The great escape; the hallmarks of resistance to antiangiogenic therapy

Pharmacological Reviews

Volumn 67, Issue 2, 2015, Pages 441-461

  van Beijnum, Judy R ^a   Nowak Sliwinska, Patrycja ^b   Huijbers, Elisabeth J M ^a   Thijssen, Victor L ^a   Griffioen, Arjan W ^a  

^a VU UNIVERSITY MEDICAL CENTER   (Netherlands)

^b EPFL   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

ANGIOGENESIS INHIBITOR; GROWTH FACTOR; VASCULOTROPIN;

ANTIANGIOGENIC THERAPY; BONE MARROW CELL; CANCER CELL; CANCER CHEMOTHERAPY; CANCER RESISTANCE; CELL HETEROGENEITY; ENDOTHELIAL PROGENITOR CELL; ENDOTHELIUM CELL; EXOSOME; EYE DISEASE; FIBROBLAST; GENETIC POLYMORPHISM; GLYCOSYLATION; HUMAN; LYSOSOME; MALIGNANT NEOPLASTIC DISEASE; METASTASIS; MOLECULAR MIMICRY; NONHUMAN; PERICYTE; PHARMACOGENETICS; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; STROMA CELL; TARGET CELL; TUMOR INVASION; ANIMAL; BIOLOGICAL MODEL; DRUG EFFECTS; DRUG RESISTANCE; METABOLISM; NEOPLASM INVASIVENESS; NEOPLASM METASTASIS; NEOPLASMS; NEOVASCULARIZATION, PATHOLOGIC; PATHOLOGY; RETINAL NEOVASCULARIZATION; VASCULAR ENDOTHELIUM; VASCULAR SMOOTH MUSCLE;

ANGIOGENESIS INHIBITORS; ANIMALS; DRUG RESISTANCE, NEOPLASM; ENDOTHELIUM, VASCULAR; HUMANS; MODELS, BIOLOGICAL; MUSCLE, SMOOTH, VASCULAR; NEOPLASM INVASIVENESS; NEOPLASM METASTASIS; NEOPLASMS; NEOVASCULARIZATION, PATHOLOGIC; PERICYTES; RETINAL NEOVASCULARIZATION; STROMAL CELLS;

EID: 84931271695     PISSN: 00316997     EISSN: 15210081     Source Type: Journal    
DOI: 10.1124/pr.114.010215     Document Type: Review

References (242)

1. Abramsson A, Lindblom P, and Betsholtz C (2003) Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors. J Clin Invest 112:1142–1151.
2. Adar Y, Stark M, Bram EE, Nowak-Sliwinska P, van den Bergh H, Szewczyk G, Sarna T, Skladanowski A, Griffioen AW, and Assaraf YG (2012) Imidazoacridinonedependent lysosomal photodestruction: a pharmacological Trojan horse approach to eradicate multidrug-resistant cancers. Cell Death Dis 3:e293.
3. Akino T, Hida K, Hida Y, Tsuchiya K, Freedman D, Muraki C, Ohga N, Matsuda K, Akiyama K, Harabayashi T, et al. (2009) Cytogenetic abnormalities of tumorassociated endothelial cells in human malignant tumors. Am J Pathol 175: 2657–2667.
4. Akiyama K, Ohga N, Hida Y, Kawamoto T, Sadamoto Y, Ishikawa S, Maishi N, Akino T, Kondoh M, Matsuda A, et al. (2012) Tumor endothelial cells acquire drug resistance by MDR1 up-regulation via VEGF signaling in tumor microenvironment. Am J Pathol 180:1283–1293.
5. Anderberg C, Cunha SI, Zhai Z, Cortez E, Pardali E, Johnson JR, Franco M, Páez- Ribes M, Cordiner R, Fuxe J, et al. (2013) Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination. J Exp Med 210:563–579.
6. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, and Isner JM (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967.
7. Ayyadurai VA and Dewey CF (2011) CytoSolve: A Scalable Computational Method for Dynamic Integration of Multiple Molecular Pathway Models. Cell Mol Bioeng 4: 28–45.
8. Azab AK, Sahin I, Azab F, Moschetta M, Mishima Y, Burwick N, Zimmermann J, Romagnoli B, Patel K, Chevalier E, et al. (2014). CXCR7-dependent angiogenic mononuclear cells trafficking regulates tumor progression in multiple myeloma. Blood 124:1905–1914.
9. Bajou K, Herkenne S, Thijssen VL, D’Amico S, Nguyen NQ, Bouché A, Tabruyn S, Srahna M, Carabin JY, Nivelles O, et al. (2014) PAI-1 mediates the antiangiogenic and profibrinolytic effects of 16K prolactin. Nat Med 20:741–747.
10. Bakall B, Folk JC, Boldt HC, Sohn EH, Stone EM, Russell SR, and Mahajan VB (2013) Aflibercept therapy for exudative age-related macular degeneration resistant to bevacizumab and ranibizumab. Am J Ophthalmol 156: 15–22.e1.
11. Batchelor TT, Duda DG, di Tomaso E, Ancukiewicz M, Plotkin SR, Gerstner E, Eichler AF, Drappatz J, Hochberg FH, Benner T, et al. (2010) Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol 28: 2817–2823.
12. Batchelor TT, Gerstner ER, Emblem KE, Duda DG, Kalpathy-Cramer J, Snuderl M, Ancukiewicz M, Polaskova P, Pinho MC, Jennings D, et al. (2013) Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation. Proc Natl Acad Sci USA 110: 19059–19064.
13. Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M, et al. (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11:83–95.
14. Bates DO, Mavrou A, Qiu Y, Carter JG, Hamdollah-Zadeh M, Barratt S, Gammons MV, Millar AB, Salmon AH, Oltean S, et al. (2013) Detection of VEGF-A(xxx) b isoforms in human tissues. PLoS ONE 8:e68399.
15. Bauvois B (2012) New facets of matrix metalloproteinases MMP-2 and MMP-9 as cell surface transducers: outside-in signaling and relationship to tumor progression. Biochim Biophys Acta 1825:29–36.
16. Berg K, Weyergang A, Prasmickaite L, Bonsted A, Høgset A, Strand MT, Wagner E, and Selbo PK (2010) Photochemical internalization (PCI): a technology for drug delivery. Methods Mol Biol 635:133–145.
17. Bergers G and Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8:592–603.
18. Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z, et al. (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2:737–744.
19. Bergers G, Song S, Meyer-Morse N, Bergsland E, and Hanahan D (2003) Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 111:1287–1295.
20. Beuselinck B, Karadimou A, Lambrechts D, Claes B, Wolter P, Couchy G, Berkers J, Paridaens R, Schöffski P, Méjean A, et al. (2013) Single-nucleotide polymorphisms associated with outcome in metastatic renal cell carcinoma treated with sunitinib. Br J Cancer 108:887–900.
21. Bhowmick NA, Neilson EG, and Moses HL (2004) Stromal fibroblasts in cancer initiation and progression. Nature 432:332–337.
22. Bockhorn M, Tsuzuki Y, Xu L, Frilling A, Broelsch CE, and Fukumura D (2003) Differential vascular and transcriptional responses to anti-vascular endothelial growth factor antibody in orthotopic human pancreatic cancer xenografts. Clin Cancer Res 9:4221–4226.
23. Boire A, Covic L, Agarwal A, Jacques S, Sherifi S, and Kuliopulos A (2005) PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 120:303–313.
24. Bourdeau A, Dumont DJ, and Letarte M (1999) A murine model of hereditary hemorrhagic telangiectasia. J Clin Invest 104:1343–1351.
