required for T cell activation through CD73. Cell Immunol 1995;161:213-17
100. Resta R, Hooker SW, Laurent AB, et al. Glycosyl phosphatidylinositol membrane anchor is not required for T cell activation through CD73. J Immunol 1994;153:1046-53 (Pubitemid 24228496)
101. Yamashita Y, Hooker SW, Jiang H, et al. CD73 expression and fyn-dependent signaling on murine lymphocytes. Eur J Immunol 1998;28:2981-90 (Pubitemid 28470244)
102. Carrière M, Lacabaratz C, Kok A, et al. HIV "elite controllers" are characterized by a high frequency of memory CD8 +CD73+ T cells involved in the antigenspecific CD8+ T-cell response. J Infect Dis 2014;209(9):1321-30
103. Tóth I, Le AQ, Hartjen P, et al. Decreased frequency of CD73+CD8+ T cells of HIV-infected patients correlates with immune activation and T cell exhaustion. J Leukoc Biol 2013;94:551-61
104. Allard B, Turcotte M, Spring K, et al. Anti-CD73 therapy impairs tumor angiogenesis. Int J Cancer 2014;134:1466-73.
105. Wu X-R, He X-S, Chen Y-F, et al. High expression of CD73 as a poor prognostic biomarker in human colorectal cancer. J Surg Oncol 2012;106:130-7
106. Allard B, Turcotte M, Stagg J. CD73-generated adenosine: Orchestrating the tumor-stroma interplay to promote cancer growth. J Biomed Biotechnol 2012;2012:1-8
107. Leth-Larsen R, Lund R, Hansen HV, et al. Metastasis-related plasma membrane proteins of human breast cancer cells identified by comparative quantitative mass spectrometry. Mol Cell Proteomic 2009;8:1436-49.
108. Serra S, Horenstein AL, Vaisitti T, et al. CD73-generated extracellular adenosine in chronic lymphocytic leukemia creates local conditions counteracting druginduced cell death. Blood 2011;118:6141-52
109. Eltzschig HK, Ibla JC, Furuta GT, et al. Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: Role of ectonucleotidases and adenosine A2B receptors. J Exp Med 2003;198:783-96 (Pubitemid 37087777)
110. Eltzschig HK, Abdulla P, Hoffman E, et al. HIF-1-dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia. J Exp Med 2005;202:1493-505 (Pubitemid 41746596)
111. Blay J, White TD, Hoskin DW. The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. Cancer Res 1997;57:2602-5. (Pubitemid 27283766)
112. Ohta A, Gorelik E, Prasad SJ, et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci USA 2006;103:13132-7. (Pubitemid 44338928)
113. Hoskin DW, Reynolds T, Blay J. Adenosine as a possible inhibitor of killer T-cell activation in the microenvironment of solid tumours. Int J Cancer 1994;59:854-5
114. Sitkovsky MV, Kjaergaard J, Lukashev D, Ohta A. Hypoxia-adenosinergic immunosuppression: Tumor protection by t regulatory cells and cancerous tissue hypoxia. Clin Cancer Res 2008;14:5947-52.
115. Sitkovsky M, Ohta A. Targeting the hypoxia-adenosinergic signaling pathway to improve the adoptive immunotherapy of cancer. J Mol Med 2013;91:147-55
116. Stagg J, Smyth MJ. Extracellular adenosine triphosphate and adenosine in cancer. Oncogene 2010;29:5346-58.
117. Clayton A, Al-Taei S, Webber J, et al. Cancer exosomes express CD39 and CD73, which suppress T cells through adenosine production. J Immunol 2011;187:676-83.
118. Sceneay J, Smyth MJ, Moller A. The pre-metastatic niche: Finding common ground. Cancer Metastasis Rev 2013;32:449-64
119. Stagg J, Beavis PA, Divisekera U, et al. CD73-Deficient Mice Are Resistant to Carcinogenesis. Cancer Res 2012;72:2190-6.
120. Jin D, Fan J, Wang L, et al. CD73 on tumor cells impairs antitumor T-Cell responses: A novel mechanism of tumorinduced immune suppression. Cancer Res 2010;70:2245-55.
121. Wang L, Fan J, Thompson LF, et al. CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice. J Clin Invest 2011;121:2371-82.
122. Yegutkin GG, Marttila-Ichihara F, Karikoski M, et al. Altered purinergic signaling in CD73-deficient mice inhibits tumor progression. Eur J Immunol 2011;41:1231-41.
123. Künzli BM, Bernlochner M-I, Rath S, et al. Impact of CD39 and purinergic signalling on the growth and metastasis of colorectal cancer. Purinergic Signal 2011;7:231-41
124. Sun X, Wu Y, Gao W, et al. CD39/ENTPD1 expression by CD4+Foxp3+ regulatory T cells promotes hepatic metastatic tumor growth in mice. Gastroenterology 2010;139:1030-40.
