Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions

Naveen S. Vasudev1, Andrew R. Reynolds1
1Tumour Biology Team, Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, Fulham Road, London, SW3 6JB, UK

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Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285(21):1182–1186

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

Leite de Oliveira R, Hamm A, Mazzone M (2011) Growing tumor vessels: more than one way to skin a cat—implications for angiogenesis targeted cancer therapies. Mol Aspects Med 32(2):71–87

Ellis LM, Hicklin DJ (2008) VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer 8(8):579–591

Kerbel RS (2008) Tumor angiogenesis. N Engl J Med 358(19):2039–2049

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

Carmeliet P et al (2009) Branching morphogenesis and antiangiogenesis candidates: tip cells lead the way. Nat Rev Clin Oncol 6(6):315–326

Olsson AK et al (2006) VEGF receptor signalling—in control of vascular function. Nat Rev Mol Cell Biol 7(5):359–371

Escudier B et al (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356(2):125–134

Escudier B et al (2009) Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol 27(20):3312–3318

Motzer RJ et al (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356(2):115–124

Motzer RJ 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

Sternberg CN et al (2010) Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 28(6):1061–1068

Sternberg CN et al (2013) A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer 49(6):1287–1296

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

Rini BI et al (2011) Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 378(9807):1931–1939

Llovet JM et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359(4):378–390

Raymond E et al (2011) Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 364(6):501–513

Hurwitz H et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350(23):2335–2342

Giantonio BJ et al (2007) Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25(12):1539–1544

Saltz LB et al (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26(12):2013–2019

Cunningham D et al (2013) Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol 14(11):1077–1085

Fischer C et al (2008) FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy? Nat Rev Cancer 8(12):942–956

Li X et al (2009) VEGF-B: a survival, or an angiogenic factor? Cell Adh Migr 3(4):322–327

Zhang F et al (2009) VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis. Proc Natl Acad Sci USA 106(15):6152–6157

Fischer C et al (2007) Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131(3):463–475

Van Cutsem E et al (2012) Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 30(28):3499–3506

Carrato A et al (2013) Fluorouracil, leucovorin, and irinotecan plus either sunitinib or placebo in metastatic colorectal cancer: a randomized, phase III trial. J Clin Oncol 31(10):1341–1347

Hecht JR et al (2011) Randomized, placebo-controlled, phase III study of first-line oxaliplatin-based chemotherapy plus PTK787/ZK 222584, an oral vascular endothelial growth factor receptor inhibitor, in patients with metastatic colorectal adenocarcinoma. J Clin Oncol 29(15):1997–2003

Van Cutsem E et al (2011) Randomized, placebo-controlled, phase III study of oxaliplatin, fluorouracil, and leucovorin with or without PTK787/ZK 222584 in patients with previously treated metastatic colorectal adenocarcinoma. J Clin Oncol 29(15):2004–2010

Grothey 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

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

Reck M et al (2009) Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 27(8):1227–1234

Reck M 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

Soria JC 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

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

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

Aghajanian C 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

Miller KD et al (2005) Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23(4):792–799

Miller K et al (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357(26):2666–2676

Miles DW et al (2010) Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 28(20):3239–3247

Robert NJ et al (2011) RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol 29(10):1252–1260

Brufsky AM et al (2011) RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 29(32):4286–4293

Crown JP et al (2013) Phase III trial of sunitinib in combination with capecitabine versus capecitabine monotherapy for the treatment of patients with pretreated metastatic breast cancer. J Clin Oncol 31(23):2870–2878

Bergh J et al (2012) First-line treatment of advanced breast cancer with sunitinib in combination with docetaxel versus docetaxel alone: results of a prospective, randomized phase III study. J Clin Oncol 30(9):921–929

Robert NJ et al (2011) Sunitinib plus paclitaxel versus bevacizumab plus paclitaxel for first-line treatment of patients with advanced breast cancer: a phase III, randomized, open-label trial. Clin Breast Cancer 11(2):82–92