25. Boyer DS (2013). A Phase 2b Study of Fovista™, a Platelet Derived Growth Factor (PDGF) inhibitor in combination with a Vascular Endothelial Growth Factor (VEGF) inhibitor for Neovascular Age-Related Macular Degeneration (AMD). Invest Ophthalmol Vis Sci 54:E-Abstract 2175.
26. Brooks AN, Kilgour E, and Smith PD (2012) Molecular pathways: fibroblast growth factor signaling: a new therapeutic opportunity in cancer. Clin Cancer Res 18: 1855–1862.
27. Burger JA and Stewart DJ (2009) CXCR4 chemokine receptor antagonists: perspectives in SCLC. Expert Opin Investig Drugs 18:481–490.
28. Capece D, Fischietti M, Verzella D, Gaggiano A, Cicciarelli G, Tessitore A, Zazzeroni F, and Alesse E (2013) The inflammatory microenvironment in hepatocellular carcinoma: a pivotal role for tumor-associated macrophages. Biomed Res Int 2013:187204.
29. Carbone C, Moccia T, Zhu C, Paradiso G, Budillon A, Chiao PJ, Abbruzzese JL, and Melisi D (2011) Anti-VEGF treatment-resistant pancreatic cancers secrete proinflammatory factors that contribute to malignant progression by inducing an EMT cell phenotype. Clin Cancer Res 17:5822–5832.
30. Carmeliet P and Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473:298–307.
31. Casanovas O, Hicklin DJ, Bergers G, and Hanahan D (2005) Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8:299–309.
32. Cascone T, Herynk MH, Xu L, Du Z, Kadara H, Nilsson MB, Oborn CJ, Park YY, Erez B, Jacoby JJ, et al. (2011) Upregulated stromal EGFR and vascular remodeling in mouse xenograft models of angiogenesis inhibitor-resistant human lung adenocarcinoma. J Clin Invest 121:1313–1328.
33. Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, and Gurtner GC (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10:858–864.
34. Chantrain CF, Henriet P, Jodele S, Emonard H, Feron O, Courtoy PJ, DeClerck YA, and Marbaix E (2006) Mechanisms of pericyte recruitment in tumour angiogenesis: a new role for metalloproteinases. Eur J Cancer 42:310–318.
35. Chen HF, Huang CH, Liu CJ, Hung JJ, Hsu CC, Teng SC, and Wu KJ (2014) Twist1 induces endothelial differentiation of tumour cells through the Jagged1-KLF4 axis. Nat Commun 5:4697.
36. Chiappori AA, Eckhardt SG, Bukowski R, Sullivan DM, Ikeda M, Yano Y, Yamada- Sawada T, Kambayashi Y, Tanaka K, Javle MM, et al. (2007) A phase I pharmacokinetic and pharmacodynamic study of s-3304, a novel matrix metalloproteinase inhibitor, in patients with advanced and refractory solid tumors. Clin Cancer Res 13:2091–2099.
37. Chung AS, Kowanetz M, Wu X, Zhuang G, Ngu H, Finkle D, Komuves L, Peale F, and Ferrara N (2012) Differential drug class-specific metastatic effects following treatment with a panel of angiogenesis inhibitors. J Pathol 227:404–416.
38. Chung AS, Wu X, Zhuang G, Ngu H, Kasman I, Zhang J, Vernes JM, Jiang Z, Meng YG, Peale FV, et al. (2013) An interleukin-17-mediated paracrine network promotes tumor resistance to anti-angiogenic therapy. Nat Med 19: 1114–1123.
39. Cianfrocca M, Lee S, Von Roenn J, Rudek MA, Dezube BJ, Krown SE, and Sparano JA (2011) Pilot study evaluating the interaction between paclitaxel and protease inhibitors in patients with human immunodeficiency virus-associated Kaposi’s sarcoma: an Eastern Cooperative Oncology Group (ECOG) and AIDS Malignancy Consortium (AMC) trial. Cancer Chemother Pharmacol 68:827–833.
40. Clarke JM and Hurwitz HI (2013) Understanding and targeting resistance to antiangiogenic therapies. J Gastrointest Oncol 4:253–263.
41. Coffelt SB, Tal AO, Scholz A, De Palma M, Patel S, Urbich C, Biswas SK, Murdoch C, Plate KH, Reiss Y, et al. (2010) Angiopoietin-2 regulates gene expression in TIE2- expressing monocytes and augments their inherent proangiogenic functions. Cancer Res 70:5270–5280.
42. Cooke VG, LeBleu VS, Keskin D, Khan Z, O’Connell JT, Teng Y, Duncan MB, Xie L, Maeda G, Vong S, et al. (2012) Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway. Cancer Cell 21:66–81.
43. Coussens LM and Werb Z (2002) Inflammation and cancer. Nature 420:860–867.
44. Crawford Y and Ferrara N (2009) Tumor and stromal pathways mediating refractoriness/ resistance to anti-angiogenic therapies. Trends Pharmacol Sci 30:624–630.
45. Croci DO, Cerliani JP, Dalotto-Moreno T, Méndez-Huergo SP, Mascanfroni ID, Dergan-Dylon S, Toscano MA, Caramelo JJ, García-Vallejo JJ, Ouyang J, et al. (2014) Glycosylation-dependent lectin-receptor interactions preserve angiogenesis in anti-VEGF refractory tumors. Cell 156:744–758.
46. Croci DO, Salatino M, Rubinstein N, Cerliani JP, Cavallin LE, Leung HJ, Ouyang J, Ilarregui JM, Toscano MA, Domaica CI, et al. (2012) Disrupting galectin-1 interactions with N-glycans suppresses hypoxia-driven angiogenesis and tumorigenesis in Kaposi’s sarcoma. J Exp Med 209:1985–2000.
47. Czabanka M, Bruenner J, Parmaksiz G, Broggini T, Topalovic M, Bayerl SH, Auf G, Kremenetskaia I, Nieminen M, Jabouille A, et al. (2013) Combined temozolomide and sunitinib treatment leads to better tumour control but increased vascular resistance in O6-methylguanine methyltransferase-methylated gliomas. Eur J Cancer 49:2243–2252.
48. Dai X, Tan Y, Cai S, Xiong X, Wang L, Ye Q, Yan X, Ma K, and Cai L (2011) The role of CXCR7 on the adhesion, proliferation and angiogenesis of endothelial progenitor cells. J Cell Mol Med 15:1299–1309.
49. de Groot JF, Fuller G, Kumar AJ, Piao Y, Eterovic K, Ji Y, and Conrad CA (2010) Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice. Neuro-oncol 12:233–242.
50. de Haas S, Delmar P, Bansal AT, Moisse M, Miles DW, Leighl N, Escudier B, Van Cutsem E, Carmeliet P, Scherer SJ, et al. (2014) Genetic variability of VEGF pathway genes in six randomized phase III trials assessing the addition of bevacizumab to standard therapy. Angiogenesis 17:909–920.
51. Delgado VM, Nugnes LG, Colombo LL, Troncoso MF, Fernández MM, Malchiodi EL, Frahm I, Croci DO, Compagno D, Rabinovich GA, et al. (2011) Modulation of endothelial cell migration and angiogenesis: a novel function for the “tandemrepeat” lectin galectin-8. FASEB J 25:242–254.
52. De Palma M and Naldini L (2011) Angiopoietin-2 TIEs up macrophages in tumor angiogenesis. Clin Cancer Res 17:5226–5232.
