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Therapeutic Implications of Angiogenesis in Cancer

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Biochemical Basis and Therapeutic Implications of Angiogenesis

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 6))

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Abstract

Angiogenesis is one of the hallmarks of cancer. Many primed cells endowed with all cancer characteristics arise in our body but they cannot progress to become cancer-disease without activating angiogenesis. This chapter addresses the factors involved in tumor angiogenesis and the progress made to exploit this phenomenon. Tumors are very heterogeneous in their angiogenic pathways and drugs targeting angiogenesis are moderately effective in the metastatic setting with variable efficacy in different tumor types and within the same type. Antiangiogenic agents do not have any role in the adjuvant setting. The biggest challenge facing this discipline is the identification of biomarkers to select patients who are more likely to respond to these expensive treatments and those likely to suffer severe toxicity. Hence, the complexity of the task and the need to embed the study of these markers in the design of phase III randomized controlled trials.

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References

  1. Mittal D, Gubin MM, Schreiber RD, Smyth MJ (2014) New insights into cancer immunoediting and its three component phases—elimination, equilibrium and escape. Curr Opin Immunol 27:16–25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331(6024):1565–1570

    Article  CAS  PubMed  Google Scholar 

  3. Croxford JL, Tang ML, Pan MF et al (2013) ATM-dependent spontaneous regression of early emu-myc-induced murine B-cell leukemia depends on natural killer and T cells. Blood 121(13):2512–2521. doi:10.1182/blood-2012-08-449025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Senovilla L, Vitale I, Martins I et al (2012) An immunosurveillance mechanism controls cancer cell ploidy. Science 337(6102):1678–1684. doi:10.1126/science.1224922

  5. Wu X, Peng M, Huang B et al (2013) Immune microenvironment profiles of tumor immune equilibrium and immune escape states of mouse sarcoma. Cancer Lett 340(1):124–133

    Article  CAS  PubMed  Google Scholar 

  6. Salgado R, Denkert C, Demaria S et al (2015) The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an international TILs working group 2014. Ann Oncol 26(2):259–271. doi:10.1093/annonc/mdu450

    Article  CAS  PubMed  Google Scholar 

  7. Dieci MV, Griguolo G, Miglietta F, Guarneri V (2016) The immune system and hormone-receptor positive breast cancer: is it really a dead end? Cancer Treat Rev 46:9–19

    Article  CAS  PubMed  Google Scholar 

  8. Baumgarten SC, Frasor J (2012) Minireview: inflammation: an instigator of more aggressive estrogen receptor (ER) positive breast cancers. Mol Endocrinol 26(3):360–371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Jinushi M, Komohara Y (2015) Tumor-associated macrophages as an emerging target against tumors: creating a new path from bench to bedside. Biochimi Biophys Acta 1855(2):123–130

    CAS  Google Scholar 

  10. Montecino-Rodriguez E, Berent-Maoz B, Dorshkind K (2013) Causes, consequences, and reversal of immune system aging. J Clin Invest 123(3):958–965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bonafe M, Storci G, Franceschi C (2012) Inflamm-aging of the stem cell niche: breast cancer as a paradigmatic example. BioEssays 34(1):40–49

    Article  CAS  PubMed  Google Scholar 

  12. Irahara N, Miyoshi Y, Taguchi T, Tamaki Y, Noguchi S (2006) Quantitative analysis of aromatase mRNA expression derived from various promoters (I. 4, I. 3, PII and I. 7) and its association with expression of TNF-α, IL-6 and COX-2 mRNAs in human breast cancer. Int J Cancer 118(8):1915–1921

    Article  CAS  PubMed  Google Scholar 

  13. Prieto GA, Rosenstein Y (2006) Oestradiol potentiates the suppressive function of human CD4 CD25 regulatory T cells by promoting their proliferation. Immunology 118(1):58–65

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Polanczyk MJ, Hopke C, Vandenbark AA, Offner H (2006) Estrogen-mediated immunomodulation involves reduced activation of effector T cells, potentiation of treg cells, and enhanced expression of the PD-1 costimulatory pathway. J Neurosci Res 84(2):370–378

    Article  CAS  PubMed  Google Scholar 

  15. Nadkarni S, McArthur S (2013) Oestrogen and immunomodulation: new mechanisms that impact on peripheral and central immunity. Curr Opin Pharmacol 13(4):576–581

    Article  CAS  PubMed  Google Scholar 

  16. Rossini A, Rumio C, Sfondrini L et al (2006) Influence of antibiotic treatment on breast carcinoma development in proto-neu transgenic mice. Cancer Res 66(12):6219–6224. doi:10.1158/0008-5472.CAN-05-4592

  17. Kassayova M, Bobrov N, Strojny L et al (2014) Preventive effects of probiotic bacteria lactobacillus plantarum and dietary fiber in chemicallyinduced mammary carcinogenesis. Anticancer Res 34(9):4969–4975.

    Google Scholar 

  18. Velicer CM, Heckbert SR, Lampe JW, Potter JD, Robertson CA, Taplin SH (2004) Antibiotic use in relation to the risk of breast cancer. JAMA 291(7):827–835

    Article  CAS  PubMed  Google Scholar 

  19. Rutkowski MR, Stephen TL, Svoronos N et al (2015) Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation. Cancer Cell 27(1):27–40

    Article  CAS  PubMed  Google Scholar 

  20. Papetti M, Herman IM (2002) Mechanisms of normal and tumor-derived angiogenesis. Am J Physiol Cell Physiol 282(5):C947–C970. doi:10.1152/ajpcell.00389.2001

    Article  CAS  PubMed  Google Scholar 

  21. Sato Y, Rifkin DB (1989) Inhibition of endothelial cell movement by pericytes and smooth muscle cells: activation of a latent transforming growth factor-beta 1-like molecule by plasmin during co-culture. J Cell Biol 109(1):309–315

