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Molecular Determinants of Head and Neck Cancer pp 439–467Cite as

Angiogenesis and Anti-angiogenic Therapy in Head and Neck Cancer

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Part of the book series: Current Cancer Research ((CUCR))

Abstract

The formation of new blood vessels, or angiogenesis, takes place through a variety of different physiologic and unique pathologic processes in tumor tissue. While the control mechanisms of some of these processes are not yet understood, as in the case of de novo vessel formation or intussusceptive angiogenesis, a closer examination of the process of sprouting angiogenesis highlights the complexity of the molecular mechanisms of angiogenesis. Through both positive regulation with proteins such as vascular endothelial growth factors (VEGFs), fibroblast growth factor (FGF), and NOTCH and negative regulation with other signals such as thrombospondin, endostatin, and angiostatin, the endothelial cells of an existing vessel can reorganize into new functional luminal architecture. As our comprehension of the regulatory machinery has improved, so has the desire to create anti-angiogenic therapies using targeted monoclonal antibodies, tyrosine kinase inhibitors, and other novel targeted small molecular inhibitors directed at interrupting these regulatory signals. Drugs directed against vascular endothelial growth factors in particular (e.g., bevacizumab or sunitinib) have been studied as antineoplastic agents either alone or in combination with cytotoxic chemotherapy or other targeted agents. A unique toxicity profile has been seen with anti-angiogenics that may include events such as bleeding, hypertension, and proteinuria. The interest in targeting angiogenesis continues, and more clinical trials are underway with new targets and evolving strategies.

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References

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Ribatti D, et al. Postnatal vasculogenesis. Mech Dev. 2001;100(2):157–63.

    Article  PubMed  CAS  Google Scholar 

  3. Tang DG, Conti CJ. Endothelial cell development, vasculogenesis, angiogenesis, and tumor neovascularization: an update. Semin Thromb Hemost. 2004;30(01):109–17.

    Article  PubMed  Google Scholar 

  4. Lee S-P, et al. Integrin-linked kinase, a hypoxia-responsive molecule, controls postnatal vasculogenesis by recruitment of endothelial progenitor cells to ischemic tissue. Circulation. 2006;114(2):150–9.

    Article  PubMed  CAS  Google Scholar 

  5. Makanya AN, Hlushchuk R, Djonov VG. Intussusceptive angiogenesis and its role in vascular morphogenesis, patterning, and remodeling. Angiogenesis. 2009;12(2):113.

    Article  PubMed  CAS  Google Scholar 

  6. Djonov V, Baum O, Burri PH. Vascular remodeling by intussusceptive angiogenesis. Cell Tissue Res. 2003;314(1):107–17.

    Article  PubMed  Google Scholar 

  7. Michiels C, Arnould T, Remacle J. Endothelial cell responses to hypoxia: initiation of a cascade of cellular interactions. Biochim Biophys Acta, Mol Cell Res. 2000;1497(1):1–10.

    Article  PubMed  CAS  Google Scholar 

  8. Bergers G, Song S. The role of pericytes in blood-vessel formation and maintenance. Neuro-Oncology. 2005;7(4):452–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. van Hinsbergh VWM, Koolwijk P. Endothelial sprouting and angiogenesis: matrix metalloproteinases in the lead. Cardiovasc Res. 2008;78(2):203–12.

    Article  PubMed  CAS  Google Scholar 

  10. Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis. Cell. 2011;146(6):873–87.

    Article  CAS  PubMed  Google Scholar 

  11. Siekmann AF, Affolter M, Belting H-G. The tip cell concept 10 years after: new players tune in for a common theme. Exp Cell Res. 2013;319(9):1255–63.

    Article  PubMed  CAS  Google Scholar 

  12. Ribatti D, Crivellato E. “Sprouting angiogenesis”, a reappraisal. Dev Biol. 2012;372(2):157–65.

    Article  PubMed  CAS  Google Scholar 

  13. Schmidt T, Carmeliet P. Blood-vessel formation: bridges that guide and unite. Nature. 2010;465(7299):697–9.

    Article  PubMed  CAS  Google Scholar 

  14. Koch S, et al. Signal transduction by vascular endothelial growth factor receptors. Biochem J. 2011;437(2):169–83.

    Article  PubMed  CAS  Google Scholar 

  15. Robinson CJ, Stringer SE. The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J Cell Sci. 2001;114(5):853–65.

    PubMed  CAS  Google Scholar 

  16. Vincenti V, et al. Assignment of the vascular endothelial growth factor gene to human chromosome 6p21.3. Circulation. 1996;93(8):1493–5.

    Article  PubMed  CAS  Google Scholar 

  17. Ladomery MR, Harper SJ, Bates DO. Alternative splicing in angiogenesis: the vascular endothelial growth factor paradigm. Cancer Lett. 2007;249(2):133–42.

    Article  PubMed  CAS  Google Scholar 

  18. Biselli-Chicote PM, et al. VEGF gene alternative splicing: pro- and anti-angiogenic isoforms in cancer. J Cancer Res Clin Oncol. 2012;138(3):363–70.