125. Feng L, Sun X, Csizmadia E, et al. Vascular CD39/ENTPD1 directly promotes tumor cell growth by scavenging extracellular adenosine triphosphate. Neoplasia 2011;13:206-16.
126. Jackson SW, Hoshi T, Wu Y, et al. Disordered purinergic signaling inhibits pathological angiogenesis in Cd39/Entpd1-null mice. Am J Pathol 2007;171:1395-404. (Pubitemid 47582911)
127. Sim GC, Martin-Orozco N, Jin L, et al. IL-2 therapy promotes suppressive ICOS + Treg expansion in melanoma patients. J Clin Invest 2014;124:99-110
128. Chalmin F, Mignot G, Bruchard M, et al. Stat3 and Gfi-1 transcription factors control Th17 cell immunosuppressive activity via the regulation of ectonucleotidase expression. Immunity 2012;36:362-73
129. Beavis PA, Divisekera U, Paget C, et al. Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumors. Proc Natl Acad Sci USA 2013;110:14711-16.
130. Ryzhov S, Novitskiy SV, Zaynagetdinov R, et al. Host A2B adenosine receptors promote carcinoma growth. Neoplasia 2008;10:987-95.
131. Waickman AT, Alme A, Senaldi L, et al. Enhancement of tumor immunotherapy by deletion of the A2A adenosine receptor. Cancer Immunol Immunother 2012;61:917-26
132. Cekic C, Sag D, Li Y, et al. Adenosine A2B receptor blockade slows growth of bladder and breast tumors. J Immunol 2012;188:198-205.
133. Iannone R, Miele L, Maiolino P, et al. Blockade of A2b adenosine receptor reduces tumor growth and immune suppression mediated by myeloid-derived suppressor cells in a mouse model of melanoma. Neoplasia 2013;15:1400-IN14.
134. Huang S, Apasov S, Koshiba M, Sitkovsky M. Role of A2a extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion. Blood 1997;90:1600-10. (Pubitemid 27355433)
135. Lappas CM, Rieger JM, Linden J. A2A adenosine receptor induction inhibits IFN-gamma production in murine CD4+ T cells. J Immunol 2005;174:1073-80 (Pubitemid 40094304)
136. Koshiba M, Kojima H, Huang S, et al. Memory of extracellular adenosine A2A purinergic receptor-mediated signaling in murine T cells. J Biol Chem 1997;272:25881-9 (Pubitemid 27438913)
137. Csóka B, Himer L, Selmeczy Z, et al. Adenosine A2A receptor activation inhibits T helper 1 and T helper 2 cell development and effector function. FASEB J 2008;22:3491-9
138. Ohta A, Ohta A, Madasu M, et al. A2A adenosine receptor may allow expansion of T cells lacking effector functions in extracellular adenosine-rich microenvironments. J Immunol 183:5487-93
139. Raskovalova T, Lokshin A, Huang X, et al. Inhibition of cytokine production and cytotoxic activity of human antimelanoma specific CD8+ and CD4+ T lymphocytes by adenosine-protein kinase a type I signaling. Cancer Res 2007;67:5949-56 (Pubitemid 46985031)
140. Zarek PE, Huang C-T, Lutz ER, et al. A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. Blood 2008;111:251-9.
141. Ohta A, Kini R, Ohta A, et al. The development and immunosuppressive functions of CD4(+) CD25(+) FoxP3(+) regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway. Front Immunol 2012;3:190
142. Armstrong JM, Chen JF, Schwarzschild MA, et al. Gene dose effect reveals no Gs-coupled A2A adenosine receptor reserve in murine T-lymphocytes: Studies of cells from A2A-receptor-gene-deficient mice. Biochem J 2001;354:123-30 (Pubitemid 32183452)
143. Minguet S, Huber M, Rosenkranz L, et al. Adenosine and cAMP are potent inhibitors of the NF-kB pathway downstream of immunoreceptors. Eur J Immunol 2005;35:31-41 (Pubitemid 40123849)
144. Linnemann C, Schildberg FA, Schurich A, et al. Adenosine regulates CD8 T-cell priming by inhibition of membrane-proximal T-cell receptor signalling. Immunology 2009;128:e728-37
145. Feoktistov I, Biaggioni I. Role of adenosine A2B receptors in inflammation. Adv Pharmacol 2011;61:115-44
146. Spychala J, Lazarowski E, Ostapkowicz A, et al. Role of estrogen receptor in the regulation of ecto-5¢-nucleotidase and adenosine in breast cancer. Clin Cancer Res 2004;10:708-17. (Pubitemid 38174010)
147. Lo Nigro C, Monteverde M, Lee S, et al. NT5E CpG island methylation is a favourable breast cancer biomarker. Br J Cancer 2012;107:75-83.