    Article  CAS  PubMed  Google Scholar 

  22. Robinson CJ, Stringer SE (2001) The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J Cell Sci 114(Pt 5):853–865

    CAS  PubMed  Google Scholar 

  23. Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M (1998) Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92(6):735–745

    Article  CAS  PubMed  Google Scholar 

  24. Kaipainen A, Korhonen J, Mustonen T et al (1995) Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci U S a 92(8):3566–3570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pepper MS (1997) Transforming growth factor-beta: Vasculogenesis, angiogenesis, and vessel wall integrity. Cytokine Growth Factor Rev 8(1):21–43

    Article  CAS  PubMed  Google Scholar 

  26. Unemori EN, Ferrara N, Bauer EA, Amento EP (1992) Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells. J Cell Physiol 153(3):557–562

    Article  CAS  PubMed  Google Scholar 

  27. Kimura H, Weisz A, Ogura T et al (2001) Identification of hypoxia-inducible factor 1 ancillary sequence and its function in vascular endothelial growth factor gene induction by hypoxia and nitric oxide. J Biol Chem 276(3):2292–2298. doi:10.1074/jbc.M008398200

    Article  CAS  PubMed  Google Scholar 

  28. Dvorak HF, Brown LF, Detmar M, Dvorak AM (1995) Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146(5):1029–1039

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473(7347):298–307. doi:10.1038/nature10144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Puri MC, Rossant J, Alitalo K, Bernstein A, Partanen J (1995) The receptor tyrosine kinase TIE is required for integrity and survival of vascular endothelial cells. EMBO J 14(23):5884–5891

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Thurston G, Suri C, Smith K et al (1999) Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 286(5449):2511–2514. doi:10.1126/science.286.5449.2511

  32. Huang H, Bhat A, Woodnutt G, Lappe R (2010) Targeting the ANGPT-TIE2 pathway in malignancy. Nat Rev Cancer 10(8):575–585. doi:10.1038/nrc2894

    Article  CAS  PubMed  Google Scholar 

  33. Tait CR, Jones PF (2004) Angiopoietins in tumours: the angiogenic switch. J Pathol 204(1):1–10

    Article  CAS  PubMed  Google Scholar 

  34. Ornitz DM, Itoh N (2015) The fibroblast growth factor signaling pathway. Wiley Interdiscip Rev Dev Biol 4(3):215–266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cao Y, Cao R, Hedlund E (2008) R regulation of tumor angiogenesis and metastasis by FGF and PDGF signaling pathways. J Mol Med 86(7):785–789

    Article  CAS  PubMed  Google Scholar 

  36. Turner N, Pearson A, Sharpe R et al (2010) FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res 70(5):2085–2094. doi:10.1158/0008-5472.CAN-09-3746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Heldin CH, Westermark B (1999) Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 79(4):1283–1316

    CAS  PubMed  Google Scholar 

  38. Turner N, Grose R (2010) Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 10(2):116–129

    Article  CAS  PubMed  Google Scholar 

  39. Weis SM, Cheresh DA (2011) alphaV integrins in angiogenesis and cancer. Cold Spring Harb Perspect med 1(1):a006478. doi:10.1101/cshperspect.a006478

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Giannotta M, Trani M, Dejana E (2013) VE-cadherin and endothelial adherens junctions: active guardians of vascular integrity. Dev Cell 26(5):441–454

    Article  CAS  PubMed  Google Scholar 

  41. Pasquale EB (2010) Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nat Rev Cancer 10(3):165–180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Risau W (1997) Mechanisms of angiogenesis. Nature 386(6626):671

    Article  CAS  PubMed  Google Scholar 

  43. Ribatti D (2009) Endogenous inhibitors of angiogenesis: a historical review. Leuk Res 33(5):638–644

    Article  CAS  PubMed  Google Scholar 

  44. Gimbrone MA Jr, Leapman SB, Cotran RS, Folkman J (1972) Tumor dormancy in vivo by prevention of neovascularization. J Exp Med 136(2):261–276

    Article  PubMed  PubMed Central  Google Scholar 

  45. Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86(3):353–364

    Article  CAS  PubMed  Google Scholar 

  46. Folkman J, Watson K, Ingber D, Hanahan D (1989) Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339(6219):58–61. doi:10.1038/339058a0

    Article  CAS  PubMed  Google Scholar 

  47. Weidner N, Semple JP, Welch WR, Folkman J (1991) Tumor angiogenesis and metastasis—correlation in invasive breast carcinoma. N Engl J Med 324(1):1–8

    Article  CAS  PubMed  Google Scholar 

  48. Folkman J (1995) Clinical applications of research on angiogenesis. N Engl J Med 333(26):1757–1763

    Article  CAS  PubMed  Google Scholar 

  49. THOMLINSON RH, GRAY LH (1955) The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 9(4):539–549

    Google Scholar 

  50. Gao D, Nolan DJ, Mellick AS, Bambino K, McDonnell K, Mittal V (2008) Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science 319(5860):195–198. doi:10.1126/science.1150224

    Article  CAS  PubMed  Google Scholar 

  51. Lyden D, Hattori K, Dias S et al (2001) Impaired recruitment of bone-marrow–derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 7(11):1194–1201

    Article  CAS  PubMed  Google Scholar 

  52. Monestiroli S, Mancuso P, Burlini A et al (2001) Kinetics and viability of circulating endothelial cells as surrogate angiogenesis marker in an animal model of human lymphoma. Cancer Res 61(11):4341–4344

    CAS  PubMed  Google Scholar 

  53. Holash J, Maisonpierre PC, Compton D et al (1999) Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284(5422):1994–1998. doi:10.1126/science.284.5422.1994

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

    Article  PubMed  PubMed Central  Google Scholar 

  55. Hamada J, Cavanaugh PG, Miki K, Nicolson GL (1993) A paracrine migration-stimulating factor for metastatic tumor cells secreted by mouse hepatic sinusoidal endothelial cells: identification as complement component C3b. Cancer Res 53(18):4418–4423

