Skip to main content
SpringerLink
Log in

Resistance to Angiokinase Inhibitors

  • Chapter
  • First Online:
Resistance to Tyrosine Kinase Inhibitors

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT))

  • 474 Accesses

Abstract

Sustained angiogenesis is essential for cancer progression and metastasis. Targeting on proangiogenic factors has been demonstrated to improve overall survival in several cancers when combined with chemotherapy. However, the clinical benefits are transient and drug resistance is usually developed rapidly. In this chapter, the characteristics of key pro-angiogenic factors and their targeted therapies were summarized. The postulated mechanisms of the drug resistance and the potential strategies to improve antiangiogenic therapies are briefly discussed.

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

Abbreviations

BMDCs:

Bone marrow-derived cells (BMDCs)

FGF:

Fibroblast growth factor

ICAM:

Intercellular adhesion molecule

MMPs:

Matrix metalloproteinases

NSCLC:

Non-small cell lung cancer

PDGF:

Platelet-derived growth factor

PFS:

Progression-free survival

PIGF:

Placental growth factor

VEGF:

Vascular endothelial growth factor

VPF:

Vascular permeability factor

References

  1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    Article  CAS  PubMed  Google Scholar 

  2. Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473(7347):298–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Dvorak HF et al. Fibrin gel investment associated with line 1 and line 10 solid tumor growth, angiogenesis, and fibroplasia in guinea pigs. Role of cellular immunity, myofibroblasts, microvascular damage, and infarction in line 1 tumor regression. J Natl Cancer Inst. 1979;62(6):1459–72.

    CAS  PubMed  Google Scholar 

  4. Senger DR et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983;219(4587):983–5.

    Article  CAS  PubMed  Google Scholar 

  5. Keck PJ et al. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science. 1989;246(4935):1309–12.

    Article  CAS  PubMed  Google Scholar 

  6. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004;25(4):581–611.

    Article  CAS  PubMed  Google Scholar 

  7. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23(5):1011–27.

    Article  CAS  PubMed  Google Scholar 

  8. Roskoski Jr R. Vascular endothelial growth factor (VEGF) signaling in tumor progression. Crit Rev Oncol Hematol. 2007;62(3):179–213.

    Article  PubMed  Google Scholar 

  9. Carmeliet P et al. Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Nat Med. 1999;5(5):495–502.

    Article  CAS  PubMed  Google Scholar 

  10. Stalmans I et al. Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms. J Clin Invest. 2002;109(3):327–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gerber HP, Ferrara N. The role of VEGF in normal and neoplastic hematopoiesis. J Mol Med. 2003;81(1):20–31.

    Article  CAS  PubMed  Google Scholar 

  12. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–76.

    Article  CAS  PubMed  Google Scholar 

  13. Takahashi H, Shibuya M. The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions. Clin Sci (Lond). 2005;109(3):227–41.

    Article  CAS  Google Scholar 

  14. Fong GH et al. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature. 1995;376(6535):66–70.

    Article  CAS  PubMed  Google Scholar 

  15. Hiratsuka S et al. Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc Natl Acad Sci U S A. 1998;95(16):9349–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hiratsuka S et al. Membrane fixation of vascular endothelial growth factor receptor 1 ligand-binding domain is important for vasculogenesis and angiogenesis in mice. Mol Cell Biol. 2005;25(1):346–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Shalaby F et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature. 1995;376(6535):62–6.

    Article  CAS  PubMed  Google Scholar 

  18. Li B et al. Receptor-selective variants of human vascular endothelial growth factor. Generation and characterization. J Biol Chem. 2000;275(38):29823–8.

    Article  CAS  PubMed  Google Scholar 

  19. Li B et al. KDR (VEGF receptor 2) is the major mediator for the hypotensive effect of VEGF. Hypertension. 2002;39(6):1095–100.

    Article  CAS  PubMed  Google Scholar 

  20. Gille H et al. Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2). A reassessment using novel receptor-specific vascular endothelial growth factor mutants. J Biol Chem. 2001;276(5):3222–30.

