Skip to main content
SpringerLink
Log in

Purinergic Signaling Within the Tumor Microenvironment

  • Chapter
  • First Online:
Tumor Microenvironment

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1270))

Abstract

Accumulating studies have clearly demonstrated high concentrations of extracellular ATP (eATP) within the tumor microenvironment (TME). Implications of these findings are multifold as ATP-mediated purinergic signaling has been shown to mediate a variety of cancer-related processes, including cell migration, resistance to cytotoxic therapy, and immune regulation. Broad roles of ATP within the tumor microenvironment are linked to the abundance of ATP-regulated purinergic receptors on cancer and stromal and various immune cell types, as well as on the importance of ATP release and signaling in the regulation of multiple cellular processes. ATP release and downstream purinergic signaling are emerging as a central regulator of tumor growth and an important target for therapeutic intervention. In this chapter, we summarize the major roles of purinergic signaling in the tumor microenvironment with a specific focus on its critical roles in the induction of immunogenic cancer cell death and immune modulation.

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 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
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

  1. Mazumdar J et al (2010) O2 regulates stem cells through Wnt/beta-catenin signalling. Nat Cell Biol 12(10):1007–1013

    Article  CAS  Google Scholar 

  2. Kaidi A, Williams AC, Paraskeva C (2007) Interaction between beta-catenin and HIF-1 promotes cellular adaptation to hypoxia. Nat Cell Biol 9(2):210–217

    Article  CAS  Google Scholar 

  3. Burnstock G, Di Virgilio F (2013) Purinergic signalling and cancer. Purinergic Signal 9(4):491–540

    Article  CAS  Google Scholar 

  4. Pellegatti P et al (2008) Increased level of extracellular ATP at tumor sites: in vivo imaging with plasma membrane luciferase. PLoS One 3(7):e2599

    Article  CAS  Google Scholar 

  5. Cekic C et al (2013) Extracellular adenosine regulates naive T cell development and peripheral maintenance. J Exp Med 210(12):2693–2706

    Article  CAS  Google Scholar 

  6. Cekic C et al (2012) Adenosine A2B receptor blockade slows growth of bladder and breast tumors. J Immunol 188(1):198–205

    Article  CAS  Google Scholar 

  7. Di Virgilio F et al (2018) Extracellular ATP and P2 purinergic signalling in the tumour microenvironment. Nat Rev Cancer 18(10):601–618

    Article  CAS  Google Scholar 

  8. Sawada K et al (2008) Identification of a vesicular nucleotide transporter. Proc Natl Acad Sci U S A 105(15):5683–5686

    Article  CAS  Google Scholar 

  9. Tokunaga A et al (2010) Involvement of SLC17A9-dependent vesicular exocytosis in the mechanism of ATP release during T cell activation. J Biol Chem 285(23):17406–17416

    Article  CAS  Google Scholar 

  10. Qiu F, Dahl G (2009) A permeant regulating its permeation pore: inhibition of pannexin 1 channels by ATP. Am J Physiol Cell Physiol 296(2):C250–C255

    Article  CAS  Google Scholar 

  11. Iglesias R et al (2008) P2X7 receptor-Pannexin1 complex: pharmacology and signaling. Am J Physiol Cell Physiol 295(3):C752–C760

    Article  CAS  Google Scholar 

  12. Locovei S, Wang J, Dahl G (2006) Activation of pannexin 1 channels by ATP through P2Y receptors and by cytoplasmic calcium. FEBS Lett 580(1):239–244

    Article  CAS  Google Scholar 

  13. Locovei S et al (2007) Pannexin1 is part of the pore forming unit of the P2X(7) receptor death complex. FEBS Lett 581(3):483–488

    Article  CAS  Google Scholar 

  14. Dubyak GR (2009) Both sides now: multiple interactions of ATP with pannexin-1 hemichannels. Focus on “a permeant regulating its permeation pore: inhibition of pannexin 1 channels by ATP”. Am J Physiol Cell Physiol 296(2):C235–C241

    Article  CAS  Google Scholar 

  15. Kroemer G et al (2013) Immunogenic cell death in cancer therapy. Annu Rev Immunol 31:51–72

    Article  CAS  Google Scholar 

  16. Galluzzi L et al (2017) Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol 17(2):97–111

    Article  CAS  Google Scholar 

  17. Galluzzi L et al (2017) Activating autophagy to potentiate immunogenic chemotherapy and radiation therapy. Nat Rev Clin Oncol 14(4):247–258