    CAS  PubMed  Google Scholar 

  56. Nicosia RF, Tchao R, Leighton J (1986) Interactions between newly formed endothelial channels and carcinoma cells in plasma clot culture. Clin Exp Metastasis 4(2):91–104

    Article  CAS  PubMed  Google Scholar 

  57. Holmgren L, O’Reilly MS, Folkman J (1995) Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1(2):149–153

    Article  CAS  PubMed  Google Scholar 

  58. Ellis L, Fidler I (1995) Angiogenesis and breast cancer metastasis. Lancet 346(8972):388–390

    Article  CAS  PubMed  Google Scholar 

  59. Dvorak HF, Nagy JA, Dvorak JT, Dvorak AM (1988) Identification and characterization of the blood vessels of solid tumors that are leaky to circulating macromolecules. Am J Pathol 133(1):95–109

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674

    Article  CAS  PubMed  Google Scholar 

  61. Weilbaecher KN, Guise TA, McCauley LK (2011) Cancer to bone: a fatal attraction. Nat Rev Cancer 11(6):411–425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. O’Reilly MS, Holmgren L, Shing Y et al (1994) Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a lewis lung carcinoma. Cell 79(2):315–328

    Article  PubMed  Google Scholar 

  63. Weledji EP (2014) Cytokines and the metabolic response to surgery. J Clin Cell Immunol 3(1):1–6

    Google Scholar 

  64. Demicheli R, Retsky MW, Hrushesky WJ, Baum M (2007) Tumor dormancy and surgery-driven interruption of dormancy in breast cancer: learning from failures. Nat Clin Pract Oncol 4(12):699–710

    Article  PubMed  Google Scholar 

  65. Kang Y, Siegel PM, Shu W et al (2003) A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3(6):537–549

    Article  CAS  PubMed  Google Scholar 

  66. Minn AJ, Kang Y, Serganova I et al (2005) Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors. J Clin Invest 115(1):44–55. doi:10.1172/JCI22320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Bendre MS, Gaddy-Kurten D, Mon-Foote T et al (2002) Expression of interleukin 8 and not parathyroid hormone-related protein by human breast cancer cells correlates with bone metastasis in vivo. Cancer Res 62(19):5571–5579

    CAS  PubMed  Google Scholar 

  68. Kaplan RN, Psaila B, Lyden D (2007) Niche-to-niche migration of bone-marrow-derived cells. Trends Mol Med 13(2):72–81

    Article  CAS  PubMed  Google Scholar 

  69. Furusato B, Mohamed A, Uhlén M, Rhim JS (2010) CXCR4 and cancer. Pathol Int 60(7):497–505

    Article  CAS  PubMed  Google Scholar 

  70. Chantrain CF, Henriet P, Jodele S et al (2006) Mechanisms of pericyte recruitment in tumour angiogenesis: a new role for metalloproteinases. Eur J Cancer 42(3):310–318

    Article  CAS  PubMed  Google Scholar 

  71. Eberhard A, Kahlert S, Goede V, Hemmerlein B, Plate KH, Augustin HG (2000) Heterogeneity of angiogenesis and blood vessel maturation in human tumors: implications for antiangiogenic tumor therapies. Cancer Res 60(5):1388–1393

    CAS  PubMed  Google Scholar 

  72. Mesri M, Birse C, Heidbrink J et al (2013) Identification and characterization of angiogenesis targets through proteomic profiling of endothelial cells in human cancer tissues. PLoS One 8(11):e78885

    Article  PubMed  PubMed Central  Google Scholar 

  73. Fukumura D, Jain RK (2008) Imaging angiogenesis and the microenvironment. APMIS 116(7–8):695–715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kerbel RS (2000) Tumor angiogenesis: past, present and the near future. Carcinogenesis 21(3):505–515

    Article  CAS  PubMed  Google Scholar 

  75. Angara K, Rashid MH, Shankar A, et al (2016) Vascular mimicry in glioblastoma following anti-angiogenic and anti-20-HETE therapies. Histol Histopathol:11856. doi:10.14670/HH-11-856

  76. Jain RK (2002) Tumor angiogenesis and accessibility: role of vascular endothelial growth factor. Semin Oncol 29(6):3–9

    Article  CAS  PubMed  Google Scholar 

  77. Welter M, Bartha K, Rieger H (2009) Vascular remodelling of an arterio-venous blood vessel network during solid tumour growth. J Theor Biol 259(3):405–422

    Article  CAS  PubMed  Google Scholar 

  78. Tailor TD, Hanna G, Yarmolenko PS et al (2010) Effect of pazopanib on tumor microenvironment and liposome delivery. Mol Cancer Ther 9(6):1798–1808. doi:10.1158/1535-7163.MCT-09-0856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Magagnin MG, Koritzinsky M, Wouters BG (2006) Patterns of tumor oxygenation and their influence on the cellular hypoxic response and hypoxia-directed therapies. Drug Resist Updat 9(4):185–197

    Article  CAS  PubMed  Google Scholar 

  80. Makhoul I, Griffin RJ, Siegel E et al (2016) High-circulating Tie2 is associated with pathologic complete response to chemotherapy and antiangiogenic therapy in breast cancer. Am J Clin Oncol 39(3):248–254. doi:10.1097/COC.0000000000000046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Makhoul I, Todorova VK, Siegel ER et al (2017) Germline genetic variants in TEK, ANGPT1, ANGPT2, MMP9, FGF2 and VEGFA are associated with pathologic complete response to bevacizumab in breast cancer patients. PLoS One 12(1):e0168550

    Article  PubMed  PubMed Central  Google Scholar 

  82. Mirando AC, Abdi K, Wo P, Lounsbury KM (2016) Assessing the effects of threonyl-tRNA synthetase on angiogenesis-related responses. Methods. 113(2017):132–138.