53. De Palma M, Venneri MA, Galli R, Sergi Sergi L, Politi LS, Sampaolesi M, and Naldini L (2005) Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8:211–226.
54. De Wever O and Mareel M (2003) Role of tissue stroma in cancer cell invasion. J Pathol 200:429–447.
55. D’Haene N, Sauvage S, Maris C, Adanja I, Le Mercier M, Decaestecker C, Baum L, and Salmon I (2013) VEGFR1 and VEGFR2 involvement in extracellular galectin- 1- and galectin-3-induced angiogenesis. PLoS ONE 8:e67029.
56. Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, and Montero AJ (2009) Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicincyclophosphamide chemotherapy. Cancer Immunol Immunother 58:49–59.
57. Dineen SP, Lynn KD, Holloway SE, Miller AF, Sullivan JP, Shames DS, Beck AW, Barnett CC, Fleming JB, and Brekken RA (2008) Vascular endothelial growth factor receptor 2 mediates macrophage infiltration into orthotopic pancreatic tumors in mice. Cancer Res 68:4340–4346.
58. Ding X, Liu W, Weiss A, Li Y, Wong I, Griffioen AW, van den Bergh H, Xu H, Nowak- Sliwinska P, and Ho CM (2014) Discovery of a low order drug-cell response surface for applications in personalized medicine. Phys Biol 11:065003.
59. Djonov V, Schmid M, Tschanz SA, and Burri PH (2000) Intussusceptive angiogenesis: its role in embryonic vascular network formation. Circ Res 86:286–292.
60. Dong J, Grunstein J, Tejada M, Peale F, Frantz G, Liang WC, Bai W, Yu L, Kowalski J, Liang X, et al. (2004) VEGF-null cells require PDGFR alpha signaling-mediated stromal fibroblast recruitment for tumorigenesis. EMBO J 23:2800–2810.
61. Donnem T, Hu J, Ferguson M, Adighibe O, Snell C, Harris AL, Gatter KC, and Pezzella F (2013) Vessel co-option in primary human tumors and metastases: an obstacle to effective anti-angiogenic treatment? Cancer Med 2:427–436.
62. Du R, Lu KV, Petritsch C, Liu P, Ganss R, Passegué E, Song H, Vandenberg S, Johnson RS, Werb Z, et al. (2008) HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13:206–220.
63. Duda DG, Kozin SV, Kirkpatrick ND, Xu L, Fukumura D, and Jain RK (2011) CXCL12 (SDF1alpha)-CXCR4/CXCR7 pathway inhibition: an emerging sensitizer for anticancer therapies? Clin Cancer Res 17:2074–2080.
64. Dudley AC, Khan ZA, Shih SC, Kang SY, Zwaans BM, Bischoff J, and Klagsbrun M (2008) Calcification of multipotent prostate tumor endothelium. Cancer Cell 14:201–211.
65. Duff SE, Li C, Garland JM, and Kumar S (2003) CD105 is important for angiogenesis: evidence and potential applications. FASEB J 17:984–992.
66. Ebos JM and Kerbel RS (2011) Antiangiogenic therapy: impact on invasion, disease progression, and metastasis. Nat Rev Clin Oncol 8:210–221.
67. Ebos JM, Lee CR, Christensen JG, Mutsaers AJ, and Kerbel RS (2007) Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proc Natl Acad Sci USA 104:17069–17074.
68. Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, and Kerbel RS (2009) Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15:232–239.
69. Fagiani E and Christofori G (2013) Angiopoietins in angiogenesis. Cancer Lett 328: 18–26.
70. Fantin A, Vieira JM, Gestri G, Denti L, Schwarz Q, Prykhozhij S, Peri F, Wilson SW, and Ruhrberg C (2010) Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood 116:829–840.
71. Ferrara N, Hillan KJ, Gerber HP, and Novotny W (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3:391–400.
72. Ferreras C, Rushton G, Cole CL, Babur M, Telfer BA, van Kuppevelt TH, Gardiner JM, Williams KJ, Jayson GC, and Avizienyte E (2012) Endothelial heparan sulfate 6-O-sulfation levels regulate angiogenic responses of endothelial cells to fibroblast growth factor 2 and vascular endothelial growth factor. J Biol Chem 287:36132–36146.
73. Finn NA and Searles CD (2012) Intracellular and extracellular miRNAs in regulation of angiogenesis signaling. Curr Angiogenes 4:299–307.
74. Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S, Pattarini L, Chorianopoulos E, Liesenborghs L, Koch M, and De Mol M, et al. (2007) Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131: 463–475.
75. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285: 1182–1186.
76. Fujimura A, Michiue H, Cheng Y, Uneda A, Tani Y, Nishiki T, Ichikawa T, Wei FY, Tomizawa K, and Matsui H (2013) Cyclin G2 promotes hypoxia-driven local invasion of glioblastoma by orchestrating cytoskeletal dynamics. Neoplasia 15: 1272–1281.
77. Gacche RN and Meshram RJ (2014) Angiogenic factors as potential drug target: efficacy and limitations of anti-angiogenic therapy. Biochim Biophys Acta 1846: 161–179.
78. Gitay-Goren H, Soker S, Vlodavsky I, and Neufeld G (1992) The binding of vascular endothelial growth factor to its receptors is dependent on cell surface-associated heparin-like molecules. J Biol Chem 267:6093–6098.
79. Goodman VL, Rock EP, Dagher R, Ramchandani RP, Abraham S, Gobburu JV, Booth BP, Verbois SL, Morse DE, Liang CY, et al. (2007) Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res 13:1367–1373.
80. Gordon MS, Robert F, Matei D, Mendelson DS, Goldman JW, Chiorean EG, Strother RM, Seon BK, Figg WD, Peer CJ, et al. (2014) An open-label phase Ib doseescalation study of TRC105 (anti-endoglin antibody) with bevacizumab in patients with advanced cancer. Clin Cancer Res 20:5918–5926.
81. Gotink KJ, Broxterman HJ, Labots M, de Haas RR, Dekker H, Honeywell RJ, Rudek MA, Beerepoot LV, Musters RJ, Jansen G, et al. (2011) Lysosomal sequestration of sunitinib: a novel mechanism of drug resistance. Clin Cancer Res 17:7337–7346.
82. Griffioen AW, Weiss A, Berndsen RH, Abdul UK, te Winkel MT, and Nowak-Sliwinska P (2014) The emerging quest for the optimal angiostatic combination therapy. Biochem Soc Trans 42:1608–1615.
83. Griffioen AW and Molema G (2000) Angiogenesis: potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation. Pharmacol Rev 52:237–268.
84. Griffioen AW, Mans LA, de Graaf AM, Nowak-Sliwinska P, de Hoog CL, de Jong TA, Vyth-Dreese FA, van Beijnum JR, Bex A, and Jonasch E (2012) Rapid angiogenesis onset after discontinuation of sunitinib treatment of renal cell carcinoma patients. Clin Cancer Res 18:3961–3971.
85. Grunewald M, Avraham I, Dor Y, Bachar-Lustig E, Itin A, Jung S, Chimenti S, Landsman L, Abramovitch R, and Keshet E (2006) VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 124: 175–189.
86. Gyanchandani R, Ortega Alves MV, Myers JN, and Kim S (2013a) A proangiogenic signature is revealed in FGF-mediated bevacizumab-resistant head and neck squamous cell carcinoma. Mol Cancer Res 11:1585–1596.
87. Gyanchandani R, Sano D, Ortega Alves MV, Klein JD, Knapick BA, Oh S, Myers JN, and Kim S (2013b) Interleukin-8 as a modulator of response to bevacizumab in preclinical models of head and neck squamous cell carcinoma. Oral Oncol 49: 761–770.