Barrios CH et al (2010) Phase III randomized trial of sunitinib versus capecitabine in patients with previously treated HER2-negative advanced breast cancer. Breast Cancer Res Treat 121(1):121–131

Kim KB et al (2012) BEAM: a randomized phase II study evaluating the activity of bevacizumab in combination with carboplatin plus paclitaxel in patients with previously untreated advanced melanoma. J Clin Oncol 30(1):34–41

Flaherty KT et al (2013) Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. J Clin Oncol 31(3):373–379

Hauschild A et al (2009) Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol 27(17):2823–2830

Kindler HL et al (2010) Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol 28(22):3617–3622

Kelly WK et al (2012) Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J Clin Oncol 30(13):1534–1540

Tannock IF et al (2013) Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial. Lancet Oncol 14(8):760–768

Ebos JM, Kerbel RS (2011) Antiangiogenic therapy: impact on invasion, disease progression, and metastasis. Nat Rev Clin Oncol 8(4):210–221

Allegra CJ et al (2011) Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol 29(1):11–16

Allegra CJ et al (2013) 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

de Gramont A et al (2012) Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol 13(12):1225–1233

Cameron D, et al. (2012) Primary results of BEATRICE, a randomized phase III trial evaluating adjuvant bevacizumab-containing therapy in triple-negative breast cancer. San Antonio Breast Cancer Symposium (SABCS), (Abstract S6-5)

Alberts SR et al (2012) Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial. JAMA 307(13):1383–1393

Porschen R et al (2001) Fluorouracil plus leucovorin as effective adjuvant chemotherapy in curatively resected stage III colon cancer: results of the trial adjCCA-01. J Clin Oncol 19(6):1787–1794

Andre T et al (2004) Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350(23):2343–2351

Van Cutsem E et al (2009) Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol 27(19):3117–3125

Bear HD et al (2012) Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med 366(4):310–320

von Minckwitz G et al (2012) Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med 366(4):299–309

Grunhagen D et al (2013) The history of adoption of hepatic resection for metastatic colorectal cancer: 1984–95. Crit Rev Oncol Hematol 86(3):222–231

Nordlinger B et al (2009) Combination of surgery and chemotherapy and the role of targeted agents in the treatment of patients with colorectal liver metastases: recommendations from an expert panel. Ann Oncol 20(6):985–992

Wong R et al (2011) A multicentre study of capecitabine, oxaliplatin plus bevacizumab as perioperative treatment of patients with poor-risk colorectal liver-only metastases not selected for upfront resection. Ann Oncol 22(9):2042–2048

Gruenberger T, Arnold D, Rubbia-Brandt L (2012) Pathologic response to bevacizumab-containing chemotherapy in patients with colorectal liver metastases and its correlation with survival. Surg Oncol 21(4):309–315

Loupakis F et al (2013) Histopathologic evaluation of liver metastases from colorectal cancer in patients treated with FOLFOXIRI plus bevacizumab. Br J Cancer 108(12):2549–2556

Kaye SB (2007) Bevacizumab for the treatment of epithelial ovarian cancer: will this be its finest hour? J Clin Oncol 25(33):5150–5152

Jain RK (2001) Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 7(9):987–989

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

Van der Veldt AA et al (2012) 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

Kamoun WS et al (2009) Edema control by cediranib, a vascular endothelial growth factor receptor-targeted kinase inhibitor, prolongs survival despite persistent brain tumor growth in mice. J Clin Oncol 27(15):2542–2552

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

Shaked Y et al (2008) Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell 14(3):263–273

Alishekevitz D, et al. (2013) Differential therapeutic effects of anti-VEGF-A antibody in different tumor models: implications for choosing appropriate tumor models for drug testing. Mol Cancer Ther 13(1):202–13

Smith NR, et al. (2013) Tumour-stromal architecture can define the intrinsic tumour response to VEGF-targeted therapy. Clin Cancer Res 19(24):6943–56

Rugo HS (2012) Inhibiting angiogenesis in breast cancer: the beginning of the end or the end of the beginning? J Clin Oncol 30(9):898–901