    Article  CAS  PubMed  Google Scholar 

  21. Wu Q et al. Emerging roles of PDGF-D in EMT progression during tumorigenesis. Cancer Treat Rev. 2013;39(6):640–6.

    Article  CAS  PubMed  Google Scholar 

  22. Hellberg C, Ostman A, Heldin CH. PDGF and vessel maturation. Recent Results Cancer Res. 2010;180:103–14.

    Article  CAS  PubMed  Google Scholar 

  23. Gaengel K et al. Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler Thromb Vasc Biol. 2009;29(5):630–8.

    Article  CAS  PubMed  Google Scholar 

  24. Yao Q et al. Sonic hedgehog mediates a novel pathway of PDGF-BB-dependent vessel maturation. Blood. 2014;123(15):2429–37.

    Article  CAS  PubMed  Google Scholar 

  25. Hamdan R, Zhou Z, Kleinerman ES. Blocking SDF-1alpha/CXCR4 downregulates PDGF-B and inhibits bone marrow-derived pericyte differentiation and tumor vascular expansion in Ewing tumors. Mol Cancer Ther. 2014;13(2):483–91.

    Article  CAS  PubMed  Google Scholar 

  26. Song S et al. PDGFRbeta + perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival. Nat Cell Biol. 2005;7(9):870–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bergers G et al. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest. 2003;111(9):1287–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. McCarty MF et al. Overexpression of PDGF-BB decreases colorectal and pancreatic cancer growth by increasing tumor pericyte content. J Clin Invest. 2007;117(8):2114–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sennino B et al. Cellular source and amount of vascular endothelial growth factor and platelet-derived growth factor in tumors determine response to angiogenesis inhibitors. Cancer Res. 2009;69(10):4527–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Nisancioglu MH, Betsholtz C, Genove G. The absence of pericytes does not increase the sensitivity of tumor vasculature to vascular endothelial growth factor-A blockade. Cancer Res. 2010;70(12):5109–15.

    Article  CAS  PubMed  Google Scholar 

  31. Gerhardt H, Semb H. Pericytes: gatekeepers in tumour cell metastasis? J Mol Med (Berl). 2008;86(2):135–44.

    Article  Google Scholar 

  32. Jayson GC et al. Blockade of platelet-derived growth factor receptor-beta by CDP860, a humanized, PEGylated di-Fab′, leads to fluid accumulation and is associated with increased tumor vascularized volume. J Clin Oncol. 2005;23(5):973–81.

    Article  CAS  PubMed  Google Scholar 

  33. Meseure D, Drak Alsibai K, Nicolas A. Pivotal role of pervasive neoplastic and stromal cells reprogramming in circulating tumor cells dissemination and metastatic colonization. Cancer Microenviron. 2014;7(3):95–115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Katoh M, Nakagama H. FGF receptors: cancer biology and therapeutics. Med Res Rev. 2014;34(2):280–300.

    Article  CAS  PubMed  Google Scholar 

  35. Bae JH, Schlessinger J. Asymmetric tyrosine kinase arrangements in activation or autophosphorylation of receptor tyrosine kinases. Mol Cells. 2010;29(5):443–8.

    Article  CAS  PubMed  Google Scholar 

  36. Beenken A, Mohammadi M. The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov. 2009;8(3):235–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008;8(8):592–603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Murakami M et al. The FGF system has a key role in regulating vascular integrity. J Clin Invest. 2008;118(10):3355–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ferrara N, Hillan KJ, Novotny W. Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun. 2005;333(2):328–35.

    Article  CAS  PubMed  Google Scholar 

  40. Sandler A et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355(24):2542–50.

    Article  CAS  PubMed  Google Scholar 

  41. Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer. 2008;8(8):579–91.

    Article  CAS  PubMed  Google Scholar 

  42. Janne PA, Gray N, Settleman J. Factors underlying sensitivity of cancers to small-molecule kinase inhibitors. Nat Rev Drug Discov. 2009;8(9):709–23.

    Article  CAS  PubMed  Google Scholar 

  43. Hida K, Klagsbrun M. A new perspective on tumor endothelial cells: unexpected chromosome and centrosome abnormalities. Cancer Res. 2005;65(7):2507–10.

    Article  CAS  PubMed  Google Scholar 

  44. Hillen F, Griffioen AW. Tumour vascularization: sprouting angiogenesis and beyond. Cancer Metastasis Rev. 2007;26(3-4):489–502.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Crawford Y et al. PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. Cancer Cell. 2009;15(1):21–34.

    Article  CAS  PubMed  Google Scholar 

  46. Motzer RJ et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24(1):16–24.

    Article  CAS  PubMed  Google Scholar 

  47. Casanovas O et al. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell. 2005;8(4):299–309.

    Article  CAS  PubMed  Google Scholar 

  48. Cao Y, Cao R, Hedlund EM. R Regulation of tumor angiogenesis and metastasis by FGF and PDGF signaling pathways. J Mol Med (Berl). 2008;86(7):785–9.

