Seminars in Oncology
Volume 36 , Pages S12-S19 , April 2009

Targeting Tumor Angiogenesis

  • Puja Gaur

      Affiliations

    • Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX
  • ,
  • Debashish Bose

      Affiliations

    • Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX
  • ,
  • Shaija Samuel

      Affiliations

    • Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX
  • ,
  • Lee M. Ellis

      Affiliations

    • Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX
    • Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX
    • Corresponding Author InformationAddress correspondence to Lee M. Ellis, MD, The University of Texas M.D. Anderson Cancer Center, Department of Surgical Oncology, Unit 444, PO Box 301402, Houston, TX 77230-1402

References 

  1. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182–1186
  2. Folkman J. What is the evidence that tumors are angiogenesis dependent?. J Natl Cancer Inst. 1990;82:4–6
  3. Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983;219:983–985
  4. Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, et al. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science. 1989;246:1309–1312
  5. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246:1306–1309
  6. Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 1993;362:841–844
  7. Hurwitz H. Integrating the anti-VEGF-A humanized monoclonal antibody bevacizumab with chemotherapy in advanced colorectal cancer. Clin Colorectal Cancer. 2004;4(Suppl 2):S62–S68
  8. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–2342
  9. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125–134
  10. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–390
  11. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666–2676
  12. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542–2550
  13. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23:1011–1027
  14. Betsholtz C, Karlsson L, Lindahl P. Developmental roles of platelet-derived growth factors. Bioessays. 2001;23:494–507
  15. Dong J, Grunstein J, Tejada M, Peale F, Frantz G, Liang WC, et al. VEGF-null cells require PDGFR alpha signaling-mediated stromal fibroblast recruitment for tumorigenesis. EMBO J. 2004;23:2800–2810
  16. Reinmuth N, Liu W, Jung YD, Ahmad SA, Shaheen RM, Fan F, et al. Induction of VEGF in perivascular cells defines a potential paracrine mechanism for endothelial cell survival. FASEB J. 2001;15:1239–1241
  17. Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature. 1996;380:435–439
  18. Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O'Shea KS, et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature. 1996;380:439–442
  19. Akagi M, Kawaguchi M, Liu W, McCarty MF, Takeda A, Fan F, et al. Induction of neuropilin-1 and vascular endothelial growth factor by epidermal growth factor in human gastric cancer cells. Br J Cancer. 2003;88:796–802
  20. Bates RC, Goldsmith JD, Bachelder RE, Brown C, Shibuya M, Oettgen P, et al. Flt-1-dependent survival characterizes the epithelial-mesenchymal transition of colonic organoids. Curr Biol. 2003;13:1721–1727
  21. Duff SE, Jeziorska M, Rosa DD, Kumar S, Haboubi N, Sherlock D, et al. Vascular endothelial growth factors and receptors in colorectal cancer: implications for anti-angiogenic therapy. Eur J Cancer. 2006;42:112–117
  22. Fan F, Wey JS, McCarty MF, Belcheva A, Liu W, Bauer TW, et al. Expression and function of vascular endothelial growth factor receptor-1 on human colorectal cancer cells. Oncogene. 2005;24:2647–2653
  23. Fukahi K, Fukasawa M, Neufeld G, Itakura J, Korc M. Aberrant expression of neuropilin-1 and −2 in human pancreatic cancer cells. Clin Cancer Res. 2004;10:581–590