Rossari JR et al (2012) Bevacizumab and breast cancer: a meta-analysis of first-line phase III studies and a critical reappraisal of available evidence. J Oncol 2012:417673

Chen HX, Cleck JN (2009) Adverse effects of anticancer agents that target the VEGF pathway. Nat Rev Clin Oncol 6(8):465–477

Hutson TE et al (2008) Targeted therapies for metastatic renal cell carcinoma: an overview of toxicity and dosing strategies. Oncologist 13(10):1084–1096

Dienstmann R et al (2011) Toxicity as a biomarker of efficacy of molecular targeted therapies: focus on EGFR and VEGF inhibiting anticancer drugs. Oncologist 16(12):1729–1740

Schuster C et al (2012) Clinical efficacy and safety of bevacizumab monotherapy in patients with metastatic melanoma: predictive importance of induced early hypertension. PLoS ONE 7(6):e38364

Rini BI et al (2011) Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 103(9):763–773

Osterlund P et al (2011) Hypertension and overall survival in metastatic colorectal cancer patients treated with bevacizumab-containing chemotherapy. Br J Cancer 104(4):599–604

Mancuso MR et al (2006) Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest 116(10):2610–2621

Griffioen AW et al (2012) Rapid angiogenesis onset after discontinuation of sunitinib treatment of renal cell carcinoma patients. Clin Cancer Res 18(14):3961–3971

Wolter P et al (2009) Flare-up: an often unreported phenomenon nevertheless familiar to oncologists prescribing tyrosine kinase inhibitors. Acta Oncol 48(4):621–624

Desar IM et al (2009) The reverse side of the victory: flare up of symptoms after discontinuation of sunitinib or sorafenib in renal cell cancer patients. A report of three cases. Acta Oncol 48(6):927–931

Grothey A et al (2008) Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (BRiTE). J Clin Oncol 26(33):5326–5334

Bennouna J 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

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

Rini BI et al (2008) Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma. J Clin Oncol 26(22):3743–3748

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

Zama IN et al (2010) Sunitinib rechallenge in metastatic renal cell carcinoma patients. Cancer 116(23):5400–5406

Kuczynski EA et al (2013) Drug rechallenge and treatment beyond progression–implications for drug resistance. Nat Rev Clin Oncol 10(10):571–587

Tang TC et al (2010) Development of a resistance-like phenotype to sorafenib by human hepatocellular carcinoma cells is reversible and can be delayed by metronomic UFT chemotherapy. Neoplasia 12(11):928–940

Zhang L et al (2011) Resistance of renal cell carcinoma to sorafenib is mediated by potentially reversible gene expression. PLoS ONE 6(4):e19144

Jayson GC, Hicklin DJ, Ellis LM (2012) Antiangiogenic therapy—evolving view based on clinical trial results. Nat Rev Clin Oncol 9(5):297–303

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

Jubb AM, Harris AL (2010) Biomarkers to predict the clinical efficacy of bevacizumab in cancer. Lancet Oncol 11(12):1172–1183

Hegde PS et al (2013) Predictive impact of circulating vascular endothelial growth factor in four phase III trials evaluating bevacizumab. Clin Cancer Res 19(4):929–937

Gianni L et al (2013) AVEREL: a randomized phase III Trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer. J Clin Oncol 31(14):1719–1725

Miles DW et al (2013) Biomarker results from the AVADO phase 3 trial of first-line bevacizumab plus docetaxel for HER2-negative metastatic breast cancer. Br J Cancer 108(5):1052–1060

Van Cutsem E et al (2012) Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial. J Clin Oncol 30(17):2119–2127

Tran HT et al (2012) Prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell cancer: a retrospective analysis of phase 2 and phase 3 trials. Lancet Oncol 13(8):827–837

Collinson F et al (2013) Predicting response to bevacizumab in ovarian cancer: a panel of potential biomarkers informing treatment selection. Clin Cancer Res 19(18):5227–5239