88. Harper SJ and Bates DO (2008) VEGF-A splicing: the key to anti-angiogenic therapeutics? Nat Rev Cancer 8:880–887.
89. Harris S, Craze M, Newton J, Fisher M, Shima DT, Tozer GM, and Kanthou C (2012) Do anti-angiogenic VEGF (VEGFxxxb) isoforms exist? A cautionary tale. PLoS ONE 7:e35231.
90. Hasnis E, Alishekevitz D, Gingis-Veltski S, Bril R, Fremder E, Voloshin T, Raviv Z, Karban A, and Shaked Y (2014) Anti-Bv8 antibody and metronomic gemcitabine improve pancreatic adenocarcinoma treatment outcome following weekly gemcitabine therapy. Neoplasia 16:501–510.
91. Hecht JR, Mitchell E, Chidiac T, Scroggin C, Hagenstad C, Spigel D, Marshall J, Cohn A, McCollum D, Stella P, et al. (2009) A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol 27:672–680.
92. Hendrix MJ, Seftor EA, Meltzer PS, Gardner LM, Hess AR, Kirschmann DA, Schatteman GC, and Seftor RE (2001) Expression and functional significance of VE-cadherin in aggressive human melanoma cells: role in vasculogenic mimicry. Proc Natl Acad Sci USA 98:8018–8023.
93. Heusschen R, Schulkens IA, van Beijnum J, Griffioen AW, and Thijssen VL (2014) Endothelial LGALS9 splice variant expression in endothelial cell biology and angiogenesis. Biochim Biophys Acta 1842:284–292.
94. Hida K, Hida Y, Amin DN, Flint AF, Panigrahy D, Morton CC, and Klagsbrun M (2004) Tumor-associated endothelial cells with cytogenetic abnormalities. Cancer Res 64:8249–8255.
95. Hida K, Ohga N, Akiyama K, Maishi N, and Hida Y (2013) Heterogeneity of tumor endothelial cells. Cancer Sci 104:1391–1395.
96. Hillen F and Griffioen AW (2007) Tumour vascularization: sprouting angiogenesis and beyond. Cancer Metastasis Rev 26:489–502.
97. Hillen F, Baeten CI, van de Winkel A, Creytens D, van der Schaft DW, Winnepenninckx V, and Griffioen AW (2008) Leukocyte infiltration and tumor cell plasticity are parameters of aggressiveness in primary cutaneous melanoma. Cancer Immunol Immunother 57:97–106.
98. Hotchkiss KA, Ashton AW, Klein RS, Lenzi ML, Zhu GH, and Schwartz EL (2003) Mechanisms by which tumor cells and monocytes expressing the angiogenic factor thymidine phosphorylase mediate human endothelial cell migration. Cancer Res 63:527–533.
99. Hsieh SH, Ying NW, Wu MH, Chiang WF, Hsu CL, Wong TY, Jin YT, Hong TM, and Chen YL (2008) Galectin-1, a novel ligand of neuropilin-1, activates VEGFR-2 signaling and modulates the migration of vascular endothelial cells. Oncogene 27: 3746–3753.
100. Huang D, Ding Y, Zhou M, Rini BI, Petillo D, Qian CN, Kahnoski R, Futreal PA, Furge KA, and Teh BT (2010) Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma. Cancer Res 70:1063–1071.
101. Huang J, Soffer SZ, Kim ES, McCrudden KW, Huang J, New T, Manley CA, Middlesworth W, O’Toole K, Yamashiro DJ, et al. (2004) Vascular remodeling marks tumors that recur during chronic suppression of angiogenesis. Mol Cancer Res 2:36–42.
102. Huang S, Van Arsdall M, Tedjarati S, McCarty M, Wu W, Langley R, and Fidler IJ (2002) Contributions of stromal metalloproteinase-9 to angiogenesis and growth of human ovarian carcinoma in mice. J Natl Cancer Inst 94:1134–1142.
103. Ito K, Scott SA, Cutler S, Dong LF, Neuzil J, Blanchard H, and Ralph SJ (2011) Thiodigalactoside inhibits murine cancers by concurrently blocking effects of galectin-1 on immune dysregulation, angiogenesis and protection against oxidative stress. Angiogenesis 14:293–307.
104. Jo N, Mailhos C, Ju M, Cheung E, Bradley J, Nishijima K, Robinson GS, Adamis AP, and Shima DT (2006) Inhibition of platelet-derived growth factor B signaling enhances the efficacy of anti-vascular endothelial growth factor therapy in multiple models of ocular neovascularization. Am J Pathol 168:2036–2053.
105. Jung HY, Fattet L, and Yang J (2014) Molecular Pathways: Linking Tumor Microenvironment to Epithelial-Mesenchymal Transition in Metastasis. Clin Cancer Res [epub ahead of print].
106. Kalluri R and Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6:392–401.
107. Kane RC, Farrell AT, Saber H, Tang S, Williams G, Jee JM, Liang C, Booth B, Chidambaram N, Morse D, et al. (2006) Sorafenib for the treatment of advanced renal cell carcinoma. Clin Cancer Res 12:7271–7278.
108. Kao YC, Jiang SJ, Pan WA, Wang KC, Chen PK, Wei HJ, Chen WS, Chang BI, Shi GY, and Wu HL (2012) The epidermal growth factor-like domain of CD93 is a potent angiogenic factor. PLoS ONE 7:e51647.
109. Kashima K, Watanabe M, Sato Y, Hata J, Ishii N, and Aoki Y (2014) Inhibition of metastasis of rhabdomyosarcoma by a novel neutralizing antibody to CXCR4. Cancer Sci 105:1343–1350.
110. Kopetz S, Hoff PM, Morris JS, Wolff RA, Eng C, Glover KY, Adinin R, Overman MJ, Valero V, Wen S, et al. (2010) Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol 28:453–459.
111. Kosaka N, Iguchi H, Yoshioka Y, Takeshita F, Matsuki Y, and Ochiya T (2010) Secretory mechanisms and intercellular transfer of microRNAs in living cells. J Biol Chem 285:17442–17452.
112. Kumar S, Mokhtari RB, Oliveira ID, Islam S, Toledo SR, Yeger H, and Baruchel S (2013) Tumor dynamics in response to antiangiogenic therapy with oral metronomic topotecan and pazopanib in neuroblastoma xenografts. Transl Oncol 6: 493–503.
113. Lambrechts D, Claes B, Delmar P, Reumers J, Mazzone M, Yesilyurt BT, Devlieger R, Verslype C, Tejpar S, Wildiers H, et al. (2012) VEGF pathway genetic variants as biomarkers of treatment outcome with bevacizumab: an analysis of data from the AViTA and AVOREN randomised trials. Lancet Oncol 13:724–733.
114. Lambrechts D, Moisse M, Delmar P, Miles DW, Leighl N, Escudier B, Van Cutsem E, Bansal AT, Carmeliet P, Scherer SJ, et al. (2014) Genetic markers of bevacizumabinduced hypertension. Angiogenesis 17:685–694.
115. Lebrin F, Goumans MJ, Jonker L, Carvalho RL, Valdimarsdottir G, Thorikay M, Mummery C, Arthur HM, and ten Dijke P (2004) Endoglin promotes endothelial cell proliferation and TGF-beta/ALK1 signal transduction. EMBO J 23:4018–4028.
116. LeCouter J, Zlot C, Tejada M, Peale F, and Ferrara N (2004) Bv8 and endocrine gland-derived vascular endothelial growth factor stimulate hematopoiesis and hematopoietic cell mobilization. Proc Natl Acad Sci USA 101:16813–16818.
