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PMID: 21593862 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Review

Molecular mechanisms and clinical applications of angiogenesis.

Nature ·Vol. 473 ·No. 7347 ·2011-05-19 ·Pages 298-307

Carmeliet P, Jain RK

Abstract

Blood vessels deliver oxygen and nutrients to every part of the body, but also nourish diseases such as cancer. Over the past decade, our understanding of the molecular mechanisms of angiogenesis (blood vessel growth) has increased at an explosive rate and has led to the approval of anti-angiogenic drugs for cancer and eye diseases. So far, hundreds of thousands of patients have benefited from blockers of the angiogenic protein vascular endothelial growth factor, but limited efficacy and resistance remain outstanding problems. Recent preclinical and clinical studies have shown new molecular targets and principles, which may provide avenues for improving the therapeutic benefit from anti-angiogenic strategies.

MeSH Terms
Angiogenesis Inhibitors/pharmacology,therapeutic use Animals Blood Vessels/growth & development,pathology,physiology,physiopathology Fibroblast Growth Factors/metabolism Humans Neovascularization, Physiologic/physiology Platelet-Derived Growth Factor/metabolism Transforming Growth Factor beta/metabolism Vascular Endothelial Growth Factor A/antagonists & inhibitors,metabolism Vesicular Transport Proteins/metabolism
Chemicals
Angiogenesis Inhibitors Platelet-Derived Growth Factor Transforming Growth Factor beta Vascular Endothelial Growth Factor A Vesicular Transport Proteins Fibroblast Growth Factors
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Carmeliet Peter
Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven B-3000, Belgium. peter.carmeliet@vib-kuleuven.be
Jain Rakesh K
References (100)
100 references, click to expand
  1. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy.
    Nat Med. 2001 Sep;7(9):987-9 PMID: 11533692
  2. Arterial-venous specification during development.
    Circ Res. 2009 Mar 13;104(5):576-88 PMID: 19286613
  3. uPAR: a versatile signalling orchestrator.
    Nat Rev Mol Cell Biol. 2002 Dec;3(12):932-43 PMID: 12461559
  4. Axon guidance molecules in vascular patterning.
    Cold Spring Harb Perspect Biol. 2010 May;2(5):a001875 PMID: 20452960
  5. Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting.
    Nat Cell Biol. 2010 Oct;12(10):943-53 PMID: 20871601
  6. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors.
    Cancer Cell. 2005 Sep;8(3):211-26 PMID: 16169466
  7. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors.
    J Clin Invest. 2003 May;111(9):1287-95 PMID: 12727920
  8. Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia.
    Nat Med. 2010 Apr;16(4):420-8 PMID: 20364125
  9. The Delta paradox: DLL4 blockade leads to more tumour vessels but less tumour growth.
    Nat Rev Cancer. 2007 May;7(5):327-31 PMID: 17457300
  10. Chronic DLL4 blockade induces vascular neoplasms.
    Nature. 2010 Feb 11;463(7282):E6-7 PMID: 20147986
  11. Pericytes: gatekeepers in tumour cell metastasis?
    J Mol Med (Berl). 2008 Feb;86(2):135-44 PMID: 17891366
  12. CXCL12 (SDF1alpha)-CXCR4/CXCR7 pathway inhibition: an emerging sensitizer for anticancer therapies?
    Clin Cancer Res. 2011 Apr 15;17(8):2074-80 PMID: 21349998
  13. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis.
    Cancer Cell. 2009 Mar 3;15(3):232-9 PMID: 19249681
  14. Genetics, epigenetics and pharmaco-(epi)genomics in angiogenesis.
    J Cell Mol Med. 2008 Dec;12(6B):2533-51 PMID: 19210754
  15. Autocrine VEGF signaling synergizes with EGFR in tumor cells to promote epithelial cancer development.
    Cell. 2010 Jan 22;140(2):268-79 PMID: 20141840
  16. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis.
    Nat Cell Biol. 2000 Oct;2(10):737-44 PMID: 11025665
  17. VEGF-A and the induction of pathological angiogenesis.
    Annu Rev Pathol. 2007;2:251-75 PMID: 18039100
  18. Effective suppression of vascular network formation by combination of antibodies blocking VEGFR ligand binding and receptor dimerization.
    Cancer Cell. 2010 Dec 14;18(6):630-40 PMID: 21130043
  19. The FGF family: biology, pathophysiology and therapy.
    Nat Rev Drug Discov. 2009 Mar;8(3):235-53 PMID: 19247306
  20. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis.