    Article  PubMed  CAS  Google Scholar 

  19. Shibuya M. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: a crucial target for anti- and pro-angiogenic therapies. Genes Cancer. 2011;2(12):1097–105.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Hoeben A, et al. Vascular endothelial growth factor and angiogenesis. Pharmacol Rev. 2004;56(4):549–80.

    Article  PubMed  CAS  Google Scholar 

  21. Forsythe JA, et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996;16(9):4604–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Krock BL, Skuli N, Simon MC. Hypoxia-induced angiogenesis: good and evil. Genes Cancer. 2011;2(12):1117–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Niu G, et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene. 2002;21(13):2000–8.

    Article  PubMed  CAS  Google Scholar 

  24. McColl BK, Stacker SA, Achen MG. Molecular regulation of the VEGF family – inducers of angiogenesis and lymphangiogenesis. APMIS. 2004;112(7–8):463–80.

    Article  PubMed  CAS  Google Scholar 

  25. Lee S, et al. Autocrine VEGF signaling is required for vascular homeostasis. Cell. 2007;130(4):691–703.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Rashdan N, Lloyd P. Autocrine and paracrine effects of VEGF-A on PLGF in an in vitro model of the vessel wall. FASEB J. 2015;29(1 Supplement). Abstract number:797.7

    Google Scholar 

  27. Vassilakopoulou M, Psyrri A, Argiris A. Targeting angiogenesis in head and neck cancer. Oral Oncol. 2015;51(5):409–15.

    Article  PubMed  CAS  Google Scholar 

  28. Shibuya M. Structure and function of VEGF/VEGF-receptor system involved in angiogenesis. Cell Struct Funct. 2001;26(1):25–35.

    Article  PubMed  CAS  Google Scholar 

  29. Cébe-Suarez S, Zehnder-Fjällman A, Ballmer-Hofer K. The role of VEGF receptors in angiogenesis; complex partnerships. Cell Mol Life Sci. 2006;63(5):601–15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Smith GA, et al. The cellular response to vascular endothelial growth factors requires co-ordinated signal transduction, trafficking and proteolysis. Biosci Rep. 2015;35(5):e00253.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Taimeh Z, et al. Vascular endothelial growth factor in heart failure. Nat Rev Cardiol. 2013;10(9):519–30.

    Article  CAS  PubMed  Google Scholar 

  32. Meyer RD, Mohammadi M, Rahimi N. A single amino acid substitution in the activation loop defines the decoy characteristic of VEGFR-1/FLT-1. J Biol Chem. 2006;281(2):867–75.

    Article  CAS  PubMed  Google Scholar 

  33. Fischer C, et al. FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy? Nat Rev Cancer. 2008;8(12):942–56.

    Article  CAS  PubMed  Google Scholar 

  34. Miettinen M, et al. Vascular endothelial growth factor receptor 2 (Vegfr2) as a marker for malignant vascular tumors and mesothelioma – Immunohistochemical study of 262 vascular endothelial and 1640 nonvascular tumors. Am J Surg Pathol. 2012;36(4):629–39.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Karar J, Maity A. PI3K/AKT/mTOR pathway in angiogenesis. Front Mol Neurosci. 2011;4:51.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Deng Y, Zhang X, Simons M. Molecular controls of lymphatic VEGFR3 signaling. Arterioscler Thromb Vasc Biol. 2015;35(2):421–9.

    Article  CAS  PubMed  Google Scholar 

  37. Alam A, et al. Heterodimerization with vascular endothelial growth factor receptor-2 (VEGFR-2) is necessary for VEGFR-3 activity. Biochem Biophys Res Commun. 2004;324(2):909–15.

    Article  CAS  PubMed  Google Scholar 

  38. Tvorogov D, et al. Effective suppression of vascular network formation by combination of antibodies blocking VEGFR ligand binding and receptor dimerization. Cancer Cell. 2010;18(6):630–40.

    Article  CAS  PubMed  Google Scholar 

  39. Meadows KN, Bryant P, Pumiglia K. Vascular endothelial growth factor induction of the Angiogenic phenotype requires Ras activation. J Biol Chem. 2001;276(52):49289–98.

    Article  CAS  PubMed  Google Scholar 

  40. Shu X, et al. Sphingosine kinase mediates vascular endothelial growth factor-induced activation of ras and mitogen-activated protein kinases. Mol Cell Biol. 2002;22(22):7758–68.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Takahashi T, Ueno H, Shibuya M. VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells. Oncogene. 1999;18(13):2221–30.

    Article  CAS  PubMed  Google Scholar 

  42. Roberts PJ, Der CJ. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene. 2007;26(22):3291–310.

    Article  CAS  PubMed  Google Scholar 

  43. Abid MR, et al. Vascular endothelial growth factor activates PI3K/Akt/Forkhead signaling in endothelial cells. Arterioscler Thromb Vasc Biol. 2004;24(2):294–300.