    Article  CAS  Google Scholar 

  49. Fischer C et al. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell. 2007;131(3):463–75.

    Article  CAS  PubMed  Google Scholar 

  50. Bais C et al. PlGF blockade does not inhibit angiogenesis during primary tumor growth. Cell. 2010;141(1):166–77.

    Article  CAS  PubMed  Google Scholar 

  51. Ferrara N. Pathways mediating VEGF-independent tumor angiogenesis. Cytokine Growth Factor Rev. 2010;21(1):21–6.

    Article  CAS  PubMed  Google Scholar 

  52. Cao Y et al. Systemic overexpression of angiopoietin-2 promotes tumor microvessel regression and inhibits angiogenesis and tumor growth. Cancer Res. 2007;67(8):3835–44.

    Article  CAS  PubMed  Google Scholar 

  53. Chae SS et al. Angiopoietin-2 interferes with anti-VEGFR2-induced vessel normalization and survival benefit in mice bearing gliomas. Clin Cancer Res. 2010;16(14):3618–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Noguera-Troise I et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature. 2006;444(7122):1032–7.

    Article  CAS  PubMed  Google Scholar 

  55. Ridgway J et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature. 2006;444(7122):1083–7.

    Article  CAS  PubMed  Google Scholar 

  56. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182–6.

    Article  CAS  PubMed  Google Scholar 

  57. Jain RK. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell. 2014;26(5):605–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ruffell B, Affara NI, Coussens LM. Differential macrophage programming in the tumor microenvironment. Trends Immunol. 2012;33(3):119–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Shojaei F et al. Tumor refractoriness to anti-VEGF treatment is mediated by CD11b(+)Gr1(+) myeloid cells. Nat Biotechnol. 2007;25(8):911–20.

    Article  CAS  PubMed  Google Scholar 

  60. Mazzieri R et al. Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell. 2011;19(4):512–26.

    Article  CAS  PubMed  Google Scholar 

  61. Yang L et al. Expansion of myeloid immune suppressor Gr + CD11b + cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell. 2004;6(4):409–21.

    Article  CAS  PubMed  Google Scholar 

  62. Huang Y, Carbone DP. Mechanisms of and strategies for overcoming resistance to anti-vascular endothelial growth factor therapy in non-small cell lung cancer. Biochim Biophys Acta. 2015;1855(2):193–201.

    CAS  PubMed  Google Scholar 

  63. Llovet JM et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90.

    Article  CAS  PubMed  Google Scholar 

  64. Blumenschein Jr GR et al. Phase II, multicenter, uncontrolled trial of single-agent sorafenib in patients with relapsed or refractory, advanced non-small-cell lung cancer. J Clin Oncol. 2009;27(26):4274–80.

    Article  CAS  PubMed  Google Scholar 

  65. Scagliotti G et al. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol. 2010;28(11):1835–42.

    Article  CAS  PubMed  Google Scholar 

  66. Socinski MA et al. Multicenter, phase II trial of sunitinib in previously treated, advanced non-small-cell lung cancer. J Clin Oncol. 2008;26(4):650–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Crown JP et al. Phase III trial of sunitinib in combination with capecitabine versus capecitabine monotherapy for the treatment of patients with pretreated metastatic breast cancer. J Clin Oncol. 2013;31(23):2870–8.

    Article  CAS  PubMed  Google Scholar 

  68. Wedge SR et al. AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res. 2005;65(10):4389–400.

    Article  CAS  PubMed  Google Scholar 

  69. Goss GD et al. Randomized, double-blind trial of carboplatin and paclitaxel with either daily oral cediranib or placebo in advanced non-small-cell lung cancer: NCIC clinical trials group BR24 study. J Clin Oncol. 2010;28(1):49–55.

    Article  CAS  PubMed  Google Scholar 

  70. Batchelor TT et al. Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol. 2013;31(26):3212–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Batchelor TT et al. Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation. Proc Natl Acad Sci U S A. 2013;110(47):19059–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Sternberg CN et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28(6):1061–8.

    Article  CAS  PubMed  Google Scholar 

  73. Altorki N et al. Phase II proof-of-concept study of pazopanib monotherapy in treatment-naive patients with stage I/II resectable non-small-cell lung cancer. J Clin Oncol. 2010;28(19):3131–7.