117. Leenders WP, Küsters B, Verrijp K, Maass C, Wesseling P, Heerschap A, Ruiter D, Ryan A, and de Waal R (2004) Antiangiogenic therapy of cerebral melanoma metastases results in sustained tumor progression via vessel co-option. Clin Cancer Res 10:6222–6230.
118. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, and Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246:1306–1309.
119. Li W, Gomez E, and Zhang Z (2007) Immunohistochemical expression of stromal cellderived factor-1 (SDF-1) and CXCR4 ligand receptor system in hepatocellular carcinoma. J Exp Clin Cancer Res 26:527–533.
120. Lin EY, Li JF, Gnatovskiy L, Deng Y, Zhu L, Grzesik DA, Qian H, Xue XN, and Pollard JW (2006) Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res 66:11238–11246.
121. Liu BY, Soloviev I, Chang P, Lee J, Huang X, Zhong C, Ferrara N, Polakis P, and Sakanaka C (2010) Stromal cell-derived factor-1/CXCL12 contributes to MMTV-Wnt1 tumor growth involving Gr1+CD11b+ cells. PLoS ONE 5:e8611.
122. Liu Y, Tian H, Blobe GC, Theuer CP, Hurwitz HI, and Nixon AB (2014a) Effects of the combination of TRC105 and bevacizumab on endothelial cell biology. Invest New Drugs 32:851–859.
123. Liu Z, Lebrin F, Maring JA, van den Driesche S, van der Brink S, van Dinther M, Thorikay M, Martin S, Kobayashi K, Hawinkels LJ, et al. (2014b) ENDOGLIN is dispensable for vasculogenesis, but required for vascular endothelial growth factorinduced angiogenesis. PLoS ONE 9:e86273.
124. Loges S, Schmidt T, and Carmeliet P (2010) Mechanisms of resistance to antiangiogenic therapy and development of third-generation anti-angiogenic drug candidates. Genes Cancer 1:12–25.
125. Löhr M, Schmidt C, Ringel J, Kluth M, Müller P, Nizze H, and Jesnowski R (2001) Transforming growth factor-beta1 induces desmoplasia in an experimental model of human pancreatic carcinoma. Cancer Res 61:550–555.
126. Lu KV, Chang JP, Parachoniak CA, Pandika MM, Aghi MK, Meyronet D, Isachenko N, Fouse SD, Phillips JJ, Cheresh DA, et al. (2012) VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer Cell 22:21–35.
127. Lv LH, Wan YL, Lin Y, Zhang W, Yang M, Li GL, Lin HM, Shang CZ, Chen YJ, and Min J (2012) Anticancer drugs cause release of exosomes with heat shock proteins from human hepatocellular carcinoma cells that elicit effective natural killer cell antitumor responses in vitro. J Biol Chem 287:15874–15885.
128. Lynn KD, Roland CL, and Brekken RA (2010) VEGF and pleiotrophin modulate the immune profile of breast cancer. Cancers (Basel) 2:970–988.
129. Maione F, Capano S, Regano D, Zentilin L, Giacca M, Casanovas O, Bussolino F, Serini G, and Giraudo E (2012) Semaphorin 3A overcomes cancer hypoxia and metastatic dissemination induced by antiangiogenic treatment in mice. J Clin Invest 122:1832–1848.
130. Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM, Pe’er J, Trent JM, Meltzer PS, and Hendrix MJ (1999) Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol 155:739–752.
131. Mantovani A, Biswas SK, Galdiero MR, Sica A, and Locati M (2013) Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol 229:176–185.
132. Mantovani A, Romero P, Palucka AK, and Marincola FM (2008) Tumour immunity: effector response to tumour and role of the microenvironment. Lancet 371:771–783.
133. Mantovani A, Sozzani S, Locati M, Allavena P, and Sica A (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23:549–555.
134. Marigo I, Dolcetti L, Serafini P, Zanovello P, and Bronte V (2008) Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells. Immunol Rev 222:162–179.
135. Markowska AI, Jefferies KC, and Panjwani N (2011) Galectin-3 protein modulates cell surface expression and activation of vascular endothelial growth factor receptor 2 in human endothelial cells. J Biol Chem 286:29913–29921.
136. Markowska AI, Liu FT, and Panjwani N (2010) Galectin-3 is an important mediator of VEGF- and bFGF-mediated angiogenic response. J Exp Med 207:1981–1993.
137. Matsuda K, Ohga N, Hida Y, Muraki C, Tsuchiya K, Kurosu T, Akino T, Shih SC, Totsuka Y, Klagsbrun M, et al. (2010) Isolated tumor endothelial cells maintain specific character during long-term culture. Biochem Biophys Res Commun 394: 947–954.
138. Mazzieri R, Pucci F, Moi D, Zonari E, Ranghetti A, Berti A, Politi LS, Gentner B, Brown JL, Naldini L, et al. (2011) Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell 19:512–526.
139. Mikami S, Mizuno R, Kosaka T, Saya H, Oya M, and Okada Y (2015) Expression of TNF-a and CD44 is implicated in poor prognosis, cancer cell invasion, metastasis and resistance to the sunitinib treatment in clear cell renal cell carcinomas. Int J Cancer 136:1504–1514.
140. Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE, et al. (2006) Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and plateletderived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 24:16–24.
141. Mueller MM and Fusenig NE (2004) Friends or foes - bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 4:839–849.
142. Murdoch C, Muthana M, Coffelt SB, and Lewis CE (2008) The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8:618–631.
143. Murdoch C, Tazzyman S, Webster S, and Lewis CE (2007) Expression of Tie-2 by human monocytes and their responses to angiopoietin-2. J Immunol 178: 7405–7411.
144. Najib S, Kowalski-Chauvel A, Do C, Roche S, Cohen-Jonathan-Moyal E, and Seva C (2014) Progastrin a new pro-angiogenic factor in colorectal cancer. Oncogene doi: 10.1038/onc.2014.255 [Epub ahead of print]
145. Nangia-Makker P, Honjo Y, Sarvis R, Akahani S, Hogan V, Pienta KJ, and Raz A (2000) Galectin-3 induces endothelial cell morphogenesis and angiogenesis. Am J Pathol 156:899–909.
146. Nangia-Makker P, Wang Y, Raz T, Tait L, Balan V, Hogan V, and Raz A (2010) Cleavage of galectin-3 by matrix metalloproteases induces angiogenesis in breast cancer. Int J Cancer 127:2530–2541.
147. Negri L, Lattanzi R, Giannini E, and Melchiorri P (2007) Bv8/Prokineticin proteins and their receptors. Life Sci 81:1103–1116.
148. Nisancioglu MH, Betsholtz C, and Genové G (2010) The absence of pericytes does not increase the sensitivity of tumor vasculature to vascular endothelial growth factor- A blockade. Cancer Res 70:5109–5115.
149. Nowak DG, Amin EM, Rennel ES, Hoareau-Aveilla C, Gammons M, Damodoran G, Hagiwara M, Harper SJ, Woolard J, Ladomery MR, et al. (2010) Regulation of vascular endothelial growth factor (VEGF) splicing from pro-angiogenic to antiangiogenic isoforms: a novel therapeutic strategy for angiogenesis. J Biol Chem 285:5532–5540.
150. Nowak DG, Woolard J, Amin EM, Konopatskaya O, Saleem MA, Churchill AJ, Ladomery MR, Harper SJ, and Bates DO (2008) Expression of pro- and antiangiogenic isoforms of VEGF is differentially regulated by splicing and growth factors. J Cell Sci 121:3487–3495.