    Article  CAS  PubMed  Google Scholar 

  44. Shiojima I, Walsh K. Role of Akt signaling in vascular homeostasis and angiogenesis. Circ Res. 2002;90(12):1243–50.

    Article  CAS  PubMed  Google Scholar 

  45. Jiang BH, Liu LZ. Chapter 2 PI3K/PTEN Signaling in Angiogenesis and Tumorigenesis. Adv Cancer Res. 2009., Academic Press;102:19–65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Zhong H, et al. Modulation of hypoxia-inducible factor 1α expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate Cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res. 2000;60(6):1541–5.

    CAS  PubMed  Google Scholar 

  47. Rousseau S, et al. p38 MAP kinase activation by vascular endothelial growth factor mediates actin reorganization and cell migration in human endothelial cells. Oncogene. 1997;15(18):2169–77.

    Article  CAS  PubMed  Google Scholar 

  48. Eriksson A, et al. Small GTP-binding protein Rac is an essential mediator of vascular endothelial growth factor-induced endothelial fenestrations and vascular permeability. Circulation. 2003;107(11):1532–8.

    Article  CAS  PubMed  Google Scholar 

  49. De Falco S. The discovery of placenta growth factor and its biological activity. Exp Mol Med. 2012;44:1–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Kim K-J, Cho C-S, Kim W-U. Role of placenta growth factor in cancer and inflammation. Exp Mol Med. 2012;44(1):10–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Hiratsuka S, et al. MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell. 2002;2(4):289–300.

    Article  CAS  PubMed  Google Scholar 

  52. Zhang W, et al. Placental growth factor promotes metastases of non-small cell lung cancer through MMP9. Cell Physiol Biochem. 2015;37(3):1210–8.

    Article  CAS  PubMed  Google Scholar 

  53. Heldin C-H, Lennartsson J. Structural and functional properties of platelet-derived growth factor and stem cell factor receptors. Cold Spring Harb Perspect Biol. 2013;5(8):a009100.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Pietras K, et al. PDGF receptors as cancer drug targets. Cancer Cell. 2003;3(5):439–43.

    Article  CAS  PubMed  Google Scholar 

  55. Jastrzębski K, et al. Multiple routes of endocytic internalization of PDGFRβ contribute to PDGF-induced STAT3 signaling. J Cell Sci. 2016;130(3):577–589

    Google Scholar 

  56. Seki T, Yun J, Oh SP. Arterial endothelium-specific Activin receptor-like kinase 1 expression suggests its role in arterialization and vascular remodeling. Circ Res. 2003;93(7):682–9.

    Article  CAS  PubMed  Google Scholar 

  57. de Vinuesa AG, et al. Targeting tumour vasculature by inhibiting activin receptor-like kinase (ALK)1 function. Biochem Soc Trans. 2016;44(4):1142–9.

    Article  CAS  PubMed  Google Scholar 

  58. Cunha SI, Pietras K. ALK1 as an emerging target for antiangiogenic therapy of cancer. Blood. 2011;117(26):6999–7006.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Ellis LM. Epidermal growth factor receptor in tumor angiogenesis. Hematol Oncol Clin North Am. 2004;18(5):1007–21.

    Article  PubMed  Google Scholar 

  60. Yarden Y. The EGFR family and its ligands in human cancer: signalling mechanisms and therapeutic opportunities. Eur J Cancer. 2001;37(Supplement 4):3–8.

    Article  Google Scholar 

  61. van Cruijsen H, Giaccone G, Hoekman K. Epidermal growth factor receptor and angiogenesis: opportunities for combined anticancer strategies. Int J Cancer. 2005;117(6):883–8.

    Article  CAS  PubMed  Google Scholar 

  62. Ucuzian AA, et al. Molecular mediators of angiogenesis. J Burn Care Res. 2010;31(1):158.

    Article  PubMed  Google Scholar 

  63. Cook KM, Figg WD. Angiogenesis inhibitors – current strategies and future prospects. CA Cancer J Clin. 2010;60(4):222–43.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Tamura K, Sakurai T, Kogo H. Relationship between prostaglandin E2 and vascular endothelial growth factor (VEGF) in angiogenesis in human vascular endothelial cells. Vasc Pharmacol. 2006;44(6):411–6.

    Article  CAS  Google Scholar 

  65. Cohen EE, et al. Erlotinib and bevacizumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck: a phase I/II study. Lancet Oncol. 2009;10:247–57.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Ren Y, et al. Hepatocyte growth factor promotes cancer cell migration and angiogenic factors expression: a prognostic marker of human esophageal squamous cell carcinomas. Clin Cancer Res. 2005;11(17):6190–7.