    Google Scholar 

  83. Weiss A, Ding X, Beijnum JR et al (2015) Rapid optimization of drug combinations for the optimal angiostatic treatment of cancer. Angiogenesis 18(3):233–244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Barendsz-Janson AF, Griffioen AW, Muller AD, van Dam-Mieras MC, Hillen HF (1998) In vitro tumor angiogenesis assays: plasminogen lysine binding site 1 inhibits in vitro tumor-induced angiogenesis. J Vasc Res 35(2):109–114

    Article  CAS  PubMed  Google Scholar 

  85. Abdollahi A, Lipson KE, Sckell A et al (2003) Combined therapy with direct and indirect angiogenesis inhibition results in enhanced antiangiogenic and antitumor effects. Cancer Res 63(24):8890–8898

    CAS  PubMed  Google Scholar 

  86. Wessels J, Busse A, Mahrt J, Dullin C, Grabbe E, Mueller G (2007) In vivo imaging in experimental preclinical tumor research–a review. Cytometry A 71(8):542–549

    Article  CAS  PubMed  Google Scholar 

  87. Sonveaux P, Copetti T, De Saedeleer CJ et al (2012) Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis. PLoS One 7(3):e33418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Kleibeuker EA, Schulkens IA, Castricum KC, Griffioen AW, Thijssen VL (2015) Examination of the role of galectins during in vivo angiogenesis using the chick chorioallantoic membrane assay. Methods Mol Biol 1207:305–315

    Article  CAS  PubMed  Google Scholar 

  89. Mikirova NA, Casciari JJ, Riordan NH (2010) Ascorbate inhibition of angiogenesis in aortic rings ex vivo and subcutaneous matrigel plugs in vivo. J Angiogenes Res 2(1):2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Park K, Kim Y, Lee GY et al (2008) Tumor endothelial cell targeted cyclic RGD-modified heparin derivative: inhibition of angiogenesis and tumor growth. Pharm Res 25(12):2786

    Article  CAS  PubMed  Google Scholar 

  91. Jain RK, Duda DG, Willett CG et al (2009) Biomarkers of response and resistance to antiangiogenic therapy. Nat Rev Clin Oncol 6(6):327–338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Cidon EU, Alonso P, Masters B (2016) Markers of response to antiangiogenic therapies in colorectal cancer: where are we now and what should be next? Clinical Medicine InsightsOncology 10(Suppl 1):41

    Google Scholar 

  93. Witte MH, Dellinger MT, McDonald DM et al (2011) Lymphangiogenesis and hemangiogenesis: potential targets for therapy. J Surg Oncol 103(6):489–500

    Article  PubMed  PubMed Central  Google Scholar 

  94. Baluk P, McDonald DM (2008) Markers for microscopic imaging of lymphangiogenesis and angiogenesis. Ann N Y Acad Sci 1131(1):1–12

    Article  PubMed  Google Scholar 

  95. Wahal SP, Goel MM, Mehrotra R (2015) Lymphatic vessel assessment by podoplanin (D2-40) immunohistochemistry in breast cancer. J Cancer Res Ther 11(4):798–804. doi:10.4103/0973-1482.146123

    Article  CAS  PubMed  Google Scholar 

  96. Le CT, Laidlaw G, Morehouse CA et al (2015) Synergistic actions of blocking angiopoietin-2 and tumor necrosis factor-α in suppressing remodeling of blood vessels and lymphatics in airway inflammation. Am J Pathol 185(11):2949–2968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Gore J, Imasuen-Williams IE, Conteh AM, Craven KE, Cheng M, Korc M (2016) Combined targeting of TGF-β, EGFR and HER2 suppresses lymphangiogenesis and metastasis in a pancreatic cancer model. Cancer Lett 379(1):143–153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Liu C, Li M, Hu Y et al (2016) miR-486-5p attenuates tumor growth and lymphangiogenesis by targeting neuropilin-2 in colorectal carcinoma. Onco Targets Ther 9:2865

    PubMed  PubMed Central  Google Scholar 

  99. Galanzha EI, Kokoska MS, Shashkov EV, Kim J, Tuchin VV, Zharov VP (2009) In vivo fiber-based multicolor photoacoustic detection and photothermal purging of metastasis in sentinel lymph nodes targeted by nanoparticles. J Biophotonics 2(8–9):528–539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Zhao Y, Adjei AA (2015) Targeting angiogenesis in cancer therapy: moving beyond vascular endothelial growth factor. Oncologist 20(6):660–673. doi:10.1634/theoncologist.2014-0465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. PDR Prescriber’s Digital Reference. Drug information. http://www.pdr.net/browse-by-drug-name. Updated 2017. Accessed Feb 2017

  102. Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307(5706):58–62. doi:307/5706/58 [pii]

    Article  CAS  PubMed  Google Scholar 

  103. Willett CG, Boucher Y, Di Tomaso E et al (2004) Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10(2):145–147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Makhoul I, Kiwan E (2011) Neoadjuvant systemic treatment of breast cancer. J Surg Oncol 103(4):348–357. doi:10.1002/jso.21696

    Article  PubMed  Google Scholar 

  105. Ferrara N, Adamis AP (2016) Ten years of anti-vascular endothelial growth factor therapy. Nat Rev Drug Discov 15(6):385–403

    Article  CAS  PubMed  Google Scholar 

  106. Bennouna J, Sastre J, Arnold D et al (2013) Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol 14(1):29–37

    Article  CAS  PubMed  Google Scholar 

  107. Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8(8):592–603. doi:10.1038/nrc2442; 10.1038/nrc2442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Cao Y, Langer R (2010) Optimizing the delivery of cancer drugs that block angiogenesis. Sci Transl med 2(15):15ps3. doi:10.1126/scitranslmed.3000399

    Article  PubMed  CAS  Google Scholar 

  109. Hlushchuk R, Makanya AN, Djonov V (2011) Escape mechanisms after antiangiogenic treatment, or why are the tumors growing again? Int J Dev Biol 55(4–5):563–567. doi:10.1387/ijdb.103231rh