    Article  CAS  Google Scholar 

  18. Kroemer G, Galluzzi L (2017) Autophagy-dependent danger signaling and adaptive immunity to poorly immunogenic tumors. Oncotarget 8(4):5686–5691

    Article  Google Scholar 

  19. Martins I et al (2014) Molecular mechanisms of ATP secretion during immunogenic cell death. Cell Death Differ 21(1):79–91

    Article  CAS  Google Scholar 

  20. Bedognetti D et al (2019) Toward a comprehensive view of cancer immune responsiveness: a synopsis from the SITC workshop. J Immunother Cancer 7(1):131

    Article  Google Scholar 

  21. Joiner ML, Koval OM (2014) CaMKII and stress mix it up in mitochondria. Front Pharmacol 5:67

    Article  CAS  Google Scholar 

  22. Michaud M et al (2011) Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334(6062):1573–1577

    Article  CAS  Google Scholar 

  23. Yang D et al (2015) Caspase-11 requires the pannexin-1 channel and the purinergic P2X7 pore to mediate pyroptosis and endotoxic shock. Immunity 43(5):923–932

    Article  CAS  Google Scholar 

  24. Miao EA, Rajan JV, Aderem A (2011) Caspase-1-induced pyroptotic cell death. Immunol Rev 243(1):206–214

    Article  CAS  Google Scholar 

  25. Winter SE, Baumler AJ (2011) Salmonella exploits suicidal behavior of epithelial cells. Front Microbiol 2:48

    Article  Google Scholar 

  26. Derangere V et al (2014) Liver X receptor beta activation induces pyroptosis of human and murine colon cancer cells. Cell Death Differ 21(12):1914–1924

    Article  CAS  Google Scholar 

  27. Man SM, Karki R, Kanneganti TD (2017) Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol Rev 277(1):61–75

    Article  CAS  Google Scholar 

  28. Vigano E, Mortellaro A (2013) Caspase-11: the driving factor for noncanonical inflammasomes. Eur J Immunol 43(9):2240–2245

    Article  CAS  Google Scholar 

  29. Qu Y et al (2007) Nonclassical IL-1 beta secretion stimulated by P2X7 receptors is dependent on inflammasome activation and correlated with exosome release in murine macrophages. J Immunol 179(3):1913–1925

    Article  CAS  Google Scholar 

  30. Baroja-Mazo A et al (2014) The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat Immunol 15(8):738–748

    Article  CAS  Google Scholar 

  31. Martin-Sanchez F et al (2016) Inflammasome-dependent IL-1beta release depends upon membrane permeabilisation. Cell Death Differ 23(7):1219–1231

    Article  CAS  Google Scholar 

  32. Lu B et al (2013) Regulation of HMGB1 release by inflammasomes. Protein Cell 4(3):163–167

    Article  CAS  Google Scholar 

  33. Yan W et al (2012) High-mobility group box 1 activates caspase-1 and promotes hepatocellular carcinoma invasiveness and metastases. Hepatology 55(6):1863–1875

    Article  CAS  Google Scholar 

  34. Xu J et al (2014) Macrophage endocytosis of high-mobility group box 1 triggers pyroptosis. Cell Death Differ 21(8):1229–1239

    Article  CAS  Google Scholar 

  35. Manohar M et al (2012) ATP release and autocrine signaling through P2X4 receptors regulate gammadelta T cell activation. J Leukoc Biol 92(4):787–794

    Article  CAS  Google Scholar 

  36. Woehrle T et al (2010) Pannexin-1 hemichannel-mediated ATP release together with P2X1 and P2X4 receptors regulate T-cell activation at the immune synapse. Blood 116(18):3475–3484

    Article  CAS  Google Scholar 

  37. Woehrle T et al (2010) Hypertonic stress regulates T cell function via pannexin-1 hemichannels and P2X receptors. J Leukoc Biol 88(6):1181–1189

    Article  CAS  Google Scholar 

  38. Baricordi OR et al (1996) An ATP-activated channel is involved in mitogenic stimulation of human T lymphocytes. Blood 87(2):682–690