  24. Van Buren G, Rashid A, Yang AD, Abdalla EK, Gray MJ, Liu W, et al. The development and characterization of a human midgut carcinoid cell line. Clin Cancer Res. 2007;13:4704–4712
  25. Wey JS, Fan F, Gray MJ, Bauer TW, McCarty MF, Somcio R, et al. Vascular endothelial growth factor receptor-1 promotes migration and invasion in pancreatic carcinoma cell lines. Cancer. 2005;104:427–438
  26. Yang AD, Camp ER, Fan F, Shen L, Gray MJ, Liu W, et al. Vascular endothelial growth factor receptor-1 activation mediates epithelial to mesenchymal transition in human pancreatic carcinoma cells. Cancer Res. 2006;66:46–51
  27. Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell. 2007;11:83–95
  28. Goodman VL, Rock EP, Dagher R, Ramchandani RP, Abraham S, Gobburu JV, et al. Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res. 2007;13:1367–1373
  29. Kane RC, Farrell AT, Saber H, Tang S, Williams G, Jee JM, et al. Sorafenib for the treatment of advanced renal cell carcinoma. Clin Cancer Res. 2006;12:7271–7278
  30. Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008;8:592–603
  31. Motzer RJ, Michaelson MD, Rosenberg J, Bukowski RM, Curti BD, George DJ, et al. Sunitinib efficacy against advanced renal cell carcinoma. J Urol. 2007;178:1883–1887
  32. Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer. 2008;8:579–591
  33. Morgan B, Thomas AL, Drevs J, Hennig J, Buchert M, Jivan A, et al. Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies. J Clin Oncol. 2003;21:3955–3964
  34. Yao JC, Hoff PM. Molecular targeted therapy for neuroendocrine tumors. Hematol Oncol Clin North Am. 2007;21:575–581
  35. Beaudry P, Force J, Naumov GN, Wang A, Baker CH, Ryan A, et al. Differential effects of vascular endothelial growth factor receptor-2 inhibitor ZD6474 on circulating endothelial progenitors and mature circulating endothelial cells: implications for use as a surrogate marker of antiangiogenic activity. Clin Cancer Res. 2005;11:3514–3522
  36. Yao JC, Phan A, Hoff PM, Chen HX, Charnsangavej C, Yeung SC, et al. Targeting vascular endothelial growth factor in advanced carcinoid tumor: a random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alpha-2b. J Clin Oncol. 2008;26:1316–1323
  37. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307:58–62
  38. Baluk P, Morikawa S, Haskell A, Mancuso M, McDonald DM. Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. Am J Pathol. 2003;163:1801–1815
  39. Morikawa S, Baluk P, Kaidoh T, Haskell A, Jain RK, McDonald DM. Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol. 2002;160:985–1000
  40. Dickson PV, Hamner JB, Sims TL, Fraga CH, Ng CY, Rajasekeran S, et al. Bevacizumab-induced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy. Clin Cancer Res. 2007;13:3942–3950
  41. Wildiers H, Guetens G, De BG, Verbeken E, Landuyt B, Landuyt W, et al. Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11. Br J Cancer. 2003;88:1979–1986
  42. Kasman I, Bagri A, Mak J, Peale F, Carano R, Ross J, et al. Mechanistic evaluation of the combination effect of anti-VEGF and chemotherapy (AACR meeting abstracts). 2008. 2008;591;(abstr 2494)
  43. Dallas NA, Fan F, Gray MJ, Van Buren G, Lim SJ, Xia L, et al. Functional significance of vascular endothelial growth factor receptors on gastrointestinal cancer cells. Cancer Metastasis Rev. 2007;26:433–441
  44. Wu Y, Hooper AT, Zhong Z, Witte L, Bohlen P, Rafii S, et al. The vascular endothelial growth factor receptor (VEGFR-1) supports growth and survival of human breast carcinoma. Int J Cancer. 2006;119:1519–1529
  45. Wu Y, Zhong Z, Huber J, Bassi R, Finnerty B, Corcoran E, et al. Anti-vascular endothelial growth factor receptor-1 antagonist antibody as a therapeutic agent for cancer. Clin Cancer Res. 2006;12:6573–6584