    Nature. 2008 Dec 11;456(7223):814-8 PMID: 18997773
  21. Tumor-associated endothelial cells with cytogenetic abnormalities.
    Cancer Res. 2004 Nov 15;64(22):8249-55 PMID: 15548691
  22. Validation of an anti-sphingosine-1-phosphate antibody as a potential therapeutic in reducing growth, invasion, and angiogenesis in multiple tumor lineages.
    Cancer Cell. 2006 Mar;9(3):225-38 PMID: 16530706
  23. Disease course patterns after discontinuation of bevacizumab: pooled analysis of randomized phase III trials.
    J Clin Oncol. 2011 Jan 1;29(1):83-8 PMID: 21098326
  24. Overexpression of PDGF-BB decreases colorectal and pancreatic cancer growth by increasing tumor pericyte content.
    J Clin Invest. 2007 Aug;117(8):2114-22 PMID: 17641778
  25. Control of cardiovascular differentiation by microRNAs.
    Basic Res Cardiol. 2011 Jan;106(1):5-11 PMID: 21184089
  26. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand.
    Cell. 2002 May 31;109(5):625-37 PMID: 12062105
  27. Signaling by members of the TGF-beta family in vascular morphogenesis and disease.
    Trends Cell Biol. 2010 Sep;20(9):556-67 PMID: 20656490
  28. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival.
    J Clin Oncol. 2010 May 1;28(13):2144-50 PMID: 20368553
  29. Pathways mediating VEGF-independent tumor angiogenesis.
    Cytokine Growth Factor Rev. 2010 Feb;21(1):21-6 PMID: 20005148
  30. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion.
    Cancer Cell. 2008 Mar;13(3):206-20 PMID: 18328425
  31. FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy?
    Nat Rev Cancer. 2008 Dec;8(12):942-56 PMID: 19029957
  32. Role of neutrophil-derived matrix metalloproteinase-9 in tissue regeneration.
    Histol Histopathol. 2010 Jun;25(6):765-70 PMID: 20376783
  33. The molecular basis of vascular lumen formation in the developing mouse aorta.
    Dev Cell. 2009 Oct;17(4):505-15 PMID: 19853564
  34. Double antiangiogenic protein, DAAP, targeting VEGF-A and angiopoietins in tumor angiogenesis, metastasis, and vascular leakage.
    Cancer Cell. 2010 Aug 9;18(2):171-84 PMID: 20708158
  35. alphavbeta3 integrin and angiogenesis: a moody integrin in a changing environment.
    Curr Opin Cell Biol. 2008 Oct;20(5):514-9 PMID: 18638550
  36. Integrins as "functional hubs" in the regulation of pathological angiogenesis.
    Semin Cancer Biol. 2009 Oct;19(5):318-28 PMID: 19482089
  37. Differential response of primary tumor versus lymphatic metastasis to VEGFR-2 and VEGFR-3 kinase inhibitors cediranib and vandetanib.
    Mol Cancer Ther. 2008 Aug;7(8):2272-9 PMID: 18687659
  38. The role of wnt signaling in physiological and pathological angiogenesis.
    Circ Res. 2010 Oct 15;107(8):943-52 PMID: 20947863
  39. VEGF-A: a critical regulator of blood vessel growth.
    Eur Cytokine Netw. 2009 Dec;20(4):158-63 PMID: 20167554
  40. Pericytes: blood-brain barrier safeguards against neurodegeneration?
    Neuron. 2010 Nov 4;68(3):321-3 PMID: 21040834
  41. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy.
    Science. 2005 Jan 7;307(5706):58-62 PMID: 15637262
  42. Modes of resistance to anti-angiogenic therapy.
    Nat Rev Cancer. 2008 Aug;8(8):592-603 PMID: 18650835
  43. Glioblastoma recurrence after cediranib therapy in patients: lack of "rebound" revascularization as mode of escape.
    Cancer Res. 2011 Jan 1;71(1):19-28 PMID: 21199795
  44. Essential regulation of CNS angiogenesis by the orphan G protein-coupled receptor GPR124.
    Science. 2010 Nov 12;330(6006):985-9 PMID: 21071672
  45. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis.