    Article  CAS  Google Scholar 

  39. Schenk U et al (2008) Purinergic control of T cell activation by ATP released through pannexin-1 hemichannels. Sci Signal 1(39):ra6

    Article  CAS  Google Scholar 

  40. Sil P et al (2017) P2Y6 receptor antagonist MRS2578 inhibits neutrophil activation and aggregated neutrophil extracellular trap formation induced by gout-associated monosodium urate crystals. J Immunol 198(1):428–442

    Article  CAS  Google Scholar 

  41. Gicquel T et al (2015) IL-1beta production is dependent on the activation of purinergic receptors and NLRP3 pathway in human macrophages. FASEB J 29(10):4162–4173

    Article  CAS  Google Scholar 

  42. He Y, Franchi L, Nunez G (2013) TLR agonists stimulate Nlrp3-dependent IL-1beta production independently of the purinergic P2X7 receptor in dendritic cells and in vivo. J Immunol 190(1):334–339

    Article  CAS  Google Scholar 

  43. Niemi K et al (2011) Serum amyloid A activates the NLRP3 inflammasome via P2X7 receptor and a cathepsin B-sensitive pathway. J Immunol 186(11):6119–6128

    Article  CAS  Google Scholar 

  44. Luna-Gomes T, Santana PT, Coutinho-Silva R (2015) Silica-induced inflammasome activation in macrophages: role of ATP and P2X7 receptor. Immunobiology 220(9):1101–1106

    Article  CAS  Google Scholar 

  45. Silva-Vilches C, Ring S, Mahnke K (2018) ATP and its metabolite adenosine as regulators of dendritic cell activity. Front Immunol 9:2581

    Article  CAS  Google Scholar 

  46. Guo X, Dhodapkar KM (2012) Central and overlapping role of Cathepsin B and inflammasome adaptor ASC in antigen presenting function of human dendritic cells. Hum Immunol 73(9):871–878

    Article  CAS  Google Scholar 

  47. Ghiringhelli F et al (2009) Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat Med 15(10):1170–1178

    Article  CAS  Google Scholar 

  48. Willingham SB et al (2009) NLRP3 (NALP3, Cryopyrin) facilitates in vivo caspase-1 activation, necrosis, and HMGB1 release via inflammasome-dependent and -independent pathways. J Immunol 183(3):2008–2015

    Article  CAS  Google Scholar 

  49. Mortimer L et al (2015) The NLRP3 inflammasome is a pathogen sensor for invasive Entamoeba histolytica via activation of alpha5beta1 integrin at the macrophage-amebae intercellular junction. PLoS Pathog 11(5):e1004887

    Article  CAS  Google Scholar 

  50. Moreira-Souza ACA et al (2017) The P2X7 receptor mediates toxoplasma gondii control in macrophages through canonical NLRP3 inflammasome activation and reactive oxygen species production. Front Immunol 8:1257

    Article  CAS  Google Scholar 

  51. Quan JH et al (2018) P2X7 receptor mediates NLRP3-dependent IL-1beta secretion and parasite proliferation in Toxoplasma gondii-infected human small intestinal epithelial cells. Parasit Vectors 11(1):1

    Article  CAS  Google Scholar 

  52. Morandini AC, Savio LE, Coutinho-Silva R (2014) The role of P2X7 receptor in infectious inflammatory diseases and the influence of ectonucleotidases. Biom J 37(4):169–177

    Google Scholar 

  53. Savio LEB et al (2018) The P2X7 receptor in inflammatory diseases: angel or demon? Front Pharmacol 9:52

    Article  CAS  Google Scholar 

  54. Janks L, Sharma CVR, Egan TM (2018) A central role for P2X7 receptors in human microglia. J Neuroinflammation 15(1):325

    Article  CAS  Google Scholar 

  55. Janks L, Sprague RS, Egan TM (2019) ATP-gated P2X7 receptors require chloride channels to promote inflammation in human macrophages. J Immunol 202(3):883–898

    Article  CAS  Google Scholar 

  56. Dubyak GR (2012) P2X7 receptor regulation of non-classical secretion from immune effector cells. Cell Microbiol 14(11):1697–1706