  46. Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med. 1996;2:1096–1103
  47. Gabrilovich D, Ishida T, Oyama T, Ran S, Kravtsov V, Nadaf S, et al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood. 1998;92:4150–4166
  48. Gabrilovich DI, Ishida T, Nadaf S, Ohm JE, Carbone DP. Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function. Clin Cancer Res. 1999;5:2963–2970
  49. Fricke I, Mirza N, Dupont J, Lockhart C, Jackson A, Lee JH, et al. Vascular endothelial growth factor-trap overcomes defects in dendritic cell differentiation but does not improve antigen-specific immune responses. Clin Cancer Res. 2007;13:4840–4848
  50. Shi Q, Le X, Wang B, Abbruzzese JL, Xiong Q, He Y, et al. Regulation of vascular endothelial growth factor expression by acidosis in human cancer cells. Oncogene. 2001;20:3751–3756
  51. Shweiki D, Neeman M, Itin A, Keshet E. Induction of vascular endothelial growth factor expression by hypoxia and by glucose deficiency in multicell spheroids: implications for tumor angiogenesis. Proc Natl Acad Sci U S A. 1995;92:768–772
  52. Lev DC, Onn A, Melinkova VO, Miller C, Stone V, Ruiz M, et al. Exposure of melanoma cells to dacarbazine results in enhanced tumor growth and metastasis in vivo. J Clin Oncol. 2004;22:2092–2100
  53. Lev DC, Ruiz M, Mills L, McGary EC, Price JE, Bar-Eli M. Dacarbazine causes transcriptional up-regulation of interleukin 8 and vascular endothelial growth factor in melanoma cells: a possible escape mechanism from chemotherapy. Mol Cancer Ther. 2003;2:753–763
  54. Solban N, Selbo PK, Sinha AK, Chang SK, Hasan T. Mechanistic investigation and implications of photodynamic therapy induction of vascular endothelial growth factor in prostate cancer. Cancer Res. 2006;66:5633–5640
  55. Fan F, Gray MJ, Dallas NA, Yang AD, Van Buren G, Camp ER, et al. Effect of chemotherapeutic stress on induction of vascular endothelial growth factor family members and receptors in human colorectal cancer cells. Mol Cancer Ther. 2008;7:3064–3070
  56. Miller KD, Sweeney CJ, Sledge GW. Can tumor angiogenesis be inhibited without resistance?. EXS. 2005;94:95–112
  57. Shojaei F, Wu X, Malik AK, Zhong C, Baldwin ME, Schanz S, et al. Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nat Biotechnol. 2007;25:911–920
  58. Shojaei F, Wu X, Zhong C, Yu L, Liang XH, Yao J, et al. Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature. 2007;450:825–831
  59. Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell. 2005;8:299–309
  60. Willett CG, Boucher Y, Duda DG, di TE, Munn LL, Tong RT, et al. 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. 2005;23:8136–8139
  61. Tjwa M, Luttun A, Autiero M, Carmeliet P. VEGF and PlGF: two pleiotropic growth factors with distinct roles in development and homeostasis. Cell Tissue Res. 2003;314:5–14
  62. Ebos JM, Lee CR, Christensen JG, Mutsaers AJ, Kerbel RS. Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proc Natl Acad Sci U S A. 2007;104:17069–17074
  63. Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S, Pattarini L, et al. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell. 2007;131:463–475
  64. Song S, Ewald AJ, Stallcup W, Werb Z, Bergers G. PDGFRbeta+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival. Nat Cell Biol. 2005;7:870–879
  65. Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest. 2003;111:1287–1295
  66. Erber R, Thurnher A, Katsen AD, Groth G, Kerger H, Hammes HP, et al. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J. 2004;18:338–340