Maru D, Venook AP, Ellis LM (2013) Predictive biomarkers for bevacizumab: are we there yet? Clin Cancer Res 19(11):2824–2827

Lambrechts D 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(7):724–733

Beuselinck B, et al. (2013) VEGFR1 single nucleotide polymorphisms associated with outcome in patients with metastatic renal cell carcinoma treated with sunitinib—a multicentric retrospective analysis. Acta Oncol 53(1):103–12

O’Connor JP, GC Jayson (2012) Do imaging biomarkers relate to outcome in patients treated with VEGF inhibitors? Clin Cancer Res 18(24):6588–98

Hahn OM et al (2008) Dynamic contrast-enhanced magnetic resonance imaging pharmacodynamic biomarker study of sorafenib in metastatic renal carcinoma. J Clin Oncol 26(28):4572–4578

Flaherty KT et al (2008) Pilot study of DCE-MRI to predict progression-free survival with sorafenib therapy in renal cell carcinoma. Cancer Biol Ther 7(4):496–501

Han KS et al (2010) Pretreatment assessment of tumor enhancement on contrast-enhanced computed tomography as a potential predictor of treatment outcome in metastatic renal cell carcinoma patients receiving antiangiogenic therapy. Cancer 116(10):2332–2342

Fournier LS et al (2010) Metastatic renal carcinoma: evaluation of antiangiogenic therapy with dynamic contrast-enhanced CT. Radiology 256(2):511–518

Smith AD, et al. (2011) Utilizing pre-therapy clinical schema and initial CT changes to predict progression-free survival in patients with metastatic renal cell carcinoma on VEGF-targeted therapy: A preliminary analysis. Urol Oncol (7):1283–91

Nathan PD et al (2010) CT response assessment combining reduction in both size and arterial phase density correlates with time to progression in metastatic renal cancer patients treated with targeted therapies. Cancer Biol Ther 9(1):15–19

van der Veldt AA et al (2010) Choi response criteria for early prediction of clinical outcome in patients with metastatic renal cell cancer treated with sunitinib. Br J Cancer 102(5):803–809

Krajewski KM et al (2011) Comparison of four early posttherapy imaging changes (EPTIC; RECIST 1.0, tumor shrinkage, computed tomography tumordensity, Choi criteria) in assessing outcome to vascular endothelial growth factor targeted therapy in patients with advanced renal cell carcinoma. Eur Urol 59:856–62

Smith AD et al (2010) Morphology, Attenuation, Size, and Structure (MASS) criteria: assessing response and predicting clinical outcome in metastatic renal cell carcinoma on antiangiogenic targeted therapy. AJR Am J Roentgenol 194(6):1470–1478

Smith AD, Lieber ML, Shah SN (2010) Assessing tumor response and detecting recurrence in metastatic renal cell carcinoma on targeted therapy: importance of size and attenuation on contrast-enhanced CT. AJR Am J Roentgenol 194(1):157–165

Vasudev NS et al (2013) Changes in tumour vessel density upon treatment with anti-angiogenic agents: relationship with response and resistance to therapy. Br J Cancer 109(5):1230–1242

Chun YS et al (2009) Association of computed tomography morphologic criteria with pathologic response and survival in patients treated with bevacizumab for colorectal liver metastases. JAMA 302(21):2338–2344

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

Sitohy B, Nagy JA, Dvorak HF (2012) Anti-VEGF/VEGFR therapy for cancer: reassessing the target. Cancer Res 72(8):1909–1914

Helfrich I et al (2010) Resistance to antiangiogenic therapy is directed by vascular phenotype, vessel stabilization, and maturation in malignant melanoma. J Exp Med 207(3):491–503

Bergers G et al (2003) Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 111(9):1287–1295

Erber R et al (2004) Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J 18(2):338–340

Welti JC et al (2012) Contrasting effects of sunitinib within in vivo models of metastasis. Angiogenesis 15(4):623–641

Tong RT et al (2004) Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res 64(11):3731–3736