    Article  CAS  Google Scholar 

  57. Giuliani AL et al (2017) The P2X7 receptor-interleukin-1 liaison. Front Pharmacol 8:123

    Article  CAS  Google Scholar 

  58. Junger WG (2011) Immune cell regulation by autocrine purinergic signalling. Nat Rev Immunol 11(3):201–212

    Article  CAS  Google Scholar 

  59. Chen Y et al (2006) ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors. Science 314(5806):1792–1795

    Article  CAS  Google Scholar 

  60. Wu LJ, Vadakkan KI, Zhuo M (2007) ATP-induced chemotaxis of microglial processes requires P2Y receptor-activated initiation of outward potassium currents. Glia 55(8):810–821

    Article  Google Scholar 

  61. Honda S et al (2001) Extracellular ATP or ADP induce chemotaxis of cultured microglia through Gi/o-coupled P2Y receptors. J Neurosci 21(6):1975–1982

    Article  CAS  Google Scholar 

  62. Ohsawa K et al (2007) Involvement of P2X4 and P2Y12 receptors in ATP-induced microglial chemotaxis. Glia 55(6):604–616

    Article  Google Scholar 

  63. Kuehnel MP et al (2009) Lipids regulate P2X7-receptor-dependent actin assembly by phagosomes via ADP translocation and ATP synthesis in the phagosome lumen. J Cell Sci 122(Pt 4):499–504

    Article  CAS  Google Scholar 

  64. Martins I et al (2012) Premortem autophagy determines the immunogenicity of chemotherapy-induced cancer cell death. Autophagy 8(3):413–415

    Article  CAS  Google Scholar 

  65. Boyd-Tressler A et al (2014) Chemotherapeutic drugs induce ATP release via caspase-gated pannexin-1 channels and a caspase/pannexin-1-independent mechanism. J Biol Chem 289(39):27246–27263

    Article  CAS  Google Scholar 

  66. Ohshima Y et al (2010) gamma-Irradiation induces P2X(7) receptor-dependent ATP release from B16 melanoma cells. Biochim Biophys Acta 1800(1):40–46

    Article  CAS  Google Scholar 

  67. Tsukimoto M et al (2010) Involvement of purinergic signaling in cellular response to gamma radiation. Radiat Res 173(3):298–309

    Article  CAS  Google Scholar 

  68. Nishimaki N et al (2012) Autocrine regulation of gamma-irradiation-induced DNA damage response via extracellular nucleotides-mediated activation of P2Y6 and P2Y12 receptors. DNA Repair (Amst) 11(8):657–665

    Article  CAS  Google Scholar 

  69. Adinolfi E et al (2012) Expression of P2X7 receptor increases in vivo tumor growth. Cancer Res 72(12):2957–2969

    Article  CAS  Google Scholar 

  70. Takai E et al (2014) Autocrine signaling via release of ATP and activation of P2X7 receptor influences motile activity of human lung cancer cells. Purinergic Signal 10(3):487–497

    Article  CAS  Google Scholar 

  71. Vazquez-Cuevas FG et al (2014) Paracrine stimulation of P2X7 receptor by ATP activates a proliferative pathway in ovarian carcinoma cells. J Cell Biochem 115(11):1955–1966

    CAS  Google Scholar 

  72. Okamoto M et al (2010) Constitutively active inflammasome in human melanoma cells mediating autoinflammation via caspase-1 processing and secretion of interleukin-1beta. J Biol Chem 285(9):6477–6488

    Article  CAS  Google Scholar 

  73. Draganov D et al (2015) Modulation of P2X4/P2X7/Pannexin-1 sensitivity to extracellular ATP via Ivermectin induces a non-apoptotic and inflammatory form of cancer cell death. Sci Rep 5:16222

    Article  CAS  Google Scholar 

  74. Di Virgilio F (1995) The P2Z purinoceptor: an intriguing role in immunity, inflammation and cell death. Immunol Today 16(11):524–528

    Article  Google Scholar 

  75. Tsukimoto M et al (2006) P2X7 receptor-dependent cell death is modulated during murine T cell maturation and mediated by dual signaling pathways. J Immunol 177(5):2842–2850

    Article  CAS  Google Scholar 

  76. Kawano A et al (2012) Involvement of P2X4 receptor in P2X7 receptor-dependent cell death of mouse macrophages. Biochem Biophys Res Commun 419(2):374–380