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  111. Sennino B, McDonald DM (2012) Controlling escape from angiogenesis inhibitors. Nat Rev Cancer 12(10):699–709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Xu L, Duda DG, di Tomaso E et al (2009) Direct evidence that bevacizumab, an anti-VEGF antibody, up-regulates SDF1alpha, CXCR4, CXCL6, and neuropilin 1 in tumors from patients with rectal cancer. Cancer Res 69(20):7905–7910. doi:10.1158/0008-5472.CAN-09-2099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Shojaei F, Wu X, Malik AK et al (2007) Tumor refractoriness to anti-VEGF treatment is mediated by CD11b Gr1 myeloid cells. Nat Biotechnol 25(8):911–920

    Article  CAS  PubMed  Google Scholar 

  114. Ferrara N (2010) Pathways mediating VEGF-independent tumor angiogenesis. Cytokine Growth Factor Rev 21(1):21–26

    Article  CAS  PubMed  Google Scholar 

  115. Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D (2003) Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 111(9):1287–1295. doi:10.1172/JCI17929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Kamba T, McDonald D (2007) Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer 96(12):1788–1795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Yang Y, Zhang Y, Iwamoto H et al (2016) Discontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism. Nat Commun 7:12680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Miles D, Harbeck N, Escudier B et al (2010) Disease course patterns after discontinuation of bevacizumab: pooled analysis of randomized phase III trials. J Clin Oncol 29(1):83–88

    Article  PubMed  CAS  Google Scholar 

  119. Saltz LB, Cox JV, Blanke C et al (2000) Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan study group. N Engl J Med 343(13):905–914. doi:10.1056/NEJM200009283431302

    Article  CAS  PubMed  Google Scholar 

  120. Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350(23):2335–2342. doi:10.1056/NEJMoa032691

    Article  CAS  PubMed  Google Scholar 

  121. Hurwitz HI, Tebbutt NC, Kabbinavar F et al (2013) Efficacy and safety of bevacizumab in metastatic colorectal cancer: pooled analysis from seven randomized controlled trials. Oncologist 18(9):1004–1012. doi:10.1634/theoncologist.2013-0107

    Article  PubMed  PubMed Central  Google Scholar 

  122. Allegra CJ, Yothers G, O’Connell MJ et al (2012) Bevacizumab in stage II-III colon cancer: 5-year update of the national surgical adjuvant breast and bowel project C-08 trial. J Clin Oncol 31(3):359–364

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Syed YY, McKeage K (2015) Aflibercept: a review in metastatic colorectal cancer. Drugs 75(12):1435–1445

    Article  CAS  PubMed  Google Scholar 

  124. Tabernero J, Yoshino T, Cohn AL et al (2015) Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 16(5):499–508

    Article  CAS  PubMed  Google Scholar 

  125. Grothey A, Van Cutsem E, Sobrero A et al (2013) Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381(9863):303–312

    Article  CAS  PubMed  Google Scholar 

  126. Jiang H, Yang T, Lu P, Ma Y (2014) Gene expression profiling of gastric cancer. Eur Rev Med Pharmacol Sci 18(15):2109–2115

    PubMed  Google Scholar 

  127. Marimuthu A, Jacob HK, Jakharia A et al (2011) Gene expression profiling of gastric cancer. J Proteomics Bioinform 4(4):74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Yao JC, Wang L, Wei D et al (2004) Association between expression of transcription factor Sp1 and increased vascular endothelial growth factor expression, advanced stage, and poor survival in patients with resected gastric cancer. Clin Cancer Res 10(12 Pt 1):4109–4117. doi:10.1158/1078-0432.CCR-03-0628

    Article  CAS  PubMed  Google Scholar 

  129. Fondevila C, Metges J, Fuster J et al (2004) p53 and VEGF expression are independent predictors of tumour recurrence and survival following curative resection of gastric cancer. Br J Cancer 90(1):206–215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Fuchs CS, Tomasek J, Yong CJ et al (2014) Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 383(9911):31–39

    Article  CAS  PubMed  Google Scholar 

  131. Wilke H, Muro K, Van Cutsem E et al (2014) Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 15(11):1224–1235

    Article  CAS  PubMed  Google Scholar 

  132. Ohtsu A, Shah MA, Van Cutsem E et al (2011) Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol 29(30):3968–3976

    Article  CAS  PubMed  Google Scholar 

  133. Llovet JM, Ricci S, Mazzaferro V et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359(4):378–390

    Article  CAS  PubMed  Google Scholar 

  134. Bruix J, Qin S, Merle P et al (2017) Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 389(10064):56–66

    Article  CAS  PubMed  Google Scholar 

  135. Frenette CT (2012) Current status of bevacizumab for advanced hepatocellular carcinoma. Chin Clin Oncol 1(1):13

    PubMed  Google Scholar 

  136. Cheng A, Kang Y, Lin D et al (2013) Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol 31(32):4067–4075

    Article  CAS  PubMed  Google Scholar 

  137. Zhu AX, Baron AD, Malfertheiner P et al (2016) Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma: analysis of REACH trial results by child-pugh score. JAMA Oncol. doi:10.1001/jamaoncol.2016.4115

  138. Llovet JM, Decaens T, Raoul J et al (2013) Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study. J Clin Oncol 31(28):3509–3516

    Article  CAS  PubMed  Google Scholar 

  139. Kan Z, Zheng H, Liu X et al (2013) Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma. Genome Res 23(9):1422–1433. doi:10.1101/gr.154492.113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Fujimoto A, Furuta M, Totoki Y et al (2016) Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer. Nat Genet 48(5):500–509

    Article  CAS  PubMed  Google Scholar 

  141. Rak JW, St Croix BD, Kerbel RS (1995) Consequences of angiogenesis for tumor progression, metastasis and cancer therapy. Anti-Cancer Drugs 6(1):3–18

    Article  CAS  PubMed  Google Scholar 

  142. O’Byrne KJ, Koukourakis MI, Giatromanolaki A et al (2000) Vascular endothelial growth factor, platelet-derived endothelial cell growth factor and angiogenesis in non-small-cell lung cancer. Br J Cancer 82(8):1427–1432. doi:10.1054/bjoc.1999.1129