    Article  CAS  PubMed  Google Scholar 

  67. Zhang Y-W, et al. Hepatocyte growth factor/scatter factor mediates angiogenesis through positive VEGF and negative thrombospondin 1 regulation. Proc Natl Acad Sci. 2003;100(22):12718–23. Abstract number: 6000

    Google Scholar 

  68. Avraamides CJ, Garmy-Susini B, Varner JA. Integrins in angiogenesis and lymphangiogenesis. Nat Rev Cancer. 2008;8(8):604–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Weis SM, Cheresh DA. αv Integrins in angiogenesis and cancer. Cold Spring Harb Perspect Med. 2011;1(1):a006478.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. De S, et al. VEGF–integrin interplay controls tumor growth and vascularization. Proc Natl Acad Sci USA. 2005;102(21):7589–94.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  71. Lorger M, et al. Activation of tumor cell integrin α(v)β(3) controls angiogenesis and metastatic growth in the brain. Proc Natl Acad Sci USA. 2009;106(26):10666–71.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Huang Z, Bao S-D. Roles of main pro- and anti-angiogenic factors in tumor angiogenesis. World J Gastroenterol. 2004;10(4):463–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Nyberg P, Xie L, Kalluri R. Endogenous inhibitors of angiogenesis. Cancer Res. 2005;65(10):3967–79.

    Article  CAS  PubMed  Google Scholar 

  74. Sund M, Zeisberg M, Kalluri R. Endogenous stimulators and inhibitors of angiogenesis in gastrointestinal cancers: basic science to clinical application. Gastroenterology. 2005;129(6):2076–91.

    Article  CAS  PubMed  Google Scholar 

  75. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996;86(3):353–64.

    Article  CAS  PubMed  Google Scholar 

  76. Baeriswyl V, Christofori G. The angiogenic switch in carcinogenesis. Semin Cancer Biol. 2009;19(5):329–37.

    Article  CAS  PubMed  Google Scholar 

  77. Weis SM, Cheresh DA. Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med. 2011;17(11):1359–70.

    Article  CAS  PubMed  Google Scholar 

  78. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003;3:401–10.

    Article  CAS  PubMed  Google Scholar 

  79. Qian C-N, et al. Revisiting tumor angiogenesis: vessel co-option, vessel remodeling, and cancer cell-derived vasculature formation. Chin J Cancer. 2016;35(1):10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Folberg R, Hendrix MJC, Maniotis AJ. Vasculogenic mimicry and tumor angiogenesis. Am J Pathol. 2000;156(2):361–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Seftor REB, et al. Tumor cell vasculogenic mimicry: from controversy to therapeutic promise. Am J Pathol. 2012;181(4):1115–25.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Delgado-Bellido D, et al. Vasculogenic mimicry signaling revisited: focus on non-vascular VE-cadherin. Mol Cancer. 2017;16(1):65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Hendrix MJ, et al. Expression and functional significance of VE-cadherin in aggressive human melanoma cells: role in vasculogenic mimicry. Proc Natl Acad Sci USA. 2001;98:8018–23.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  84. Hendrix MJ, et al. Transendothelial function of human metastatic melanoma cells: role of the microenvironment in cell-fate determination. Cancer Res. 2002;62:665–8.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Kerbel RS. Tumor angiogenesis. N Engl J Med. 2008;358(19):2039–49.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. De Luca A, et al. The role of the EGFR signaling in tumor microenvironment. J Cell Physiol. 2008;214(3):559–67.

    Article  PubMed  CAS  Google Scholar 

  88. Baker CH, et al. Blockade of epidermal growth factor receptor signaling on tumor cells and tumor-associated endothelial cells for therapy of human carcinomas. Am J Pathol. 2002;161(3):929–38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Hirata A, et al. ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase. Cancer Res. 2002;62(9):2554–60.

    PubMed  CAS  Google Scholar 

  90. Nolan DJ, et al. Molecular signatures of tissue-specific microvascular endothelial cell heterogeneity in organ maintenance and regeneration. Dev Cell. 2013;26(2):204–19.

    Article  PubMed  CAS  Google Scholar 

  91. Nör JE, et al. Up-regulation of Bcl-2 in microvascular endothelial cells enhances intratumoral angiogenesis and accelerates tumor growth. Cancer Res. 2001;61(5):2183–8.

    PubMed  Google Scholar 

  92. Garcia-Barros M, et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science. 2003;300(5622):1155–9.

    Article  PubMed  CAS  Google Scholar 

  93. Oyama T, et al. Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-κB activation in Hemopoietic progenitor cells. J Immunol. 1998;160(3):1224–32.

    PubMed  CAS  Google Scholar 

  94. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Motz GT, Coukos G. The parallel lives of angiogenesis and immunosuppression: cancer and other tales. Nat Rev Immunol. 2011;11(10):702–11.

    Article  PubMed  CAS  Google Scholar 

  96. Ziogas AC, et al. VEGF directly suppresses activation of T cells from ovarian cancer patients and healthy individuals via VEGF receptor type 2. Int J Cancer. 2012;130(4):857–64.

    Article  PubMed  CAS  Google Scholar 

  97. Du R, et al. HIF1α induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell. 2008;13(3):206–20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Shojaei F, et al. Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature. 2007;450(7171):825–31.