Shaheen RM et al (2001) Tyrosine kinase inhibition of multiple angiogenic growth factor receptors improves survival in mice bearing colon cancer liver metastases by inhibition of endothelial cell survival mechanisms. Cancer Res 61(4):1464–1468

Winkler F 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(6):553–563

Shojaei F et al (2007) Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature 450(7171):825–831

Cascone T et al (2011) Upregulated stromal EGFR and vascular remodeling in mouse xenograft models of angiogenesis inhibitor-resistant human lung adenocarcinoma. J Clin Invest 121(4):1313–1328

Li JL et al (2011) DLL4-Notch signaling mediates tumor resistance to anti-VEGF therapy in vivo. Cancer Res 71(18):6073–6083

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

Welti JC et al (2011) Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib. Oncogene 30(10):1183–1193

Shojaei F et al (2010) HGF/c-Met acts as an alternative angiogenic pathway in sunitinib-resistant tumors. Cancer Res 70(24):10090–10100

Huang D et al (2010) Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma. Cancer Res 70(3):1063–1071

Crawford Y 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

di Tomaso E et al (2009) PDGF-C induces maturation of blood vessels in a model of glioblastoma and attenuates the response to anti-VEGF treatment. PLoS ONE 4(4):e5123

Kopetz 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(3):453–459

Porta C et al (2012) Changes in circulating pro-angiogenic cytokines, other than VEGF, before progression to sunitinib therapy in advanced renal cell carcinoma patients. Oncology 84(2):115–122

Johnson PJ et al (2013) Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J Clin Oncol 31(28):3517–3524

Llovet JM 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

Motzer R (2013) Phase 3 trial of dovitinib vs sorafenib in patients with metastatic renal cell carcinoma after 1 prior VEGF pathway-targeted and 1 prior mTOR inhibitor therapy. Presented at European cancer congress 2013; September 27–October 1, 2013; Amsterdam, The Netherlands. Abstract LBA34)

Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6(5):392–401

Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420(6917):860–867

De Palma M, Lewis CE (2013) Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell 23(3):277–286

De Palma M, Naldini L (2006) Role of haematopoietic cells and endothelial progenitors in tumour angiogenesis. Biochim Biophys Acta 1766(1):159–166

Bissell MJ, Radisky D (2001) Putting tumours in context. Nat Rev Cancer 1(1):46–54

Joyce JA, Pollard JW (2009) Microenvironmental regulation of metastasis. Nat Rev Cancer 9(4):239–252

Ebos JM, Lee CR, Kerbel RS (2009) Tumor and host-mediated pathways of resistance and disease progression in response to antiangiogenic therapy. Clin Cancer Res 15(16):5020–5025

Shojaei F et al (2008) Role of myeloid cells in tumor angiogenesis and growth. Trends Cell Biol 18(8):372–378

McMillin DW, Negri JM, Mitsiades CS (2013) The role of tumour-stromal interactions in modifying drug response: challenges and opportunities. Nat Rev Drug Discov 12(3):217–228

Reynolds AR (2010) Potential relevance of bell-shaped and u-shaped dose-responses for the therapeutic targeting of angiogenesis in cancer. Dose Response 8(3):253–284

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

Chung AS et al (2013) An interleukin-17-mediated paracrine network promotes tumor resistance to anti-angiogenic therapy. Nat Med 19(9):1114–1123

Shaked Y et al (2006) Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science 313(5794):1785–1787

Lyden D 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

Yang L et al (2004) Expansion of myeloid immune suppressor Gr+ CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 6(4):409–421

Bailey AS et al (2006) Myeloid lineage progenitors give rise to vascular endothelium. Proc Natl Acad Sci USA 103(35):13156–13161

Yu JL et al (2002) Effect of p53 status on tumor response to antiangiogenic therapy. Science 295(5559):1526–1528

Yu JL et al (2001) Heterogeneous vascular dependence of tumor cell populations. Am J Pathol 158(4):1325–1334