  143. Fontanini G, Vignati S, Boldrini L et al (1997) Vascular endothelial growth factor is associated with neovascularization and influences progression of non-small cell lung carcinoma. Clin Cancer Res 3(6):861–865

    CAS  PubMed  Google Scholar 

  144. Yuan A, Yu C, Kuo S et al (2001) 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 19(2):432–441

    Article  CAS  PubMed  Google Scholar 

  145. Sandler A, Gray R, Perry MC et al (2006) Paclitaxel–carboplatin alone or with bevacizumab for non–small-cell lung cancer. N Engl J Med 355(24):2542–2550

    Article  CAS  PubMed  Google Scholar 

  146. Reck M, von Pawel J, Zatloukal P et al (2010) Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol 21(9):1804–1809. doi:10.1093/annonc/mdq020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Soria JC, Mauguen A, Reck M et al (2013) Systematic review and meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol 24(1):20–30. doi:10.1093/annonc/mds590

    Article  PubMed  Google Scholar 

  148. Herbst RS, Ansari R, Bustin F et al (2011) Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial. Lancet 377(9780):1846–1854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Wakelee H, Dahlberg S, Keller S, et al (2015) Randomized phase III trial of adjuvant chemotherapy with or without bevacizumab in resected non small cell lung cancer: Results of E1505. 16th world conference on lung cancer. PLEN04.03

    Google Scholar 

  150. Garon EB, Ciuleanu T, Arrieta O et al (2014) Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 384(9944):665–673

    Article  CAS  PubMed  Google Scholar 

  151. Li Y, Zhao H, Ren X (2016) Relationship of VEGF/VEGFR with immune and cancer cells: staggering or forward? Cancer Biol Med 13(2):206

    Article  PubMed  PubMed Central  Google Scholar 

  152. der Veldt V, Astrid AM (2012) Lubberink M, Bahce I, et al. rapid decrease in delivery of chemotherapy to tumors after anti-VEGF therapy: implications for scheduling of anti-angiogenic drugs. Cancer Cell 21(1):82–91

    Article  PubMed  CAS  Google Scholar 

  153. Miles D, Cameron D, Bondarenko I et al (2017) Bevacizumab plus paclitaxel versus placebo plus paclitaxel as first-line therapy for HER2-negative metastatic breast cancer (MERiDiAN): a double-blind placebo-controlled randomised phase III trial with prospective biomarker evaluation. Eur J Cancer 70:146–155

    Article  CAS  PubMed  Google Scholar 

  154. Anan K, Morisaki T, Katano M et al (1996) Vascular endothelial growth factor and platelet-derived growth factor are potential angiogenic and metastatic factors in human breast cancer. Surgery 119(3):333–339

    Article  CAS  PubMed  Google Scholar 

  155. Rugo HS (2004) Bevacizumab in the treatment of breast cancer: rationale and current data. Oncologist 9(Suppl 1):43–49

    Article  CAS  PubMed  Google Scholar 

  156. Brown LF, Berse B, Jackman RW et al (1995) Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer. Hum Pathol 26(1):86–91

    Article  CAS  PubMed  Google Scholar 

  157. Relf M, LeJeune S, Scott PA et al (1997) Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res 57(5):963–969

    CAS  PubMed  Google Scholar 

  158. Li CY, Shan S, Huang Q et al (2000) Initial stages of tumor cell-induced angiogenesis: evaluation via skin window chambers in rodent models. J Natl Cancer Inst 92(2):143–147

    Article  CAS  PubMed  Google Scholar 

  159. Schneider BP, Radovich M, Miller KD (2009) The role of vascular endothelial growth factor genetic variability in cancer. Clin Cancer Res 15(17):5297–5302. doi:10.1158/1078-0432.CCR-08-2576

    Article  CAS  PubMed  Google Scholar 

  160. Warren RS, Yuan H, Matli MR, Gillett NA, Ferrara N (1995) Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis. J Clin Invest 95(4):1789–1797. doi:10.1172/JCI117857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Miller K, Wang M, Gralow J et al (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357(26):2666–2676. doi:10.1056/NEJMoa072113

    Article  CAS  PubMed  Google Scholar 

  162. Bell R, Brown J, Parmar M et al (2016) Final efficacy and updated safety results of the randomized phase III BEATRICE trial evaluating adjuvant bevacizumab-containing therapy in triple-negative early breast cancer. Ann Oncol 8(4):754–760. doi:10.1093/annonc/mdw665

    Google Scholar 

  163. Kumler I, Christiansen OG, Nielsen DL (2014) A systematic review of bevacizumab efficacy in breast cancer. Cancer Treat Rev 40(8):960–973. doi:10.1016/j.ctrv.2014.05.006

    Article  CAS  PubMed  Google Scholar 

  164. Ziello JE, Jovin IS, Huang Y (2007) Hypoxia-inducible factor (HIF)-1 regulatory pathway and its potential for therapeutic intervention in malignancy and ischemia. Yale J Biol Med 80(2):51–60

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Ferrara N, HOUCK K, Jakeman L, LEUNG DW (1992) Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocr Rev 13(1):18–32

    Google Scholar 

  166. Friedlander M, Brooks PC, Shaffer RW, Kincaid CM (1995) Definition of two angiogenic pathways by distinct alphav integrins. Science 270(5241):1500

    Article  CAS  PubMed  Google Scholar 

  167. Toge H, Inagaki T, Kojimoto Y, Shinka T, Hara I (2009) Angiogenesis in renal cell carcinoma: the role of tumor-associated macrophages. Int J Urol 16(10):801–807

    Article  CAS  PubMed  Google Scholar 

  168. del Puerto-Nevado L, Rojo F, Zazo S et al (2014) Active angiogenesis in metastatic renal cell carcinoma predicts clinical benefit to sunitinib-based therapy. Br J Cancer 110(11):2700–2707