    Cancer Cell. 2009 Mar 3;15(3):220-31 PMID: 19249680
  46. Lessons from phase III clinical trials on anti-VEGF therapy for cancer.
    Nat Clin Pract Oncol. 2006 Jan;3(1):24-40 PMID: 16407877
  47. Glioblastoma stem-like cells give rise to tumour endothelium.
    Nature. 2010 Dec 9;468(7325):829-33 PMID: 21102433
  48. The Wnt/beta-catenin pathway modulates vascular remodeling and specification by upregulating Dll4/Notch signaling.
    Dev Cell. 2010 Jun 15;18(6):938-49 PMID: 20627076
  49. Microenvironmental regulation of metastasis.
    Nat Rev Cancer. 2009 Apr;9(4):239-52 PMID: 19279573
  50. Lymphangiogenesis: Molecular mechanisms and future promise.
    Cell. 2010 Feb 19;140(4):460-76 PMID: 20178740
  51. Cellular source and amount of vascular endothelial growth factor and platelet-derived growth factor in tumors determine response to angiogenesis inhibitors.
    Cancer Res. 2009 May 15;69(10):4527-36 PMID: 19401451
  52. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche.
    Nature. 2005 Dec 8;438(7069):820-7 PMID: 16341007
  53. The semaphorins: versatile regulators of tumour progression and tumour angiogenesis.
    Nat Rev Cancer. 2008 Aug;8(8):632-45 PMID: 18580951
  54. Collateral circulation: past and present.
    Basic Res Cardiol. 2009 Jan;104(1):5-21 PMID: 19101749
  55. VEGF-PET imaging is a noninvasive biomarker showing differential changes in the tumor during sunitinib treatment.
    Cancer Res. 2011 Jan 1;71(1):143-53 PMID: 21084271
  56. Hypoxia-inducible factors and the response to hypoxic stress.
    Mol Cell. 2010 Oct 22;40(2):294-309 PMID: 20965423
  57. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha.
    Nature. 2008 Feb 21;451(7181):1008-12 PMID: 18288196
  58. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08.
    J Clin Oncol. 2011 Jan 1;29(1):11-6 PMID: 20940184
  59. HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF.
    Cancer Cell. 2011 Jan 18;19(1):31-44 PMID: 21215706
  60. Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors.
    Nat Rev Cancer. 2010 Feb;10(2):138-46 PMID: 20094048
  61. Angiogenesis in life, disease and medicine.
    Nature. 2005 Dec 15;438(7070):932-6 PMID: 16355210
  62. Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis.
    Nature. 2010 May 27;465(7297):487-91 PMID: 20445540
  63. Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts.
    Nat Cell Biol. 2008 May;10(5):527-37 PMID: 18425119
  64. Eph receptors and ephrin ligands: important players in angiogenesis and tumor angiogenesis.
    J Oncol. 2010;2010:135285 PMID: 20224755
  65. PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment.
    Cancer Cell. 2009 Jan 6;15(1):21-34 PMID: 19111878
  66. Regulation of angiogenesis by oxygen and metabolism.
    Dev Cell. 2009 Feb;16(2):167-79 PMID: 19217420
  67. Arterial-venous segregation by selective cell sprouting: an alternative mode of blood vessel formation.
    Science. 2009 Oct 9;326(5950):294-8 PMID: 19815777
  68. Cellular and molecular mechanisms of vascular lumen formation.
    Dev Cell. 2009 Feb;16(2):222-31 PMID: 19217424
  69. Integrins in cancer: biological implications and therapeutic opportunities.
    Nat Rev Cancer. 2010 Jan;10(1):9-22 PMID: 20029421
  70. Hearing improvement after bevacizumab in patients with neurofibromatosis type 2.
    N Engl J Med. 2009 Jul 23;361(4):358-67 PMID: 19587327
  71. Pleiotropic roles of matrix metalloproteinases in tumor angiogenesis: contrasting, overlapping and compensatory functions.
    Biochim Biophys Acta. 2010 Jan;1803(1):103-20 PMID: 19800930
  72. The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis.
    Cell. 2009 Jun 12;137(6):1124-35 PMID: 19524514
  73. Vascular endothelial growth factor receptor-1 in human cancer: concise review and rationale for development of IMC-18F1 (Human antibody targeting vascular endothelial growth factor receptor-1).
    Cancer. 2010 Feb 15;116(4 Suppl):1027-32 PMID: 20127948
  74. Premetastatic lung "niche": is vascular endothelial growth factor receptor 1 activation required?
    Cancer Res. 2010 Jul 15;70(14):5670-3 PMID: 20587530
  75. Rapid vascular regrowth in tumors after reversal of VEGF inhibition.
    J Clin Invest. 2006 Oct;116(10):2610-21 PMID: 17016557
  76. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system.
    Nat Rev Mol Cell Biol. 2009 Mar;10(3):165-77 PMID: 19234476
  77. PlGF blockade does not inhibit angiogenesis during primary tumor growth.
    Cell. 2010 Apr 2;141(1):166-77 PMID: 20371352
  78. The absence of pericytes does not increase the sensitivity of tumor vasculature to vascular endothelial growth factor-A blockade.