McIntyre A et al (2012) Carbonic anhydrase IX promotes tumor growth and necrosis in vivo and inhibition enhances anti-VEGF therapy. Clin Cancer Res 18(11):3100–3111

Nardo G et al (2011) Glycolytic phenotype and AMP kinase modify the pathologic response of tumor xenografts to VEGF neutralization. Cancer Res 71(12):4214–4225

Hu YL et al (2012) Hypoxia-induced autophagy promotes tumor cell survival and adaptation to antiangiogenic treatment in glioblastoma. Cancer Res 72(7):1773–1783

Rapisarda A, Melillo G (2012) Overcoming disappointing results with antiangiogenic therapy by targeting hypoxia. Nat Rev Clin Oncol 9(7):378–390

Xu J et al (2013) Colorectal cancer cells refractory to anti-VEGF treatment are vulnerable to glycolytic blockade due to persistent impairment of mitochondria. Mol Cancer Ther 12(5):717–724

Rak J et al (2002) What do oncogenic mutations have to do with angiogenesis/vascular dependence of tumors? Cancer Res 62(7):1931–1934

Dome B et al (2007) Alternative vascularization mechanisms in cancer: pathology and therapeutic implications. Am J Pathol 170(1):1–15

Donnem T et al (2013) Vessel co-option in primary human tumors and metastases: an obstacle to effective anti-angiogenic treatment? Cancer Med 2(4):427–436

Ribatti D et al (2005) Microvascular density, vascular endothelial growth factor immunoreactivity in tumor cells, vessel diameter and intussusceptive microvascular growth in primary melanoma. Oncol Rep 14(1):81–84

Nico B et al (2010) Intussusceptive microvascular growth in human glioma. Clin Exp Med 10(2):93–98

Straume O et al (2002) Prognostic importance of glomeruloid microvascular proliferation indicates an aggressive angiogenic phenotype in human cancers. Cancer Res 62(23):6808–6811

Folberg R, Maniotis AJ (2004) Vasculogenic mimicry. APMIS 112(7–8):508–525

Wang R et al (2010) Glioblastoma stem-like cells give rise to tumour endothelium. Nature 468(7325):829–833

Ricci-Vitiani L et al (2010) Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 468(7325):824–828

Cheng L et al (2013) Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell 153(1):139–152

Kilarski WW et al (2009) Biomechanical regulation of blood vessel growth during tissue vascularization. Nat Med 15(6):657–664

di Tomaso E et al (2011) Glioblastoma recurrence after cediranib therapy in patients: lack of “rebound” revascularization as mode of escape. Cancer Res 71(1):19–28

de Groot JF et al (2010) Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice. Neuro Oncol 12(3):233–242

Pezzella F et al (1997) Non-small-cell lung carcinoma tumor growth without morphological evidence of neo-angiogenesis. Am J Pathol 151(5):1417–1423

Yousem SA (2009) Peripheral squamous cell carcinoma of lung: patterns of growth with particular focus on airspace filling. Hum Pathol 40(6):861–867

Dome B et al (2002) Vascularization of cutaneous melanoma involves vessel co-option and has clinical significance. J Pathol 197(3):355–362

Sardari Nia P et al (2007) Distinct angiogenic and non-angiogenic growth patterns of lung metastases from renal cell carcinoma. Histopathology 51(3):354–361

Pezzella F et al (1996) Angiogenesis in primary lung cancer and lung secondaries. Eur J Cancer 32A(14):2494–2500

Pezzella F et al (2000) Evidence for novel non-angiogenic pathway in breast-cancer metastasis. Breast cancer progression working party. Lancet 355(9217):1787–1788

Vermeulen PB et al (2001) Liver metastases from colorectal adenocarcinomas grow in three patterns with different angiogenesis and desmoplasia. J Pathol 195(3):336–342

Stessels F et al (2004) Breast adenocarcinoma liver metastases, in contrast to colorectal cancer liver metastases, display a non-angiogenic growth pattern that preserves the stroma and lacks hypoxia. Br J Cancer 90(7):1429–1436

