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Angiopoietins

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Angiogenesis Inhibition

Part of the book series: Recent Results in Cancer Research ((RECENTCANCER,volume 180))

Abstract

The formation of new blood vessels plays an important role during the development and progression of a disease. In recent years, there has been a tremendous effort to uncover the molecular mechanisms that drive blood vessel growth in adult tissues. Angiopoietins belong to a family of growth factors that are critically involved in blood vessel formation during developmental and pathological angiogenesis. The importance of Angiopoietin signaling has been recognized in transgenic mouse models as the genetic ablation of Ang-1, and its primary receptor Tie2 has led to early embryonic lethality. Interesting and unusual for a family of ligands, Ang-2 has been identified as an antagonist of Ang-1 in endothelial cells as evidenced by a similar embryonic phenotype when Ang-2 was overexpressed in transgenic mice. In this review, we focus on the functional consequences of autocrine Angiopoietin signaling in endothelial cells.

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References

  • Carmeliet P, Ferreira V, Breier G et al (1996) Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380:435–439

    Article  PubMed  Google Scholar 

  • Ferrara N, Carver-Moore K, Chen H et al (1996) Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380:439–442

    Article  PubMed  Google Scholar 

  • Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676

    Article  PubMed  Google Scholar 

  • Conway EM, Collen D, Carmeliet P (2001) Molecular mechanisms of blood vessel growth. Cardiovasc Res 49:507–521

    Article  PubMed  Google Scholar 

  • Risau W (1997) Mechanisms of angiogenesis. Nature 386:671–674

    Article  PubMed  Google Scholar 

  • Suri C, McClain J, Thurston G et al (1998) Increased vascularization in mice overexpressing angiopoietin-1. Science 282:468–471

    Article  PubMed  Google Scholar 

  • Maisonpierre PC, Suri C, Jones PF et al (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277:55–60

    Article  PubMed  Google Scholar 

  • Brindle NP, Saharinen P, Alitalo K (2006) Signaling and functions of angiopoietin-1 in vascular protection. Circ Res 98:1014–1023

    Article  PubMed  Google Scholar 

  • Hanahan D (1997) Signaling vascular morphogenesis and maintenance. Science 277:48–50

    Article  PubMed  Google Scholar 

  • Davis S, Aldrich TH, Jones PF et al (1996) Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 87:1161–1169

    Article  PubMed  Google Scholar 

  • Valenzuela DM, Griffiths JA, Rojas J et al (1999) Angiopoietins 3 and 4: diverging gene counterparts in mice and humans. Proc Natl Acad Sci U S A 96:1904–1909

    Article  PubMed  Google Scholar 

  • Sato TN, Tozawa Y, Deutsch U et al (1995) Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 376:70–74

    Article  PubMed  Google Scholar 

  • Dumont DJ, Fong GH, Puri MC, Gradwohl G, Alitalo K, Breitman ML (1995) Vascularization of the mouse embryo: a study of flk-1, tek, tie, and vascular endothelial growth factor expression during development. Dev Dyn 203:80–92

    PubMed  Google Scholar 

  • Barton WA, Tzvetkova-Robev D, Miranda EP et al (2006) Crystal structures of the Tie2 receptor ectodomain and the angiopoietin-2-Tie2 complex. Nat Struct Mol Biol 13:524–532

    Article  PubMed  Google Scholar 

  • Fiedler U, Krissl T, Koidl S et al (2003) Angiopoietin-1 and angiopoietin-2 share the same binding domains in the Tie-2 receptor involving the first Ig-like loop and the epidermal growth factor-like repeats. J Biol Chem 278:1721–1727

    Article  PubMed  Google Scholar 

  • Dumont DJ, Gradwohl GJ, Fong GH, Auerbach R, Breitman ML (1993) The endothelial-specific receptor tyrosine kinase, tek, is a member of a new subfamily of receptors. Oncogene 8:1293–1301

    PubMed  Google Scholar 

  • Sato TN, Qin Y, Kozak CA, Audus KL (1993) Tie-1 and tie-2 define another class of putative receptor tyrosine kinase genes expressed in early embryonic vascular system. Proc Natl Acad Sci U S A 90:9355–9358

    Article  PubMed  Google Scholar 

  • Schnurch H, Risau W (1993) Expression of tie-2, a member of a novel family of receptor tyrosine kinases, in the endothelial cell lineage. Development 119:957–968