    Article  CAS  Google Scholar 

  77. Kawano A et al (2012) Regulation of P2X7-dependent inflammatory functions by P2X4 receptor in mouse macrophages. Biochem Biophys Res Commun 420(1):102–107

    Article  CAS  Google Scholar 

  78. Crespo Yanguas S et al (2017) Pannexin1 as mediator of inflammation and cell death. Biochim Biophys Acta, Mol Cell Res 1864(1):51–61

    Article  CAS  Google Scholar 

  79. Qu Y et al (2011) Pannexin-1 is required for ATP release during apoptosis but not for inflammasome activation. J Immunol 186(11):6553–6561

    Article  CAS  Google Scholar 

  80. Pelegrin P, Surprenant A (2006) Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor. EMBO J 25(21):5071–5082

    Article  CAS  Google Scholar 

  81. Hung SC et al (2013) P2X4 assembles with P2X7 and pannexin-1 in gingival epithelial cells and modulates ATP-induced reactive oxygen species production and inflammasome activation. PLoS One 8(7):e70210

    Article  CAS  Google Scholar 

  82. Compan V et al (2012) Cell volume regulation modulates NLRP3 inflammasome activation. Immunity 37(3):487–500

    Article  CAS  Google Scholar 

  83. Burnstock G, Verkhratsky A (2010) Long-term (trophic) purinergic signalling: purinoceptors control cell proliferation, differentiation and death. Cell Death Dis 1:e9

    Article  CAS  Google Scholar 

  84. White N, Burnstock G (2006) P2 receptors and cancer. Trends Pharmacol Sci 27(4):211–217

    Article  CAS  Google Scholar 

  85. Dixon CJ et al (1997) Extracellular nucleotides stimulate proliferation in MCF-7 breast cancer cells via P2-purinoceptors. Br J Cancer 75(1):34–39

    Article  CAS  Google Scholar 

  86. Amoroso F et al (2015) The P2X7 receptor is a key modulator of the PI3K/GSK3beta/VEGF signaling network: evidence in experimental neuroblastoma. Oncogene 34(41):5240–5251

    Article  CAS  Google Scholar 

  87. Amoroso F et al (2012) The P2X7 receptor is a key modulator of aerobic glycolysis. Cell Death Dis 3:e370

    Article  CAS  Google Scholar 

  88. Adinolfi E et al (2005) P2X(7) receptor: death or life? Purinergic Signal 1(3):219–227

    Article  CAS  Google Scholar 

  89. Jacques-Silva MC et al (2004) ERK, PKC and PI3K/Akt pathways mediate extracellular ATP and adenosine-induced proliferation of U138-MG human glioma cell line. Oncology 67(5–6):450–459

    Article  CAS  Google Scholar 

  90. Jacques-Silva MC et al (2004) P2X7 receptors stimulate AKT phosphorylation in astrocytes. Br J Pharmacol 141(7):1106–1117

    Article  CAS  Google Scholar 

  91. Gilbert SM et al (2019) ATP in the tumour microenvironment drives expression of nfP2X7, a key mediator of cancer cell survival. Oncogene 38(2):194–208

    Article  CAS  Google Scholar 

  92. Adinolfi E et al (2005) Basal activation of the P2X7 ATP receptor elevates mitochondrial calcium and potential, increases cellular ATP levels, and promotes serum-independent growth. Mol Biol Cell 16(7):3260–3272

    Article  CAS  Google Scholar 

  93. Adinolfi E et al (2009) Expression of the P2X7 receptor increases the Ca2+ content of the endoplasmic reticulum, activates NFATc1, and protects from apoptosis. J Biol Chem 284(15):10120–10128

    Article  CAS  Google Scholar 

  94. Giacovazzo G et al (2019) Stimulation of P2X7 enhances whole body energy metabolism in mice. Front Cell Neurosci 13:390

    Article  CAS  Google Scholar 

  95. Qian Y et al (2014) Extracellular ATP is internalized by macropinocytosis and induces intracellular ATP increase and drug resistance in cancer cells. Cancer Lett 351(2):242–251

    Article  CAS  Google Scholar 

  96. Xia M et al (2014) Mitophagy switches cell death from apoptosis to necrosis in NSCLC cells treated with oncolytic measles virus. Oncotarget 5(11):3907–3918