Carbonell WS et al (2009) The vascular basement membrane as “soil” in brain metastasis. PLoS ONE 4(6):e5857

Hlushchuk R et al (2008) Tumor recovery by angiogenic switch from sprouting to intussusceptive angiogenesis after treatment with PTK787/ZK222584 or ionizing radiation. Am J Pathol 173(4):1173–1185

Leenders WP et al (2004) Antiangiogenic therapy of cerebral melanoma metastases results in sustained tumor progression via vessel co-option. Clin Cancer Res 10(18 Pt 1):6222–6230

Rubenstein JL et al (2000) Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption. Neoplasia 2(4):306–314

Paez-Ribes M et al (2009) Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15(3):220–231

Winkler F et al (2009) Imaging glioma cell invasion in vivo reveals mechanisms of dissemination and peritumoral angiogenesis. Glia 57(12):1306–1315

Keunen O et al (2011) Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma. Proc Natl Acad Sci USA 108(9):3749–3754

Cooke VG et al (2012) Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway. Cancer Cell 21(1):66–81

Sennino B 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(3):270–287

Lu KV et al (2012) VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer Cell 22(1):21–35

Ebos JM et al (2009) Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15(3):232–239

Singh M et al (2012) Anti-VEGF antibody therapy does not promote metastasis in genetically engineered mouse tumour models. J Pathol 227(4):417–430

Chung AS et al (2012) Differential drug class-specific metastatic effects following treatment with a panel of angiogenesis inhibitors. J Pathol 227(4):404–416

Blagoev KB et al (2013) Sunitinib does not accelerate tumor growth in patients with metastatic renal cell carcinoma. Cell Rep 3(2):277–281

Powles T et al (2013) A prospective evaluation of VEGF-targeted treatment cessation in metastatic clear cell renal cancer. Ann Oncol 24(8):2098–2103

Sharpe K, et al. (2013) The effect of VEGF targeted therapy on biomarker expression in sequential tissue from patients with metastatic clear cell renal cancer. Clin Cancer Res 19(24):6924–34

Miles D et al (2011) Disease course patterns after discontinuation of bevacizumab: pooled analysis of randomized phase III trials. J Clin Oncol 29(1):83–88

Norden AD et al (2008) Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology 70(10):779–787

Ellis LM, Reardon DA (2009) Cancer: the nuances of therapy. Nature 458(7236):290–292

Loges S et al (2009) Silencing or fueling metastasis with VEGF inhibitors: antiangiogenesis revisited. Cancer Cell 15(3):167–170

Fan F et al (2011) Chronic exposure of colorectal cancer cells to bevacizumab promotes compensatory pathways that mediate tumour cell migration. Br J Cancer 104(8):1270–1277

Hammers HJ et al (2010) Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma: evidence from a xenograft study. Mol Cancer Ther 9(6):1525–1535

Ebos JM et al (2007) Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proc Natl Acad Sci USA 104(43):17069–17074

Zhu XD et al (2013) Antiangiogenic therapy promoted metastasis of hepatocellular carcinoma by suppressing host-derived interleukin-12b in mouse models. Angiogenesis 16(4):809–820

Xian X et al (2006) Pericytes limit tumor cell metastasis. J Clin Invest 116(3):642–651

Anderberg C et al (2013) Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination. J Exp Med 210(3):563–579

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

Gabrilovich DI et al (1996) Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 2(10):1096–1103

Stockmann C et al (2008) Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature 456(7223):814–818

Oosthuyse B et al (2001) Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet 28(2):131–138

Greenberg JI et al (2008) A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature 456(7223):809–813

Wedam SB et al (2006) Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J Clin Oncol 24(5):769–777

Fan F et al (2005) Expression and function of vascular endothelial growth factor receptor-1 on human colorectal cancer cells. Oncogene 24(16):2647–2653

Dales JP et al (2003) Prognostic significance of VEGF receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1) in breast carcinoma. Ann Pathol 23(4):297–305