    Article  CAS  PubMed  Google Scholar 

  74. Jain RK. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol. 2013;31(17):2205–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307(5706):58–62.

    Article  CAS  PubMed  Google Scholar 

  76. Mitchell DC, Bryan BA. Anti-angiogenic therapy: adapting strategies to overcome resistant tumors. J Cell Biochem. 2010;111(3):543–53.

    Article  CAS  PubMed  Google Scholar 

  77. Huang Y et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci U S A. 2012;109(43):17561–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Mazzone M, Comoglio PM. The Met pathway: master switch and drug target in cancer progression. FASEB J. 2006;20(10):1611–21.

    Article  CAS  PubMed  Google Scholar 

  79. Yuan A et al. Vascular endothelial growth factor 189 mRNA isoform expression specifically correlates with tumor angiogenesis, patient survival, and postoperative relapse in non-small-cell lung cancer. J Clin Oncol. 2001;19(2):432–41.

    CAS  PubMed  Google Scholar 

  80. Nakashima T et al. Expression of vascular endothelial growth factor-A and vascular endothelial growth factor-C as prognostic factors for non-small cell lung cancer. Med Sci Monit. 2004;10(6):BR157–65.

    CAS  PubMed  Google Scholar 

  81. Matsuyama M et al. Alternative splicing variant of vascular endothelial growth factor-A is a critical prognostic factor in non-small cell lung cancer. Oncol Rep. 2009;22(6):1407–13.

    CAS  PubMed  Google Scholar 

  82. Dowlati A et al. Cell adhesion molecules, vascular endothelial growth factor, and basic fibroblast growth factor in patients with non-small cell lung cancer treated with chemotherapy with or without bevacizumab--an Eastern Cooperative Oncology Group Study. Clin Cancer Res. 2008;14(5):1407–12.

    Article  CAS  PubMed  Google Scholar 

  83. Jain RK et al. Biomarkers of response and resistance to antiangiogenic therapy. Nat Rev Clin Oncol. 2009;6(6):327–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Schneider BP, Radovich M, Miller KD. The role of vascular endothelial growth factor genetic variability in cancer. Clin Cancer Res. 2009;15(17):5297–302.

    Article  CAS  PubMed  Google Scholar 

  85. Rao VS et al. Potential prognostic and therapeutic roles for cytokines in breast cancer (Review). Oncol Rep. 2006;15(1):179–85.

    CAS  PubMed  Google Scholar 

  86. Waugh DJ, Wilson C. The interleukin-8 pathway in cancer. Clin Cancer Res. 2008;14(21):6735–41.

    Article  CAS  PubMed  Google Scholar 

  87. Huang D et al. Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma. Cancer Res. 2010;70(3):1063–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Nikolinakos PG et al. Plasma cytokine and angiogenic factor profiling identifies markers associated with tumor shrinkage in early-stage non-small cell lung cancer patients treated with pazopanib. Cancer Res. 2010;70(6):2171–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Dahlberg SE et al. Clinical course of advanced non-small-cell lung cancer patients experiencing hypertension during treatment with bevacizumab in combination with carboplatin and paclitaxel on ECOG 4599. J Clin Oncol. 2010;28(6):949–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Hurwitz HI et al. Analysis of early hypertension and clinical outcome with bevacizumab: results from seven phase III studies. Oncologist. 2013;18(3):273–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work is supported in part by grants from the National Natural Science Foundation of China (81372245), the Collaborative Innovation Center of Hematology and the Priority Academic Program Development of Jiangsu Higher Education Institutions of China.

Author information

Authors and Affiliations

  1. Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China

    Yuhui Huang

Authors
  1. Yuhui Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yuhui Huang .

Editor information

Editors and Affiliations

  1. Pisa University Hospital, Pisa, Italy

    Daniele Focosi

Conflict of Interest Statement

Conflict of Interest Statement

 The author declares no conflict of interest related to this manuscript.

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Huang, Y. (2016). Resistance to Angiokinase Inhibitors. In: Focosi, D. (eds) Resistance to Tyrosine Kinase Inhibitors. Resistance to Targeted Anti-Cancer Therapeutics. Springer, Cham. https://doi.org/10.1007/978-3-319-46091-8_6

Download citation

Publish with us

Policies and ethics

Search

Navigation