151. Nowak-Sliwinska P (2012) Anti-angiogenic treatment for exudative age-related macular degeneration: new strategies are underway. Current Angiogenesis 1: 318–334.
152. Nowak-Sliwinska P, van den Bergh H, Sickenberg M, and Koh AHC (2013) Photodynamic therapy for polypoidal choroidal vasculopathy. Prog Retin Eye Res 37: 182–199.
153. Nowak-Sliwinska P, Weiss A, van Beijnum JR, Wong TJ, Kilarski WW, Szewczyk G, Verheul HM, Sarna T, van den Bergh H, and Griffioen AW (2015) Photoactivation of lysosomally sequestered sunitinib after angiostatic treatment causes vascular occlusion and enhances tumor growth inhibition. Cell Death Dis DOI:10.1038/ cddis.2015.4.
154. Obermajer N, Muthuswamy R, Odunsi K, Edwards RP, and Kalinski P (2011) PGE (2)-induced CXCL12 production and CXCR4 expression controls the accumulation of human MDSCs in ovarian cancer environment. Cancer Res 71:7463–7470.
155. Ohga N, Ishikawa S, Maishi N, Akiyama K, Hida Y, Kawamoto T, Sadamoto Y, Osawa T, Yamamoto K, Kondoh M, et al. (2012) Heterogeneity of tumor endothelial cells: comparison between tumor endothelial cells isolated from high- and lowmetastatic tumors. Am J Pathol 180:1294–1307.
156. Ohki Y, Heissig B, Sato Y, Akiyama H, Zhu Z, Hicklin DJ, Shimada K, Ogawa H, Daida H, Hattori K, et al. (2005) Granulocyte colony-stimulating factor promotes neovascularization by releasing vascular endothelial growth factor from neutrophils. FASEB J 19:2005–2007.
157. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL, and Weinberg RA (2005) Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121:335–348.
158. Orlidge A and D’Amore PA (1987) Inhibition of capillary endothelial cell growth by pericytes and smooth muscle cells. J Cell Biol 105:1455–1462.
159. Pàez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Viñals F, Inoue M, Bergers G, Hanahan D, and Casanovas O (2009) Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15:220–231.
160. Pardali E, Goumans MJ, and ten Dijke P (2010) Signaling by members of the TGFbeta family in vascular morphogenesis and disease. Trends Cell Biol 20:556–567.
161. Parri M, Pietrovito L, Grandi A, Campagnoli S, De Camilli E, Bianchini F, Marchiò S, Bussolino F, Jin B, Sarmientos P, et al. (2014). Angiopoietin-like 7, a novel proangiogenetic factor over-expressed in cancer. Angiogenesis 17:881–896.
162. Pasquier J, Thawadi HA, Ghiabi P, Abu-Kaoud N, Maleki M, Guerrouahen BS, Vidal F, Courderc B, Ferron G, Martinez A, et al. (2014) Microparticles mediated crosstalk between tumoral and endothelial cells promote the constitution of a prometastatic vascular niche through Arf6 up regulation. Cancer Microenviron 17: 41–49.
163. Paulis YW, Soetekouw PM, Verheul HM, Tjan-Heijnen VC, and Griffioen AW (2010) Signalling pathways in vasculogenic mimicry. Biochim Biophys Acta 1806:18–28.
164. Pietras K and Hanahan D (2005) A multitargeted, metronomic, and maximumtolerated dose “chemo-switch” regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. J Clin Oncol 23: 939–952.
165. Pietras K, Pahler J, Bergers G, and Hanahan D (2008) Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting. PLoS Med 5:e19.
166. Powell MA, Sill MW, Goodfellow PJ, Benbrook DM, Lankes HA, Leslie KK, Jeske Y, Mannel RS, Spillman MA, Lee PS, et al. (2014) A phase II trial of brivanib in recurrent or persistent endometrial cancer: an NRG Oncology/Gynecologic Oncology Group Study. Gynecol Oncol 135:38–43.
167. Rabinovich GA, Cumashi A, Bianco GA, Ciavardelli D, Iurisci I, D’Egidio M, Piccolo E, Tinari N, Nifantiev N, and Iacobelli S (2006) Synthetic lactulose amines: novel class of anticancer agents that induce tumor-cell apoptosis and inhibit galectinmediated homotypic cell aggregation and endothelial cell morphogenesis. Glycobiology 16:210–220.
168. Rafii S, Lyden D, Benezra R, Hattori K, and Heissig B (2002) Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy? Nat Rev Cancer 2: 826–835.
169. Reinmuth N, Liu W, Jung YD, Ahmad SA, Shaheen RM, Fan F, Bucana CD, McMahon G, Gallick GE, and Ellis LM (2001) Induction of VEGF in perivascular cells defines a potential paracrine mechanism for endothelial cell survival. FASEB J 15:1239–1241.
170. Ries CH, Cannarile MA, Hoves S, Benz J, Wartha K, Runza V, Rey-Giraud F, Pradel LP, Feuerhake F, Klaman I, et al. (2014) Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell 25: 846–859.
171. Rigamonti N, Kadioglu E, Keklikoglou I, Wyser Rmili C, Leow CC, and De Palma M (2014) Role of angiopoietin-2 in adaptive tumor resistance to VEGF signaling blockade. Cell Reports 8:696–706.
172. Roland CL, Dineen SP, Lynn KD, Sullivan LA, Dellinger MT, Sadegh L, Sullivan JP, Shames DS, and Brekken RA (2009a) Inhibition of vascular endothelial growth factor reduces angiogenesis and modulates immune cell infiltration of orthotopic breast cancer xenografts. Mol Cancer Ther 8:1761–1771.
173. Roland CL, Lynn KD, Toombs JE, Dineen SP, Udugamasooriya DG, and Brekken RA (2009b) Cytokine levels correlate with immune cell infiltration after anti-VEGF therapy in preclinical mouse models of breast cancer. PLoS ONE 4:e7669.
174. Rosen LS, Kurzrock R, Mulay M, Van Vugt A, Purdom M, Ng C, Silverman J, Koutsoukos A, Sun YN, Bass MB, et al. (2007) Safety, pharmacokinetics, and efficacy of AMG 706, an oral multikinase inhibitor, in patients with advanced solid tumors. J Clin Oncol 25:2369–2376.
175. Rovida A, Castiglioni V, Decio A, Scarlato V, Scanziani E, Giavazzi R, and Cesca M (2013) Chemotherapy counteracts metastatic dissemination induced by antiangiogenic treatment in mice. Mol Cancer Ther 12:2237–2247.
176. Rubenstein JL, Kim J, Ozawa T, Zhang M, Westphal M, Deen DF, and Shuman MA (2000) Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption. Neoplasia 2:306–314.
177. Salnikov AV, Heldin NE, Stuhr LB, Wiig H, Gerber H, Reed RK, and Rubin K (2006) Inhibition of carcinoma cell-derived VEGF reduces inflammatory characteristics in xenograft carcinoma. Int J Cancer 119:2795–2802.
178. Sandhu SK, Papadopoulos K, Fong PC, Patnaik A, Messiou C, Olmos D, Wang G, Tromp BJ, Puchalski TA, Balkwill F, et al. (2013) A first-in-human, first-in-class, phase I study of carlumab (CNTO 888), a human monoclonal antibody against CCchemokine ligand 2 in patients with solid tumors. Cancer Chemother Pharmacol 71: 1041–1050.