148. Wang H, Lee S, Nigro CL, et al. NT5E (CD73) is epigenetically regulated in malignant melanoma and associated with metastatic site specificity. Br J Cancer 2012;106:1446-52
149. Lee H, Lin ECK, Liu L, Smith JW. Gene expression profiling of tumor xenografts: In vivo analysis of organ-specific metastasis. Int J Cancer 2003;107:528-34 (Pubitemid 37296111)
150. Zhi X, Chen S, Zhou P, et al. RNA interference of ecto-5'-nucleotidase (CD73) inhibits human breast cancer cell growth and invasion. Clin Exp Metastasis 2007;24:439-48 (Pubitemid 47367686)
151. Wang L, Zhou X, Zhou T, et al. Ecto-5'-nucleotidase promotes invasion, migration and adhesion of human breast cancer cells. J Cancer Res Clin Oncol 2008;134:365-72 (Pubitemid 351170058)
152. Zhi X, Wang Y, Yu J, et al. Potential prognostic biomarker CD73 regulates epidermal growth factor receptor expression in human breast cancer. IUBMB Life 2012;64:911-20
153. Zhi X, Wang Y, Zhou X, et al. RNAi-mediated CD73 suppression induces apoptosis and cell-cycle arrest in human breast cancer cells. Cancer Sci 2010;101:2561-9
154. Zhou X, Zhi X, Zhou P, et al. Effects of ecto-5'-nucleotidase on human breast cancer cell growth in vitro and in vivo. Oncol Rep 2007;17:1341-6
155. Zhou P, Zhi X, Zhou T, et al. Overexpression of Ecto-5'-nucleotidase (CD73) promotes T-47D human breast cancer cells invasion and adhesion to extracellular matrix. Cancer Biol Ther 2007;6:426-31 (Pubitemid 47328312)
156. Ujházy P, Klobusická M, Babuśková O, et al. Ecto-5'-nucleotidase (CD73) in multidrug-resistant cell lines generated by doxorubicin. Int J Cancer 1994;59:83-93.
157. Desmet CJ, Gallenne T, Prieur A, et al. Identification of a pharmacologically tractable Fra-1/ADORA2B axis promoting breast cancer metastasis. Proc Natl Acad Sci USA 2013;110:5139-44.
158. Ntantie E, Gonyo P, Lorimer EL, et al. An adenosine-mediated signaling pathway suppresses prenylation of the GTPase Rap1B and promotes cell scattering. Sci Signal 2013;6:ra39.
159. Freundlieb M, Zimmermann H, Müller CE. A new, sensitive ecto-5'-nucleotidase assay for compound screening. Anal Biochem 2014;446:53-8
160. Sachsenmeier KF, Hay C, Brand E, et al. Development of a novel ectonucleotidase assay suitable for high-throughput screening. J Biomol Screen 2012;17:993-8
161. Ripphausen P, Freundlieb M, Brunschweiger A, et al. Virtual screening identifies novel sulfonamide inhibitors of ecto-5'-nucleotidase. J Med Chem 2012;55:6576-81
162. Feig JL, Tivon D, Miguel P-A, et al. Tenofovir but not adefovir prevents liver and skin fibrosis in two models of adenosine-mediated injury. Arthritis Rheum 2013;65:1096-7
163. Baqi Y, Lee S-Y, Iqbal J, et al. Development of potent and selective inhibitors of ecto-5¢-nucleotidase based on an anthraquinone scaffold. J Med Chem 2010;53:2076-86
164. Iqbal J, Saeed A, Raza R, et al. Identification of sulfonic acids as efficient ecto-5'-nucleotidase inhibitors. Eur J Med Chem 2013;70:685-91
165. Braganhol E, Tamajusuku ASK, Bernardi A, et al. Ecto-5'-nucleotidase/CD73 inhibition by quercetin in the human U138MG glioma cell line. Biochim Biophys Acta 2007;1770:1352-9 (Pubitemid 47248055)
166. Thomson LF, Ruedi JM, Glass A, et al. Production and characterization of monoclonal antibodies to the glycosyl phosphatidylinositol-anchored lymphocyte differentiation antigen ecto-5¢-nucleotidase (CD73). Tissue Antigens 1990;35:9-19 (Pubitemid 20044689)
167. Airas L, Salmi M, Jalkanen S. Lymphocyte-vascular adhesion protein-2 is a novel 70-kDa molecule involved in lymphocyte adhesion to vascular endothelium.
168. Forte G, Sorrentino R, Montinaro A, et al. Inhibition of CD73 improves B cell-mediated anti-tumor immunity in a mouse model of melanoma. J Immunol 2012;189:2226-33.
169. Allard B, Pommey S, Smyth MJ, Stagg J. Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs. Clin Cancer Res 2013;19:5626-35.
170. Airas L, Niemelä J, Salmi M, et al. Differential regulation and function of CD73, a glycosylphosphatidylinositol-linked 70-kD adhesion molecule, on lymphocytes and endothelial cells. J Cell Biol 1997;136:421-31 (Pubitemid 27063091)
171. Hausler SF, del Barrio IM, Diessner J, et al. Anti-CD39 and anti-CD73 antibodies A1 and 7G2 improve targeted therapy in ovarian cancer by blocking adenosine-dependent immune evasion. Am J Transl Res 2014;6:129-39