    Article  Google Scholar 

  97. Mukherjee R et al (2015) Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP. Gut

    Google Scholar 

  98. Wu P et al (2015) Oxaliplatin triggers necrosis as well as apoptosis in gastric cancer SGC-7901 cells. Biochem Biophys Res Commun 460(2):183–190

    Article  CAS  Google Scholar 

  99. Bian S et al (2013) P2X7 integrates PI3K/AKT and AMPK-PRAS40-mTOR signaling pathways to mediate tumor cell death. PLoS One 8(4):e60184

    Article  CAS  Google Scholar 

  100. Rhett JM, Yeh ES (2018) The potential for connexin hemichannels to drive breast cancer progression through regulation of the inflammatory response. Int J Mol Sci (4):19

    Google Scholar 

  101. Bianchi G et al (2014) ATP/P2X7 axis modulates myeloid-derived suppressor cell functions in neuroblastoma microenvironment. Cell Death Dis 5:e1135

    Article  CAS  Google Scholar 

  102. Hill LM et al (2010) Extracellular ATP may contribute to tissue repair by rapidly stimulating purinergic receptor X7-dependent vascular endothelial growth factor release from primary human monocytes. J Immunol 185(5):3028–3034

    Article  CAS  Google Scholar 

  103. Takai E et al (2012) Autocrine regulation of TGF-beta1-induced cell migration by exocytosis of ATP and activation of P2 receptors in human lung cancer cells. J Cell Sci 125(Pt 21):5051–5060

    CAS  Google Scholar 

  104. Lee HE et al (2019) Inhibition of NLRP3 inflammasome in tumor microenvironment leads to suppression of metastatic potential of cancer cells. Sci Rep 9(1):12277

    Article  CAS  Google Scholar 

  105. Kamo N et al (2013) ASC/caspase-1/IL-1beta signaling triggers inflammatory responses by promoting HMGB1 induction in liver ischemia/reperfusion injury. Hepatology 58(1):351–362

    Article  CAS  Google Scholar 

  106. Gombault A, Baron L, Couillin I (2012) ATP release and purinergic signaling in NLRP3 inflammasome activation. Front Immunol 3:414

    Google Scholar 

  107. Xia J et al (2015) P2X7 receptor stimulates breast cancer cell invasion and migration via the AKT pathway. Oncol Rep 34(1):103–110

    Article  CAS  Google Scholar 

  108. Qiu Y et al (2014) P2X7 mediates ATP-driven invasiveness in prostate cancer cells. PLoS One 9(12):e114371

    Article  CAS  Google Scholar 

  109. Chadet S et al (2014) The activation of P2Y2 receptors increases MCF-7 breast cancer cells migration through the MEK-ERK1/2 signalling pathway. Carcinogenesis 35(6):1238–1247

    Article  CAS  Google Scholar 

  110. Li WH et al (2015) P2Y2 receptor and EGFR cooperate to promote prostate Cancer cell invasion via ERK1/2 pathway. PLoS One 10(7):e0133165

    Article  CAS  Google Scholar 

  111. Li WH et al (2013) P2Y2 receptor promotes cell invasion and metastasis in prostate cancer cells. Br J Cancer 109(6):1666–1675

    Article  CAS  Google Scholar 

  112. Qiu Y et al (2018) P2Y2 receptor promotes the migration and invasion of breast cancer cells via EMT-related genes Snail and E-cadherin. Oncol Rep 39(1):138–150

    CAS  Google Scholar 

  113. Khalid M et al (2017) Carcinoma-specific expression of P2Y11 receptor and its contribution in ATP-induced purinergic signalling and cell migration in human hepatocellular carcinoma cells. Oncotarget 8(23):37278–37290

    Article  Google Scholar 

  114. Furlan-Freguia C et al (2011) P2X7 receptor signaling contributes to tissue factor-dependent thrombosis in mice. J Clin Invest 121(7):2932–2944

    Article  CAS  Google Scholar 

  115. Schumacher D et al (2013) Platelet-derived nucleotides promote tumor-cell transendothelial migration and metastasis via P2Y2 receptor. Cancer Cell 24(1):130–137

    Article  CAS  Google Scholar 

  116. Gu BJ, Wiley JS (2006) Rapid ATP-induced release of matrix metalloproteinase 9 is mediated by the P2X7 receptor. Blood 107(12):4946–4953