    Article  PubMed  CAS  Google Scholar 

  99. Murdoch C, et al. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer. 2008;8(8):618–31.

    Article  PubMed  CAS  Google Scholar 

  100. Rivera LB, Bergers G. Intertwined regulation of angiogenesis and immunity by myeloid cells. Trends Immunol. 2015;36(4):240–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41(1):49–61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Riabov V, et al. Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis. Front Physiol. 2014;5:75.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Guo C, et al. The role of tumor-associated macrophages in tumor vascularization. Vasc Cell. 2013;5(1):20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Ribatti D, et al. Macrophages and tumor angiogenesis. Leukemia. 2007;21(10):2085–9.

    Article  PubMed  CAS  Google Scholar 

  105. Lin EY, et al. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med. 2001;193(6):727–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Bingle L, et al. Macrophages promote angiogenesis in human breast tumour spheroids in vivo. Br J Cancer. 2005;94(1):101–7.

    Article  CAS  PubMed Central  Google Scholar 

  107. Kobayashi N, et al. Hyaluronan deficiency in tumor stroma impairs macrophage trafficking and tumor neovascularization. Cancer Res. 2010;70(18):7073–83.

    Article  PubMed  CAS  Google Scholar 

  108. Mineta H, et al. Prognostic value of vascular endothelial growth factor (VEGF) in head and neck squamous cell carcinomas. Br J Cancer. 2000;83(6):775–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Singhal A, et al. Vascular endothelial growth factor expression in oral cancer and its role as a predictive marker: a prospective study. Saudi Surg J. 2016;4(2):52–6.

    Article  Google Scholar 

  110. Kyzas PA, Cunha IW, Ioannidis JPA. Prognostic significance of vascular endothelial growth factor Immunohistochemical expression in head and neck squamous cell carcinoma: a meta-analysis. Clin Cancer Res. 2005;11(4):1434–40.

    Article  PubMed  CAS  Google Scholar 

  111. Bonhin RG, et al. Correlation between vascular endothelial growth factor expression and presence of lymph node metastasis in advanced squamous cell carcinoma of the larynx. Braz J Otorhinolaryngol. 2015;81:58–62.

    Article  PubMed  Google Scholar 

  112. de Sousa EA, et al. Head and neck squamous cell carcinoma lymphatic spread and survival: relevance of vascular endothelial growth factor family for tumor evaluation. Head Neck. 2015;37(10):1410–6.

    Article  PubMed  Google Scholar 

  113. Karatzanis AD, et al. Molecular pathways of lymphangiogenesis and lymph node metastasis in head and neck cancer. Eur Arch Otorhinolaryngol. 2012;269(3):731–7.

    Article  CAS  PubMed  Google Scholar 

  114. Kalyankrishna S, Grandis JR. Epidermal growth factor receptor biology in head and neck Cancer. J Clin Oncol. 2006;24(17):2666–72.

    Article  CAS  PubMed  Google Scholar 

  115. Ang KK, et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res. 2002;62(24):7350–6.

    CAS  PubMed  Google Scholar 

  116. Wang W-M, et al. Epidermal growth factor receptor inhibition reduces angiogenesis via hypoxia-inducible factor-1α and Notch1 in head neck squamous cell carcinoma. PLoS One. 2015;10(2):e0119723.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Tabernero J. The role of VEGF and EGFR inhibition: implications for combining anti–VEGF and anti–EGFR agents. Mol Cancer Res. 2007;5(3):203–20.

    Article  PubMed  CAS  Google Scholar 

  118. Tonra JR, et al. Synergistic antitumor effects of combined epidermal growth factor receptor and vascular endothelial growth factor receptor-2 targeted therapy. Clin Cancer Res. 2006;12(7):2197–207.

    Article  PubMed  CAS  Google Scholar 

  119. Polanska H, et al. Evaluation of EGFR as a prognostic and diagnostic marker for head and neck squamous cell carcinoma patients. Oncol Lett. 2016;12(3):2127–32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Brøndum L, et al. Plasma proteins as prognostic biomarkers in radiotherapy treated head and neck cancer patients. ClinTransl Radiat Oncol. 2017;2:46–52.

    Google Scholar 

  121. Guerra ENS, et al. Diagnostic accuracy of serum biomarkers for head and neck cancer: a systematic review and meta-analysis. Crit Rev Oncog Hematol. 2016;101:93–118.

    Article  Google Scholar 

  122. Byers LA, et al. Serum signature of hypoxia-regulated factors is associated with progression after induction therapy in head and neck squamous cell cancer. Mol Cancer Ther. 2010;9(6):1755–63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Cohen NA, et al. Dysregulation of hypoxia inducible factor-1α in head and neck squamous cell carcinoma cell lines correlates with invasive potential. Laryngoscope. 2004;114(3):418–23.

    Article  PubMed  CAS  Google Scholar 

  124. Jokilehto T, et al. Overexpression and nuclear translocation of hypoxia-inducible factor prolyl hydroxylase PHD2 in head and neck squamous cell carcinoma is associated with tumor aggressiveness. Clin Cancer Res. 2006;12(4):1080–7.