  67. Sun J, Wang DA, Jain RK, Carie A, Paquette S, Ennis E, et al. Inhibiting angiogenesis and tumorigenesis by a synthetic molecule that blocks binding of both VEGF and PDGF to their receptors. Oncogene. 2005;24:4701–4709
  68. Allenspach EJ, Maillard I, Aster JC, Pear WS. Notch signaling in cancer. Cancer Biol Ther. 2002;1:466–476
  69. Mailhos C, Modlich U, Lewis J, Harris A, Bicknell R, Ish-Horowicz D. Delta4, an endothelial specific notch ligand expressed at sites of physiological and tumor angiogenesis. Differentiation. 2001;69:135–144
  70. Noguera-Troise I, Daly C, Papadopoulos NJ, Coetzee S, Boland P, Gale NW, et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature. 2006;444:1032–1037
  71. Ridgway J, Zhang G, Wu Y, Stawicki S, Liang WC, Chanthery Y, et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature. 2006;444:1083–1087
  72. Scehnet JS, Jiang W, Kumar SR, Krasnoperov V, Trindade A, Benedito R, et al. Inhibition of Dll4-mediated signaling induces proliferation of immature vessels and results in poor tissue perfusion. Blood. 2007;109:4753–4760
  73. Segarra M, Williams CK, Sierra ML, Bernardo M, McCormick PJ, Maric D, et al. Dll4 activation of Notch signaling reduces tumor vascularity and inhibits tumor growth. Blood. 2008;112:1904–1911
  74. Zeng Q, Li S, Chepeha DB, Giordano TJ, Li J, Zhang H, et al. Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. Cancer Cell. 2005;8:13–23
  75. Reedijk M, Odorcic S, Chang L, Zhang H, Miller N, McCready DR, et al. High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival. Cancer Res. 2005;65:8530–8537
  76. Shim WS, Ho IA, Wong PE. Angiopoietin: a TIE(d) balance in tumor angiogenesis. Mol Cancer Res. 2007;5:655–665
  77. Gale NW, Thurston G, Hackett SF, Renard R, Wang Q, McClain J, et al. Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by Angiopoietin-1. Dev Cell. 2002;3:411–423
  78. Carlson TR, Feng Y, Maisonpierre PC, Mrksich M, Morla AO. Direct cell adhesion to the angiopoietins mediated by integrins. J Biol Chem. 2001;276:26516–26525
  79. Brindle NP, Saharinen P, Alitalo K. Signaling and functions of angiopoietin-1 in vascular protection. Circ Res. 2006;98:1014–1023
  80. Papapetropoulos A, Fulton D, Mahboubi K, Kalb RG, O'Connor DS, Li F, et al. Angiopoietin-1 inhibits endothelial cell apoptosis via the Akt/survivin pathway. J Biol Chem. 2000;275:9102–9105
  81. Stoeltzing O, Ahmad SA, Liu W, McCarty MF, Wey JS, Parikh AA, et al. Angiopoietin-1 inhibits vascular permeability, angiogenesis, and growth of hepatic colon cancer tumors. Cancer Res. 2003;63:3370–3377
  82. Mochizuki Y, Nakamura T, Kanetake H, Kanda S. Angiopoietin 2 stimulates migration and tube-like structure formation of murine brain capillary endothelial cells through c-Fes and c-Fyn. J Cell Sci. 2002;115:175–183
  83. Popkov M, Jendreyko N, McGavern DB, Rader C, Barbas CF. Targeting tumor angiogenesis with adenovirus-delivered anti-Tie-2 intrabody. Cancer Res. 2005;65:972–981
  84. Jendreyko N, Popkov M, Rader C, Barbas CF. Phenotypic knockout of VEGF-R2 and Tie-2 with an intradiabody reduces tumor growth and angiogenesis in vivo. Proc Natl Acad Sci U S A. 2005;102:8293–8298

 STATEMENT OF CONFLICT OF INTEREST: Lee M. Ellis, MD, the senior author of this paper, discloses the following: honoraria: Cephalon Oncology, Genentech, and Amgen; research support: Sanofi-Aventis; and Consulting: Schering Plough. The other authors have no conflicts of interest to disclose.

 Supported in part by National Institutes of Health (NIH) Grant No. 5-T32 CA009599 (P.G., D.B.), NIH Grant No. R01 CA112390 (L.M.E.), and the William C. Liedke Chair in Cancer Research (L.M.E.).

PII: S0093-7754(09)00030-X

doi: 10.1053/j.seminoncol.2009.02.002

Seminars in Oncology
Volume 36 , Pages S12-S19 , April 2009