179. Scartozzi M, Bianconi M, Faloppi L, Loretelli C, Bittoni A, Del Prete M, Giampieri R, Maccaroni E, Nicoletti S, Burattini L, et al. (2013) VEGF and VEGFR polymorphisms affect clinical outcome in advanced renal cell carcinoma patients receiving first-line sunitinib. Br J Cancer 108:1126–1132.
180. Schmidt T and Carmeliet P (2010) Blood-vessel formation: Bridges that guide and unite. Nature 465:697–699.
181. Selbo PK, Weyergang A, Høgset A, Norum OJ, Berstad MB, Vikdal M, and Berg K (2010) Photochemical internalization provides time- and space-controlled endolysosomal escape of therapeutic molecules. J Control Release 148:2–12.
182. Sennino B, Ishiguro-Oonuma T, Wei Y, Naylor RM, Williamson CW, Bhagwandin V, Tabruyn SP, You WK, Chapman HA, Christensen JG, et al. (2012) Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov 2:270–287.
183. Serafini P, Borrello I, and Bronte V (2006) Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. Semin Cancer Biol 16:53–65.
184. Shepro D and Morel NM (1993) Pericyte physiology. FASEB J 7:1031–1038.
185. Shirakawa K, Kobayashi H, Heike Y, Kawamoto S, Brechbiel MW, Kasumi F, Iwanaga T, Konishi F, Terada M, and Wakasugi H (2002) Hemodynamics in vasculogenic mimicry and angiogenesis of inflammatory breast cancer xenograft. Cancer Res 62:560–566.
186. Shojaei F and Ferrara N (2008a) Refractoriness to antivascular endothelial growth factor treatment: role of myeloid cells. Cancer Res 68:5501–5504.
187. Shojaei F and Ferrara N (2008b) Role of the microenvironment in tumor growth and in refractoriness/resistance to anti-angiogenic therapies. Drug Resist Updat 11:219–230.
188. Shojaei F, Simmons BH, Lee JH, Lappin PB, and Christensen JG (2012) HGF/c-Met pathway is one of the mediators of sunitinib-induced tumor cell type-dependent metastasis. Cancer Lett 320:48–55.
189. Shojaei F, Singh M, Thompson JD, and Ferrara N (2008) Role of Bv8 in neutrophildependent angiogenesis in a transgenic model of cancer progression. Proc Natl Acad Sci USA 105:2640–2645.
190. Shojaei F, Wu X, Malik AK, Zhong C, Baldwin ME, Schanz S, Fuh G, Gerber HP, and Ferrara N (2007a) Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nat Biotechnol 25:911–920.
191. Shojaei F, Wu X, Qu X, Kowanetz M, Yu L, Tan M, Meng YG, and Ferrara N (2009) G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models. Proc Natl Acad Sci USA 106: 6742–6747.
192. Shojaei F, Wu X, Zhong C, Yu L, Liang XH, Yao J, Blanchard D, Bais C, Peale FV, van Bruggen N, et al. (2007b) Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature 450:825–831.
193. Sica A, Porta C, Morlacchi S, Banfi S, Strauss L, Rimoldi M, Totaro MG, and Riboldi E (2012) Origin and Functions of Tumor-Associated Myeloid Cells (TAMCs). Cancer Microenviron 5:133–149.
194. Singh M, Couto SS, Forrest WF, Lima A, Cheng JH, Molina R, Long JE, Hamilton P, McNutt A, Kasman I, et al. (2012) Anti-VEGF antibody therapy does not promote metastasis in genetically engineered mouse tumour models. J Pathol 227:417–430.
195. Skog J, Würdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, Curry WT Jr, Carter BS, Krichevsky AM, and Breakefield XO (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10:1470–1476.
196. Solinas G, Germano G, Mantovani A, and Allavena P (2009) Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol 86:1065–1073.
197. Sood AK, Seftor EA, Fletcher MS, Gardner LM, Heidger PM, Buller RE, Seftor RE, and Hendrix MJ (2001) Molecular determinants of ovarian cancer plasticity. Am J Pathol 158:1279–1288.
198. Speyer CL, Hachem AH, Assi AA, Johnson JS, DeVries JA, and Gorski DH (2014) Metabotropic glutamate receptor-1 as a novel target for the antiangiogenic treatment of breast cancer. PLoS ONE 9:e88830.
199. Stefansson IM, Salvesen HB, and Akslen LA (2006) Vascular proliferation is important for clinical progress of endometrial cancer. Cancer Res 66:3303–3309.
200. Sternlicht MD, Lochter A, Sympson CJ, Huey B, Rougier JP, Gray JW, Pinkel D, Bissell MJ, and Werb Z (1999) The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell 98:137–146.
201. Stetler-Stevenson WG, Aznavoorian S, and Liotta LA (1993) Tumor cell interactions with the extracellular matrix during invasion and metastasis. Annu Rev Cell Biol 9:541–573.
202. Stoeltzing O, Ahmad SA, Liu W, McCarty MF, Wey JS, Parikh AA, Fan F, Reinmuth N, Kawaguchi M, Bucana CD, et al. (2003) Angiopoietin-1 inhibits vascular permeability, angiogenesis, and growth of hepatic colon cancer tumors. Cancer Res 63: 3370–3377.
203. Stratman AN, Davis MJ, and Davis GE (2011) VEGF and FGF prime vascular tube morphogenesis and sprouting directed by hematopoietic stem cell cytokines. Blood 117:3709–3719.
204. Sun B, Zhang D, Zhang S, Zhang W, Guo H, and Zhao X (2007) Hypoxia influences vasculogenic mimicry channel formation and tumor invasion-related protein expression in melanoma. Cancer Lett 249:188–197.
205. Sun X, Cheng G, Hao M, Zheng J, Zhou X, Zhang J, Taichman RS, Pienta KJ, and Wang J (2010) CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression. Cancer Metastasis Rev 29:709–722.
206. Teicher BA and Ellis LM (2008) Antiangiogenic Agents in Cancer Therapy, Humana Press Totowa, NJ
207. Thijssen VL and Griffioen AW (2014) Galectin-1 and galectin-9 in angiogenesis; A sweet couple. Glycobiology 24:915–920.
208. Thijssen VL, Barkan B, Shoji H, Aries IM, Mathieu V, Deltour L, Hackeng TM, Kiss R, Kloog Y, Poirier F, et al. (2010) Tumor cells secrete galectin-1 to enhance endothelial cell activity. Cancer Res 70:6216–6224.
209. Thijssen VL, Hulsmans S, and Griffioen AW (2008) The galectin profile of the endothelium: altered expression and localization in activated and tumor endothelial cells. Am J Pathol 172:545–553.
210. Thijssen VL, Poirier F, Baum LG, and Griffioen AW (2007) Galectins in the tumor endothelium: opportunities for combined cancer therapy. Blood 110:2819–2827.
211. Thijssen VL, Postel R, Brandwijk RJ, Dings RP, Nesmelova I, Satijn S, Verhofstad N, Nakabeppu Y, Baum LG, Bakkers J, et al. (2006) Galectin-1 is essential in tumor angiogenesis and is a target for antiangiogenesis therapy. Proc Natl Acad Sci USA 103:15975–15980.
212. Thijssen VL, Rabinovich GA, and Griffioen AW (2013) Vascular galectins: regulators of tumor progression and targets for cancer therapy. Cytokine Growth Factor Rev 24:547–558.
213. Thomas M, Kienast Y, Scheuer W, Bähner M, Kaluza K, Gassner C, Herting F, Brinkmann U, Seeber S, Kavlie A, et al. (2013) A novel angiopoietin-2 selective fully human antibody with potent anti-tumoral and anti-angiogenic efficacy and superior side effect profile compared to Pan-Angiopoietin-1/-2 inhibitors. PLoS ONE 8:e54923.