    Article  PubMed  CAS  Google Scholar 

  125. Schrijvers ML, et al. Overexpression of intrinsic hypoxia markers HIF1α and CA-IX predict for local recurrence in stage T1-T2 Glottic laryngeal carcinoma treated with radiotherapy. Int J Radiat Oncol Biol Phys. 2008;72(1):161–9.

    Article  PubMed  CAS  Google Scholar 

  126. Fillies T, et al. HIF1-alpha overexpression indicates a good prognosis in early stage squamous cell carcinomas of the oral floor. BMC Cancer. 2005;5(1):84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Beasley NJP, et al. Hypoxia-inducible factors HIF-1α and HIF-2α in head and neck cancer. Relationship to tumor biology and treatment outcome in surgically resected patients. Cancer Res. 2002;62(9):2493–7.

    PubMed  CAS  Google Scholar 

  128. Ongkeko WM, et al. Expression of protein tyrosine kinases in head and neck squamous cell carcinomas. Am J Clin Pathol. 2005;124(1):71–6.

    Article  CAS  PubMed  Google Scholar 

  129. Chen Z, et al. Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer. Clin Cancer Res. 1999;5(6):1369–79.

    PubMed  CAS  Google Scholar 

  130. Ninck S, et al. Expression profiles of angiogenic growth factors in squamous cell carcinomas of the head and neck. Int J Cancer. 2003;106(1):34–44.

    Article  PubMed  CAS  Google Scholar 

  131. Wheeler SE, et al. Tumor associated fibroblasts enhance head and neck squamous cell carcinoma proliferation, invasion, and metastasis in preclinical models. Head Neck. 2014;36(3):385–92.

    Article  PubMed  Google Scholar 

  132. Curry JM, et al. Tumor microenvironment in head and neck squamous cell carcinoma. Semin Oncol. 2014;41(2):217–34.

    Article  CAS  PubMed  Google Scholar 

  133. Xin X, et al. Hepatocyte growth factor enhances vascular endothelial growth factor-induced angiogenesis in vitro and in vivo. Am J Pathol. 2001;158(3):1111–20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Ferrari G, et al. Transforming growth factor-beta 1 (TGF-β1) induces angiogenesis through vascular endothelial growth factor (VEGF)-mediated apoptosis. J Cell Physiol. 2009;219(2):449–58.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Ishikawa T, et al. Hypoxia enhances CXCR4 expression by activating HIF-1 in oral squamous cell carcinoma. Oncol Rep. 2009;21(3):707–12.

    CAS  PubMed  Google Scholar 

  136. Ohm JE, Carbone DP. VEGF as a mediator of tumor-associated immunodeficiency. Immunol Res. 2001;23:263–72.

    Article  CAS  PubMed  Google Scholar 

  137. Sridharan V, et al. Effects of definitive chemoradiation on circulating immunologic angiogenic cytokines in head and neck cancer patients. J Immunother Cancer. 2016;4(1):1–10.

    Article  Google Scholar 

  138. Williams CB, Yeh ES, Soloff AC. Tumor-associated macrophages: unwitting accomplices in breast cancer malignancy. NPJ Breast Cancer. 2016;2:15025.

    Article  PubMed  PubMed Central  Google Scholar 

  139. Quatromoni JG, Eruslanov E. Tumor-associated macrophages: function, phenotype, and link to prognosis in human lung cancer. Am J Transl Res. 2012;4(4):376–89.

    PubMed  PubMed Central  Google Scholar 

  140. Balermpas P, et al. Tumour-infiltrating lymphocytes predict response to definitive chemoradiotherapy in head and neck cancer. Br J Cancer. 2014;110(2):501–9.

    Article  CAS  PubMed  Google Scholar 

  141. Li C, et al. Infiltration of tumor-associated macrophages in human oral squamous cell carcinoma. Oncol Rep. 2002;9(6):1219–23.

    PubMed  Google Scholar 

  142. Mori K, et al. Infiltration of M2 tumor-associated macrophages in oral squamous cell carcinoma correlates with tumor malignancy. Cancers. 2011;3(4):3726.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Costa NL, et al. Tumor-associated macrophages and the profile of inflammatory cytokines in oral squamous cell carcinoma. Oral Oncol. 2013;49(3):216–23.

    Article  CAS  PubMed  Google Scholar 

  144. Dahiya K, Dhankhar R. Updated overview of current biomarkers in head and neck carcinoma. World J Methodol. 2016;6(1):77–86.

    Article  PubMed  PubMed Central  Google Scholar 

  145. Williams MD. Integration of biomarkers including molecular targeted therapies in head and neck cancer. Head Neck Pathol. 2010;4(1):62–9.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Kim KJ, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 1993;362(6423):841–4.

    Article  CAS  PubMed  Google Scholar 

  147. Perrotte P, et al. Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing Orthotopically in nude mice. Clin Cancer Res. 1999;5(2):257–64.