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  169. Motzer RJ, Hutson TE, Tomczak P et al (2009) Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 27(22):3584–3590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Motzer RJ, Hutson TE, Cella D et al (2013) Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 369(8):722–731

    Article  CAS  PubMed  Google Scholar 

  171. Motzer RJ, Hutson TE, McCann L, Deen K, Choueiri TK (2014) Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. N Engl J Med 370(18):1769–1770

    Article  CAS  PubMed  Google Scholar 

  172. Choueiri TK, Halabi S, Sanford BL et al (2016) Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the alliance A031203 CABOSUN trial. J Clin Oncol 35(6):591–597. doi:10.1200/JCO.2016.70.7398

    Article  PubMed  Google Scholar 

  173. Rini BI, Melichar B, Ueda T et al (2013) Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial. Lancet Oncol 14(12):1233–1242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Bracarda S, Bellmunt J, Melichar B et al (2011) Overall survival in patients with metastatic renal cell carcinoma initially treated with bevacizumab plus interferon-α2a and subsequent therapy with tyrosine kinase inhibitors: a retrospective analysis of the phase III AVOREN trial. BJU Int 107(2):214–219

    Article  CAS  PubMed  Google Scholar 

  175. Tomita Y, Naito S, Sassa N et al (2014) Sunitinib versus sorafenib as first-line therapy for patients with metastatic renal cell carcinoma with favorable or intermediate MSKCC risk factors: a multicenter randomized trial, CROSS-J-RCC. J Clin Oncol 32(suppl 4):abstract 502

    Article  Google Scholar 

  176. Rini BI, Halabi S, Rosenberg JE et al (2010) Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: Final results of CALGB 90206. J Clin Oncol 28(13):2137–2143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Rini BI, Wilding G, Hudes G et al (2009) Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J Clin Oncol 27(27):4462–4468

    Article  CAS  PubMed  Google Scholar 

  178. Di Lorenzo G, Cartenì G, Autorino R et al (2009) Phase II study of sorafenib in patients with sunitinib-refractory metastatic renal cell cancer. J Clin Oncol 27(27):4469–4474

    Article  PubMed  Google Scholar 

  179. Hudes G, Carducci M, Tomczak P et al (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356(22):2271–2281

    Article  CAS  PubMed  Google Scholar 

  180. Hutson TE, Escudier B, Esteban E et al (2013) Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 32(8):760–767

    Article  PubMed  CAS  Google Scholar 

  181. Motzer RJ, Hutson TE, Glen H et al (2015) Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol 16(15):1473–1482

    Article  CAS  PubMed  Google Scholar 

  182. Alvarez AA, Krigman HR, Whitaker RS, Dodge RK, Rodriguez GC (1999) The prognostic significance of angiogenesis in epithelial ovarian carcinoma. Clin Cancer Res 5(3):587–591

    CAS  PubMed  Google Scholar 

  183. Yamamoto S, Konishi I, Mandai M et al (1997) Expression of vascular endothelial growth factor (VEGF) in epithelial ovarian neoplasms: correlation with clinicopathology and patient survival, and analysis of serum VEGF levels. Br J Cancer 76(9):1221–1227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Chen H, Ye D, Xie X, Chen B, Lu W (2004) VEGF, VEGFRs expressions and activated STATs in ovarian epithelial carcinoma. Gynecol Oncol 94(3):630–635

    Article  CAS  PubMed  Google Scholar 

  185. Apte SM, Bucana CD, Killion JJ, Gershenson DM, Fidler IJ (2004) Expression of platelet-derived growth factor and activated receptor in clinical specimens of epithelial ovarian cancer and ovarian carcinoma cell lines. Gynecol Oncol 93(1):78–86

    Article  CAS  PubMed  Google Scholar 

  186. Dabrow MB, Francesco MR, McBrearty FX, Caradonna S (1998) The effects of platelet-derived growth factor and receptor on normal and neoplastic human ovarian surface epithelium. Gynecol Oncol 71(1):29–37

    Article  CAS  PubMed  Google Scholar 

  187. Wilczynski SP, Chen Y, Chen W, Howell SB, Shively JE, Alberts DS (2005) Expression and mutational analysis of tyrosine kinase receptors c-kit, PDGFRα, and PDGFRβ in ovarian cancers. Hum Pathol 36(3):242–249

    Article  CAS  PubMed  Google Scholar 

  188. Crickard K, Gross JL, Crickard U et al (1994) Basic fibroblast growth factor and receptor expression in human ovarian cancer. Gynecol Oncol 55(2):277–284

    Article  CAS  PubMed  Google Scholar 

  189. Steele IA, Edmondson RJ, Bulmer JN, Bolger BS, Leung HY, Davies BR (2001) Induction of FGF receptor 2-IIIb expression and response to its ligands in epithelial ovarian cancer. Oncogene 20(41):5878

    Article  CAS  PubMed  Google Scholar 

  190. Whitworth MK, Backen AC, Clamp AR et al (2005) Regulation of fibroblast growth factor-2 activity by human ovarian cancer tumor endothelium. Clin Cancer Res 11(12):4282–4288. doi:DOI: 10.1158/1078-0432.CCR-04-1386

  191. Henriksen R, Funa K, Wilander E, Backstrom T, Ridderheim M, Oberg K (1993) Expression and prognostic significance of platelet-derived growth factor and its receptors in epithelial ovarian neoplasms. Cancer Res 53(19):4550–4554

    CAS  PubMed  Google Scholar 

  192. Matei D, Kelich S, Cao L et al (2007) PDGF BB induces VEGF secretion in ovarian cancer. Cancer Biol Ther 6(12):1951–1959

    Article  CAS  PubMed  Google Scholar 

  193. Burger RA, Brady MF, Bookman MA et al (2011) Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 365(26):2473–2483

    Article  CAS  PubMed  Google Scholar 

  194. Perren TJ, Swart AM, Pfisterer J et al (2011) A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 365(26):2484–2496

    Article  CAS  PubMed  Google Scholar 

  195. Oza AM, Cook AD, Pfisterer J et al (2015) Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. Lancet Oncol 16(8):928–936