Guo P et al (2003) Overexpression of vascular endothelial growth factor by MCF-7 breast cancer cells promotes estrogen-independent tumor growth in vivo. Cancer Res 63(15):4684–4691

Spannuth WA et al (2009) Functional significance of VEGFR-2 on ovarian cancer cells. Int J Cancer 124(5):1045–1053

Wey JS et al (2005) Vascular endothelial growth factor receptor-1 promotes migration and invasion in pancreatic carcinoma cell lines. Cancer 104(2):427–438

Barr MP, Bouchier-Hayes DJ, Harmey JJ (2008) Vascular endothelial growth factor is an autocrine survival factor for breast tumour cells under hypoxia. Int J Oncol 32(1):41–48

Hodivala-Dilke KM, Reynolds AR, Reynolds LE (2003) Integrins in angiogenesis: multitalented molecules in a balancing act. Cell Tissue Res 314(1):131–144

Koch S et al (2011) Signal transduction by vascular endothelial growth factor receptors. Biochem J 437(2):169–183

Raimondi C, Ruhrberg C (2013) Neuropilin signalling in vessels, neurons and tumours. Semin Cell Dev Biol 24(3):172–178

Tugues S et al (2011) Vascular endothelial growth factors and receptors: anti-angiogenic therapy in the treatment of cancer. Mol Aspects Med 32(2):88–111

Van de Veire S et al (2010) Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease. Cell 141(1):178–190

Bais C et al (2010) PlGF blockade does not inhibit angiogenesis during primary tumor growth. Cell 141(1):166–177

Pan Q et al (2007) Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth. Cancer Cell 11(1):53–67

Jiang T et al (2012) CD146 is a coreceptor for VEGFR-2 in tumor angiogenesis. Blood 120(11):2330–2339

Carmeliet P, Jain RK (2011) Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov 10(6):417–427

Rathmell WK, Chen S (2008) VHL inactivation in renal cell carcinoma: implications for diagnosis, prognosis and treatment. Expert Rev Anticancer Ther 8(1):63–73

Langenkamp E, Molema G (2009) Microvascular endothelial cell heterogeneity: general concepts and pharmacological consequences for anti-angiogenic therapy of cancer. Cell Tissue Res 335(1):205–222

Luzzi KJ et al (1998) Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol 153(3):865–873

Van den Eynden GG et al (2012) The histological growth pattern of colorectal cancer liver metastases has prognostic value. Clin Exp Metastasis 29(6):541–549

Van den Eynden GG et al (2013) The multifaceted role of the microenvironment in liver metastasis: biology and clinical implications. Cancer Res 73(7):2031–2043

Yap TA et al (2012) Intratumor heterogeneity: seeing the wood for the trees. Sci Transl Med 4(127):127ps10

Turner NC, Reis-Filho JS (2012) Genetic heterogeneity and cancer drug resistance. Lancet Oncol 13(4):e178–e185

Guerin E et al (2013) A model of postsurgical advanced metastatic breast cancer more accurately replicates the clinical efficacy of antiangiogenic drugs. Cancer Res 73(9):2743–2748

Shojaei F et al (2008) Role of Bv8 in neutrophil-dependent angiogenesis in a transgenic model of cancer progression. Proc Natl Acad Sci USA 105(7):2640–2645

Hashizume H et al (2010) Complementary actions of inhibitors of angiopoietin-2 and VEGF on tumor angiogenesis and growth. Cancer Res 70(6):2213–2223

Moreno Garcia V et al (2012) Combining antiangiogenics to overcome resistance: rationale and clinical experience. Clin Cancer Res 18(14):3750–3761

Olive KP et al (2009) Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324(5933):1457–1461

Butler JM, Kobayashi H, Rafii S (2010) Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors. Nat Rev Cancer 10(2):138–146

Gilbert LA, Hemann MT (2010) DNA damage-mediated induction of a chemoresistant niche. Cell 143(3):355–366

Lu J et al (2013) Endothelial cells promote the colorectal cancer stem cell phenotype through a soluble form of Jagged-1. Cancer Cell 23(2):171–185