    CAS  PubMed  Google Scholar 

  148. Smith BD, et al. Prognostic significance of vascular endothelial growth factor protein levels in oral and oropharyngeal squamous cell carcinoma. J Clin Oncol. 2000;18(10):2046–52.

    Article  CAS  PubMed  Google Scholar 

  149. Strome SE, Sausville EA, Mann D. A mechanistic perspective of monoclonal antibodies in cancer therapy beyond target-related effects. Oncologist. 2007;12(9):1084–95.

    Article  CAS  PubMed  Google Scholar 

  150. Suzuki M, Kato C, Kato A. Therapeutic antibodies: their mechanisms of action and the pathological findings they induce in toxicity studies. J Toxicol Pathol. 2015;28(3):133–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Gerber H-P, Ferrara N. Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res. 2005;65(3):671–80.

    CAS  PubMed  Google Scholar 

  152. Fujita K, Sano D, Kimura M, Yamashita Y, Kawakami M, Ishiguro Y, Nishimura G, Matsuda H, Tsukuda M. Anti-tumor effects of bevacizumab in combination with paclitaxel on head and neck squamous cell carcinoma. Oncol Rep. 2007;18(1):47–51.

    CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Batchelor TT, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell. 2007;11(1):83–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Goel S, et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev. 2011;91(3):1071–121.

    Article  PubMed  CAS  Google Scholar 

  156. Weißhardt P, et al. Tumor vessel stabilization and remodeling by anti-angiogenic therapy with bevacizumab. Histochem Cell Biol. 2012;137(3):391–401.

    Article  CAS  PubMed  Google Scholar 

  157. Patel A, Sun W. Ziv-aflibercept in metastatic colorectal cancer. Biol: Targets Ther. 2014;8:13–25.

    CAS  Google Scholar 

  158. Jimeno A, et al. A phase 2 study of dalantercept, an activin receptor-like kinase-1 ligand trap, in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Cancer. 2016;122(23):3641–9.

    Article  CAS  PubMed  Google Scholar 

  159. Jorg Thomas H, et al. Tyrosine kinase inhibitors – a review on pharmacology, metabolism and side effects. Curr Drug Metab. 2009;10(5):470–81.

    Article  Google Scholar 

  160. Gotink KJ, Verheul HMW. Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action? Angiogenesis. 2010;13(1):1–14.

    Article  CAS  PubMed  Google Scholar 

  161. Verheul HMW, Pinedo HM. Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer. 2007;7(6):475–85.

    Article  CAS  PubMed  Google Scholar 

  162. Kamba T, McDonald DM. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer. 2007;96(12):1788–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. Hapani S, et al. Increased risk of serious hemorrhage with bevacizumab in cancer patients: a meta-analysis. Oncology. 2010;79(1–2):27–38.

    Article  CAS  PubMed  Google Scholar 

  164. Johnson DH, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004;22(11):2184–91.

    Article  CAS  PubMed  Google Scholar 

  165. Argiris A, et al. Phase II trial of pemetrexed and bevacizumab in patients with recurrent or metastatic head and neck cancer. J Clin Oncol. 2011;29:1140–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  166. Argiris A, et al. Cetuximab and bevacizumab: preclinical data and phase II trial in recurrent or metastatic squamous cell carcinoma of the head and neck. Ann Oncol. 2013;24:220–5.

    Article  CAS  PubMed  Google Scholar 

  167. Argiris A, Li S, Savvides P, Ohr J, Gilbert J, Levine M, Haigentz M Jr, Saba NF, Chakravarti A, Ikpeazu C, Schneider C, Pinto H, Forastiere AA, Burtness B. Phase III randomized trial of chemotherapy with or without bevacizumab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: survival analysis of E1305, an ECOG-ACRIN Cancer research group trial. J Clin Oncol. 2017;35(Suppl). Abstract number :6000

    Google Scholar 

  168. Argiris A, et al. Phase II randomized trial of radiation therapy, cetuximab, and pemetrexed with or without bevacizumab in patients with locally advanced head and neck cancer. Ann Oncol. 2016;27(8):1594–600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Horowitz JR, et al. Vascular endothelial growth factor/vascular permeability factor produces nitric oxide–dependent hypotension. Evidence for a maintenance role in quiescent adult endothelium. Arterioscler Thromb Vasc Biol. 1997;17(11):2793–800.

    Article  CAS  PubMed  Google Scholar 

  170. de Jesus-Gonzalez N, et al. Management of antiangiogenic therapy-induced hypertension. Hypertension. 2012;60(3):607–15.

    Article  PubMed  CAS  Google Scholar 

  171. PANDE A, et al. Hypertension secondary to anti-angiogenic therapy: experience with bevacizumab. Anticancer Res. 2007;27(5B):3465–70.

    CAS  PubMed  Google Scholar 

  172. Wasserstrum Y, et al. Hypertension in cancer patients treated with anti-angiogenic based regimens. Cardio-Oncology. 2015;1(1):6.