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Aghajanian C, Blank SV, Goff BA et al (2012) OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol 30(17):2039–2045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Aghajanian C, Goff B, Nycum LR, Wang YV, Husain A, Blank SV (2015) Final overall survival and safety analysis of OCEANS, a phase 3 trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent ovarian cancer. Gynecol Oncol 139(1):10–16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Pujade-Lauraine E, Hilpert F, Weber B et al (2014) Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. J Clin Oncol 32(13):1302–1308

    Article  CAS  PubMed  Google Scholar 

  199. Du Bois A, Floquet A, Kim J et al (2014) Incorporation of pazopanib in maintenance therapy of ovarian cancer. J Clin Oncol 32(30):3374–3382

    Article  PubMed  Google Scholar 

  200. Matulonis UA, Berlin S, Ivy P et al (2009) Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer. J Clin Oncol 27(33):5601–5606

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Liu JF, Barry WT, Birrer M et al (2014) Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. Lancet Oncol 15(11):1207–1214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Ledermann JA, Embleton AC, Raja F et al (2016) Cediranib in patients with relapsed platinum-sensitive ovarian cancer (ICON6): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 387(10023):1066–1074

    Article  CAS  PubMed  Google Scholar 

  203. Merighi S, Benini A, Mirandola P et al (2007) Hypoxia inhibits paclitaxel-induced apoptosis through adenosine-mediated phosphorylation of bad in glioblastoma cells. Mol Pharmacol 72(1):162–172. doi:10.1124/mol.106.031849

  204. Eyler CE, Rich JN (2008) Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis. J Clin Oncol 26(17):2839–2845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Jensen RL (2006) Hypoxia in the tumorigenesis of gliomas and as a potential target for therapeutic measures. Neurosurg Focus 20(4):E24

    Article  PubMed  Google Scholar 

  206. Chen Z, Htay A, Dos Santos W et al (2009) In vitro angiogenesis by human umbilical vein endothelial cells (HUVEC) induced by three-dimensional co-culture with glioblastoma cells. J Neuro-Oncol 92(2):121–128

    Article  CAS  Google Scholar 

  207. Endersby R, Baker S (2008) PTEN signaling in brain: neuropathology and tumorigenesis. Oncogene 27(41):5416–5430

    Article  CAS  PubMed  Google Scholar 

  208. de Wit MC, de Bruin HG, Eijkenboom W, Sillevis Smitt PA, van den Bent MJ (2004) Immediate post-radiotherapy changes in malignant glioma can mimic tumor progression. Neurology 63(3):535–537. doi:10.1212/01.WNL.0000133398.11870.9A

  209. Rong Y, Durden DL, Van Meir EG, Brat DJ (2006) ‘Pseudopalisading’ necrosis in glioblastoma: a familiar morphologic feature that links vascular pathology, hypoxia, and angiogenesis. J Neuropathol Exp Neurol 65(6):529–539.

    Google Scholar 

  210. Lai A, Tran A, Nghiemphu PL et al (2010) Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme. J Clin Oncol 29(2):142–148

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  211. Vredenburgh JJ, Desjardins A, Reardon DA et al (2011) The addition of bevacizumab to standard radiation therapy and temozolomide followed by bevacizumab, temozolomide, and irinotecan for newly diagnosed glioblastoma. Clin Cancer Res 17(12):4119–4124. doi:10.1158/1078-0432.CCR-11-0120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Omuro A, Beal K, Gutin P et al (2014) Phase II study of bevacizumab, temozolomide, and hypofractionated stereotactic radiotherapy for newly diagnosed glioblastoma. Clin Cancer Res 20(19):5023–5031. doi:10.1158/1078-0432.CCR-14-0822

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Chinot OL, Wick W, Mason W et al (2014) Bevacizumab plus radiotherapy–temozolomide for newly diagnosed glioblastoma. N Engl J Med 370(8):709–722

    Article  CAS  PubMed  Google Scholar 

  214. Gilbert MR, Dignam JJ, Armstrong TS et al (2014) A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370(8):699–708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Nanda R, Chow LQ, Dees EC et al (2016) Pembrolizumab in patients with advanced triple-negative breast cancer: phase ib KEYNOTE-012 study. J Clin Oncol 34(21):2460–2467. doi:10.1200/JCO.2015.64.8931

    Article  CAS  PubMed  Google Scholar 

  216. Zou GM, Maitra A (2008) Small-molecule inhibitor of the AP endonuclease 1/REF-1 E3330 inhibits pancreatic cancer cell growth and migration. Mol Cancer Ther 7(7):2012–2021. doi:10.1158/1535-7163.MCT-08-0113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Kong D, Park EJ, Stephen AG et al (2005) Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Cancer Res 65(19):9047–9055. doi:10.1158/0008-5472.CAN-05-1235

  218. Zagzag D, Nomura M, Friedlander DR et al (2003) Geldanamycin inhibits migration of glioma cells in vitro: a potential role for hypoxia-inducible factor (HIF-1α) in glioma cell invasion. J Cell Physiol 196(2):394–402

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Internal Medicine, Medical Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA

    Issam Makhoul MD, Shebli Atrash, Konstantinos Arnaoutakis, Mazin Safar & Angela Pennisi

  2. Department of Surgery, Gynecologic Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA

    Laura Huffman

  3. Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA

    Robert Griffin

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  1. Divison of Cardiovascular Medicine, University of Arkansas for Medical Sciences, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA

    Jawahar L. Mehta

  2. Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

    Pankaj Mathur

  3. Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada

    Naranjan S. Dhalla

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Makhoul, I. et al. (2017). Therapeutic Implications of Angiogenesis in Cancer. In: Mehta, J., Mathur, P., Dhalla, N. (eds) Biochemical Basis and Therapeutic Implications of Angiogenesis. Advances in Biochemistry in Health and Disease, vol 6. Springer, Cham. https://doi.org/10.1007/978-3-319-61115-0_9

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