    Article  CAS  Google Scholar 

  117. Rumjahn SM et al (2009) Purinergic regulation of vascular endothelial growth factor signaling in angiogenesis. Br J Cancer 100(9):1465–1470

    Article  CAS  Google Scholar 

  118. Skurk C et al (2005) Glycogen-Synthase Kinase3beta/beta-catenin axis promotes angiogenesis through activation of vascular endothelial growth factor signaling in endothelial cells. Circ Res 96(3):308–318

    Article  CAS  Google Scholar 

  119. Birbrair A et al (2014) Type-2 pericytes participate in normal and tumoral angiogenesis. Am J Physiol Cell Physiol 307(1):C25–C38

    Article  CAS  Google Scholar 

  120. Avanzato D et al (2016) Activation of P2X7 and P2Y11 purinergic receptors inhibits migration and normalizes tumor-derived endothelial cells via cAMP signaling. Sci Rep 6:32602

    Article  CAS  Google Scholar 

  121. Garza Trevino EN et al (2019) Effects of pericytes and colon cancer stem cells in the tumor microenvironment. Cancer Cell Int 19:173

    Article  Google Scholar 

  122. Ballerini P et al (2018) P2Y12 receptors in tumorigenesis and metastasis. Front Pharmacol 9:66

    Article  CAS  Google Scholar 

  123. Leone RD, Lo YC, Powell JD (2015) A2aR antagonists: next generation checkpoint blockade for cancer immunotherapy. Comput Struct Biotechnol J 13:265–272

    Article  CAS  Google Scholar 

  124. Sek K et al (2018) Targeting adenosine receptor signaling in cancer immunotherapy. Int J Mol Sci (12):19

    Google Scholar 

  125. Sharma V et al (2011) Ras regulates interleukin-1beta-induced HIF-1alpha transcriptional activity in glioblastoma. J Mol Med (Berl) 89(2):123–136

    Article  CAS  Google Scholar 

  126. Gdynia G et al (2010) Danger signaling protein HMGB1 induces a distinct form of cell death accompanied by formation of giant mitochondria. Cancer Res 70(21):8558–8568

    Article  CAS  Google Scholar 

  127. Liu Y, Levine B (2015) Autosis and autophagic cell death: the dark side of autophagy. Cell Death Differ 22(3):367–376

    Article  CAS  Google Scholar 

  128. Crump A (2017) Ivermectin: enigmatic multifaceted ‘wonder’ drug continues to surprise and exceed expectations. J Antibiot (Tokyo) 70(5):495–505

    Article  CAS  Google Scholar 

  129. Juarez M, Schcolnik-Cabrera A, Duenas-Gonzalez A (2018) The multitargeted drug ivermectin: from an antiparasitic agent to a repositioned cancer drug. Am J Cancer Res 8(2):317–331

    CAS  Google Scholar 

  130. Canale FP et al (2018) CD39 expression defines cell exhaustion in tumor-infiltrating CD8(+) T cells. Cancer Res 78(1):115–128

    Article  CAS  Google Scholar 

  131. Bailey SR et al (2017) Human CD26(high) T cells elicit tumor immunity against multiple malignancies via enhanced migration and persistence. Nat Commun 8(1):1961

    Article  CAS  Google Scholar 

  132. Li XY et al (2019) Targeting CD39 in cancer reveals an extracellular ATP and inflammasome driven tumor immunity. Cancer Discov 9(12):1754–1773

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Calidi Biotherapeutics, San Diego, CA, USA

    Dobrin Draganov

  2. Department of Immuno-Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA

    Peter P. Lee

Authors
  1. Dobrin Draganov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter P. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter P. Lee .

Editor information

Editors and Affiliations

  1. Department of Radiology, Columbia University Medical Center, New York, NY, USA, Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

    Alexander Birbrair

Rights and permissions

Reprints and permissions

Copyright information

© 2021 The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Draganov, D., Lee, P.P. (2021). Purinergic Signaling Within the Tumor Microenvironment. In: Birbrair, A. (eds) Tumor Microenvironment. Advances in Experimental Medicine and Biology, vol 1270. Springer, Cham. https://doi.org/10.1007/978-3-030-47189-7_5

Download citation

Publish with us

Policies and ethics

Search

Navigation