214. Topczewska JM, Postovit LM, Margaryan NV, Sam A, Hess AR, Wheaton WW, Nickoloff BJ, Topczewski J, and Hendrix MJ (2006) Embryonic and tumorigenic pathways converge via Nodal signaling: role in melanoma aggressiveness. Nat Med 12:925–932.
215. Turner N and Grose R (2010) Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 10:116–129
216. van Beijnum JR and Griffioen AW (2005) In silico analysis of angiogenesis associated gene expression identifies angiogenic stage related profiles. Biochim Biophys Acta 1755:121–134
217. van Beijnum JR, Nowak-Sliwinska P, van den Boezem E, Hautvast P, Buurman WA, and Griffioen AW (2013) Tumor angiogenesis is enforced by autocrine regulation of high-mobility group box 1. Oncogene 32:363–374.
218. van der Schaft DW, Hillen F, Pauwels P, Kirschmann DA, Castermans K, Egbrink MG, Tran MG, Sciot R, Hauben E, Hogendoorn PC, et al. (2005) Tumor cell plasticity in Ewing sarcoma, an alternative circulatory system stimulated by hypoxia. Cancer Res 65:11520–11528.
219. van der Schaft DW, Seftor RE, Seftor EA, Hess AR, Gruman LM, Kirschmann DA, Yokoyama Y, Griffioen AW, and Hendrix MJ (2004) Effects of angiogenesis inhibitors on vascular network formation by human endothelial and melanoma cells. J Natl Cancer Inst 96:1473–1477.
220. van der Veldt AA, Eechoute K, Gelderblom H, Gietema J, Guchelaar HJ, van Erp NP, van den Eertwegh AJ, Haanen JB, Mathijssen RH, and Wessels JA (2011) Genetic polymorphisms associated with a prolonged progression-free survival in patients with metastatic renal cell cancer treated with sunitinib. Clin Cancer Res 17:620–629.
221. van Meeteren LA, Thorikay M, Bergqvist S, Pardali E, Stampino CG, Hu-Lowe D, Goumans MJ, and ten Dijke P (2012) Anti-human activin receptor-like kinase 1 (ALK1) antibody attenuates bone morphogenetic protein 9 (BMP9)-induced ALK1 signaling and interferes with endothelial cell sprouting. J BiolChem 287: 18551–18561.
222. van Wijk XM, Thijssen VL, Lawrence R, van den Broek SA, Dona M, Naidu N, Oosterhof A, van de Westerlo EM, Kusters LJ, Khaled Y, et al. (2013) Interfering with UDP-GlcNAc metabolism and heparan sulfate expression using a sugar analogue reduces angiogenesis. ACS Chem Biol 8:2331–2338.
223. Vasudev NS and Reynolds AR (2014) Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions. Angiogenesis 17:471–494.
224. Venneri MA, De Palma M, Ponzoni M, Pucci F, Scielzo C, Zonari E, Mazzieri R, Doglioni C, and Naldini L (2007) Identification of proangiogenic TIE2-expressing monocytes (TEMs) in human peripheral blood and cancer. Blood 109:5276–5285.
225. Vinores SA, Seo MS, Okamoto N, Ash JD, Wawrousek EF, Xiao WH, Hudish T, Derevjanik NL, and Campochiaro PA (2000) Experimental models of growth factormediated angiogenesis and blood-retinal barrier breakdown. Gen Pharmacol 35: 233–239.
226. Wang L, Park H, Chhim S, Ding Y, Jiang W, Queen C, and Kim KJ (2012) A novel monoclonal antibody to fibroblast growth factor 2 effectively inhibits growth of hepatocellular carcinoma xenografts. Mol Cancer Ther 11:864–872.
227. Weis SM and Cheresh DA (2011) Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med 17:1359–1370.
228. Welti JC, Powles T, Foo S, Gourlaouen M, Preece N, Foster J, Frentzas S, Bird D, Sharpe K, van Weverwijk A, et al. (2012) Contrasting effects of sunitinib within in vivo models of metastasis. Angiogenesis 15:623–641.
229. Willett CG, Boucher Y, Duda DG, di Tomaso E, Munn LL, Tong RT, Kozin SV, Petit L, Jain RK, Chung DC, et al. (2005) Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: continued experience of a phase I trial in rectal cancer patients. J Clin Oncol 23: 8136–8139.
230. Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, Xu L, Hicklin DJ, Fukumura D, di Tomaso E, et al. (2004) Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6:553–563.
231. Woolard J, Wang WY, Bevan HS, Qiu Y, Morbidelli L, Pritchard-Jones RO, Cui TG, Sugiono M, Waine E, Perrin R, et al. (2004) VEGF165b, an inhibitory vascular endothelial growth factor splice variant: mechanism of action, in vivo effect on angiogenesis and endogenous protein expression. Cancer Res 64:7822–7835.
232. Würdinger T, Tannous BA, Saydam O, Skog J, Grau S, Soutschek J, Weissleder R, Breakefield XO, and Krichevsky AM (2008) miR-296 regulates growth factor receptor overexpression in angiogenic endothelial cells. Cancer Cell 14:382–393.
233. Xian X, Håkansson J, Ståhlberg A, Lindblom P, Betsholtz C, Gerhardt H, and Semb H (2006) Pericytes limit tumor cell metastasis. J Clin Invest 116:642–651.
234. Xu CS, Wang ZF, Dai LM, Chu SH, Gong LL, Yang MH, and Li ZQ (2014) Induction of proline-rich tyrosine kinase 2 activation-mediated C6 glioma cell invasion after anti-vascular endothelial growth factor therapy. J Transl Med 12:148.
235. Xu Y, Li Q, Li XY, Yang QY, Xu WW, and Liu GL (2012) Short-term anti-vascular endothelial growth factor treatment elicits vasculogenic mimicry formation of tumors to accelerate metastasis. J Exp Clin Cancer Res 31:16.
236. Yan X, Cai S, Xiong X, Sun W, Dai X, Chen S, Ye Q, Song Z, Jiang Q, and Xu Z (2012) Chemokine receptor CXCR7 mediates human endothelial progenitor cells survival, angiogenesis, but not proliferation. J Cell Biochem 113:1437–1446.
237. Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, and Weinberg RA (2004a) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117:927–939.
238. Yang L, DeBusk LM, Fukuda K, Fingleton B, Green-Jarvis B, Shyr Y, Matrisian LM, Carbone DP, and Lin PC (2004b) Expansion of myeloid immune suppressor Gr +CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 6:409–421.
239. Yayon A, Klagsbrun M, Esko JD, Leder P, and Ornitz DM (1991) Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell 64:841–848.
240. Zagzag D, Lukyanov Y, Lan L, Ali MA, Esencay M, Mendez O, Yee H, Voura EB, and Newcomb EW (2006) Hypoxia-inducible factor 1 and VEGF upregulate CXCR4 in glioblastoma: implications for angiogenesis and glioma cell invasion. Lab Invest 86:1221–1232.
241. Zhong C, Qu X, Tan M, Meng YG, and Ferrara N (2009) Characterization and regulation of bv8 in human blood cells. Clin Cancer Res 15:2675–2684.
242. Zhu AX, Sahani DV, Duda DG, di Tomaso E, Ancukiewicz M, Catalano OA, Sindhwani V, Blaszkowsky LS, Yoon SS, Lahdenranta J, et al. (2009) Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study. J Clin Oncol 27:3027–3035.