    Article  PubMed  PubMed Central  Google Scholar 

  173. Schneider BP, et al. Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol. 2008;26(28):4672–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  174. Eremina V, et al. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Investig. 2003;111(5):707–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Vermorken JB, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359(11):1116–27.

    Article  PubMed  CAS  Google Scholar 

  176. Seiwert TY, et al. Phase I study of bevacizumab added to fluorouracil- and hydroxyurea-based concomitant chemoradiotherapy for poor-prognosis head and neck Cancer. J Clin Oncol. 2008;26(10):1732–41.

    Article  PubMed  CAS  Google Scholar 

  177. Fury MG, et al. A phase 2 study of bevacizumab with cisplatin plus intensity-modulated radiation therapy for stage III/IVB head and neck squamous cell cancer. Cancer. 2012;118(20):5008–14.

    Article  PubMed  CAS  Google Scholar 

  178. Hainsworth JD, et al. Combined modality treatment with chemotherapy, radiation therapy, bevacizumab, and Erlotinib in patients with locally advanced squamous carcinoma of the head and neck: a phase II trial of the Sarah Cannon oncology research consortium. Cancer J. 2011;17(5):267–72.

    Article  PubMed  CAS  Google Scholar 

  179. Vermorken JB, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol. 2007;25(16):2171–7.

    Article  CAS  PubMed  Google Scholar 

  180. Bonner JA, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567–78.

    Article  CAS  PubMed  Google Scholar 

  181. Bonner JA, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2010;11(1):21–8.

    Article  CAS  PubMed  Google Scholar 

  182. Dey N, De P, Brian L-J. Evading anti-angiogenic therapy: resistance to anti-angiogenic therapy in solid tumors. Am J Transl Res. 2015;7(10):1675–98.

    PubMed  PubMed Central  CAS  Google Scholar 

  183. Elser C, et al. Phase II trial of sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma. J Clin Oncol. 2007;25(24):3766–73.

    Article  CAS  PubMed  Google Scholar 

  184. Williamson SK, et al. Phase II evaluation of sorafenib in advanced and metastatic squamous cell carcinoma of the head and neck: southwest oncology group study S0420. J Clin Oncol. 2010;28(20):3330–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  185. Machiels J-PH, et al. Phase II study of sunitinib in recurrent or metastatic squamous cell carcinoma of the head and neck: GORTEC 2006-01. J Clin Oncol. 2010;28(1):21–8.

    Article  PubMed  CAS  Google Scholar 

  186. Choong NW, et al. Phase II study of sunitinib malate in head and neck squamous cell carcinoma. Investig New Drugs. 2010;28(5):677–83.

    Article  CAS  Google Scholar 

  187. Fountzilas G, et al. A phase II study of sunitinib in patients with recurrent and/or metastatic non-nasopharyngeal head and neck cancer. Cancer Chemother Pharmacol. 2010;65(4):649–60.

    Article  PubMed  CAS  Google Scholar 

  188. Argiris A. Safety analysis of a phase III randomized trial of chemotherapy with or without bevacizumab (B) in recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). in 2015 ASCO Annual Meeting. 2015. Chicago.

    Google Scholar 

  189. Yao M, et al. Phase II study of bevacizumab in combination with docetaxel and radiation in locally advanced squamous cell carcinoma of the head and neck. Head Neck. 2015;37(11):1665–71.

    Article  PubMed  Google Scholar 

  190. Fury MG, et al. Phase II trial of bevacizumab + cetuximab + cisplatin with concurrent intensity-modulated radiation therapy for patients with stage III/IVB head and neck squamous cell carcinoma. Head Neck. 2016;38(S1):E566–70.

    Article  PubMed  Google Scholar 

  191. Swiecicki PL, et al. A phase II study evaluating axitinib in patients with unresectable, recurrent or metastatic head and neck cancer. Investig New Drugs. 2015;33(6):1248–56.

    Article  CAS  Google Scholar 

  192. Gilbert J, et al. A randomized phase II efficacy and correlative studies of cetuximab with or without sorafenib in recurrent and/or metastatic head and neck squamous cell carcinoma. Oral Oncol. 2015;51(4):376–82.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  193. Limaye S, et al. A randomized phase II study of docetaxel with or without vandetanib in recurrent or metastatic squamous cell carcinoma of head and neck (SCCHN). Oral Oncol. 2013;49(8):835–41.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA

    Lindsay Wilde, Jennifer Johnson & Athanassios Argiris

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  1. Lindsay Wilde
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  2. Jennifer Johnson
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  3. Athanassios Argiris
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Correspondence to Athanassios Argiris .

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  1. Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA

    Barbara Burtness

  2. Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA

    Erica A. Golemis

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Wilde, L., Johnson, J., Argiris, A. (2018). Angiogenesis and Anti-angiogenic Therapy in Head and Neck Cancer. In: Burtness, B., Golemis, E. (eds) Molecular Determinants of Head and Neck Cancer. Current Cancer Research. Humana Press, Cham. https://doi.org/10.1007/978-3-319-78762-6_16

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