    Cancer Res. 2010 Jun 15;70(12):5109-15 PMID: 20501841
  79. Nrarp coordinates endothelial Notch and Wnt signaling to control vessel density in angiogenesis.
    Dev Cell. 2009 Jan;16(1):70-82 PMID: 19154719
  80. Endothelial-mural cell signaling in vascular development and angiogenesis.
    Arterioscler Thromb Vasc Biol. 2009 May;29(5):630-8 PMID: 19164813
  81. Angiogenesis: an organizing principle for drug discovery?
    Nat Rev Drug Discov. 2007 Apr;6(4):273-86 PMID: 17396134
  82. The shunt problem: control of functional shunting in normal and tumour vasculature.
    Nat Rev Cancer. 2010 Aug;10(8):587-93 PMID: 20631803
  83. VEGF receptor 2 endocytic trafficking regulates arterial morphogenesis.
    Dev Cell. 2010 May 18;18(5):713-24 PMID: 20434959
  84. Contrasting actions of selective inhibitors of angiopoietin-1 and angiopoietin-2 on the normalization of tumor blood vessels.
    Am J Pathol. 2009 Nov;175(5):2159-70 PMID: 19815705
  85. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization.
    Cell. 2009 Mar 6;136(5):839-851 PMID: 19217150
  86. Angiogenesis: a team effort coordinated by notch.
    Dev Cell. 2009 Feb;16(2):196-208 PMID: 19217422
  87. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions.
    Nat Med. 2001 May;7(5):575-83 PMID: 11329059
  88. MicroRNA-mediated integration of haemodynamics and Vegf signalling during angiogenesis.
    Nature. 2010 Apr 22;464(7292):1196-200 PMID: 20364122
  89. Biomarkers of response and resistance to antiangiogenic therapy.
    Nat Rev Clin Oncol. 2009 Jun;6(6):327-38 PMID: 19483739
  90. The control of vascular integrity by endothelial cell junctions: molecular basis and pathological implications.
    Dev Cell. 2009 Feb;16(2):209-21 PMID: 19217423
  91. Vascular endothelial growth factor B controls endothelial fatty acid uptake.
    Nature. 2010 Apr 8;464(7290):917-21 PMID: 20228789
  92. Autocrine VEGF signaling is required for vascular homeostasis.
    Cell. 2007 Aug 24;130(4):691-703 PMID: 17719546
  93. PDGFRbeta+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival.
    Nat Cell Biol. 2005 Sep;7(9):870-9 PMID: 16113679
  94. Vascular endothelial growth factor-B acts as a coronary growth factor in transgenic rats without inducing angiogenesis, vascular leak, or inflammation.
    Circulation. 2010 Oct 26;122(17):1725-33 PMID: 20937974
  95. Molecular regulation of vessel maturation.
    Nat Med. 2003 Jun;9(6):685-93 PMID: 12778167
  96. PDGF-C induces maturation of blood vessels in a model of glioblastoma and attenuates the response to anti-VEGF treatment.
    PLoS One. 2009;4(4):e5123 PMID: 19352490
  97. The FGF system has a key role in regulating vascular integrity.
    J Clin Invest. 2008 Oct;118(10):3355-66 PMID: 18776942
  98. PDGF and vessel maturation.
    Recent Results Cancer Res. 2010;180:103-14 PMID: 20033380
  99. Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease.
    Cell. 2010 Apr 2;141(1):178-90 PMID: 20371353
  100. Angiogenesis in health and disease.
    Nat Med. 2003 Jun;9(6):653-60 PMID: 12778163
Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature10144
Email
peter.carmeliet@vib-kuleuven.be
Published
2011-05-19
Pages
298-307
Language
English
Region
England
NLM ID
0410462
PMCID
PMC4049445
Subset
IM
Grants
NCI NIH HHS · R01 CA126642 · United States
NCI NIH HHS · R01 CA085140 · United States
NCI NIH HHS · P01-CA80124 · United States
NCI NIH HHS · R01-CA85140 · United States
NCI NIH HHS · R01 CA115767 · United States
NCI NIH HHS · R01 CA163815 · United States
NCI NIH HHS · R01-CA115767 · United States
NCI NIH HHS · P01 CA080124 · United States
NCI NIH HHS · R01-CA126642 · United States
External Links
PubMed source DOI: 10.1038/nature10144 PMC Full Text View journal details
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