    PubMed  Google Scholar 

  • Partanen J, Armstrong E, Makela TP et al (1992) A novel endothelial cell surface receptor tyrosine kinase with extracellular epidermal growth factor homology domains. Mol Cell Biol 12:1698–1707

    PubMed  Google Scholar 

  • Saharinen P, Kerkela K, Ekman N et al (2005) Multiple angiopoietin recombinant proteins activate the Tie1 receptor tyrosine kinase and promote its interaction with Tie2. J Cell Biol 169:239–243

    Article  PubMed  Google Scholar 

  • Jones N, Master Z, Jones J et al (1999) Identification of Tek/Tie2 binding partners. Binding to a multifunctional docking site mediates cell survival and migration. J Biol Chem 274:30896–30905

    Article  PubMed  Google Scholar 

  • Papapetropoulos A, Fulton D, Mahboubi K et al (2000) Angiopoietin-1 inhibits endothelial cell apoptosis via the Akt/survivin pathway. J Biol Chem 275:9102–9105

    Article  PubMed  Google Scholar 

  • Audero E, Cascone I, Maniero F et al (2004) Adaptor ShcA protein binds tyrosine kinase Tie2 receptor and regulates migration and sprouting but not survival of endothelial cells. J Biol Chem 279:13224–13233

    Article  PubMed  Google Scholar 

  • Hayes AJ, Huang WQ, Mallah J, Yang D, Lippman ME, Li LY (1999) Angiopoietin-1 and its receptor Tie-2 participate in the regulation of capillary-like tubule formation and survival of endothelial cells. Microvasc Res 58:224–237

    Article  PubMed  Google Scholar 

  • Koblizek TI, Weiss C, Yancopoulos GD, Deutsch U, Risau W (1998) Angiopoietin-1 induces sprouting angiogenesis in vitro. Curr Biol 8:529–532

    Article  PubMed  Google Scholar 

  • Suri C, Jones PF, Patan S et al (1996) Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87: 1171–1180

    Article  PubMed  Google Scholar 

  • Wong AL, Haroon ZA, Werner S, Dewhirst MW, Greenberg CS, Peters KG (1997) Tie2 expression and phosphorylation in angiogenic and quiescent adult tissues. Circ Res 81:567–574

    PubMed  Google Scholar 

  • Saharinen P, Eklund L, Miettinen J et al (2008) Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts. Nat Cell Biol 10:527–537

    Article  PubMed  Google Scholar 

  • Fukuhara S, Sako K, Minami T et al (2008) Differential function of Tie2 at cell-cell contacts and cell-substratum contacts regulated by angiopoietin-1. Nat Cell Biol 10:513–526

    Article  PubMed  Google Scholar 

  • Reiss Y, Droste J, Heil M et al (2007) Angiopoietin-2 impairs revascularization after limb ischemia. Circ Res 101(1):88–96

    Article  PubMed  Google Scholar 

  • Scharpfenecker M, Fiedler U, Reiss Y, Augustin HG (2005) The Tie-2 ligand angiopoietin-2 destabilizes quiescent endothelium through an internal autocrine loop mechanism. J Cell Sci 118:771–780

    Article  PubMed  Google Scholar 

  • Holash J, Maisonpierre PC, Compton D et al (1999) Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284:1994–1998

    Article  PubMed  Google Scholar 

  • Stratmann A, Risau W, Plate KH (1998) Cell type-specific expression of angiopoietin-1 and angiopoietin-2 suggests a role in glioblastoma angiogenesis. Am J Pathol 153:1459–1466

    PubMed  Google Scholar 

  • Gale NW, Thurston G, Hackett SF et al (2002) Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by Angiopoietin-1. Dev Cell 3:411–423

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J (2000) Vascular-specific growth factors and blood vessel formation. Nature 407:242–248

    Article  PubMed  Google Scholar 

  • Reiss Y, Machein MR, Plate KH (2005) The role of angiopoietins during angiogenesis in gliomas. Brain Pathol 15:311–317

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Morikawa S, Baluk P, Kaidoh T, Haskell A, Jain RK, McDonald DM (2002) Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol 160:985–1000

    PubMed  Google Scholar 

  • Ward NL, Dumont DJ (2002) The angiopoietins and Tie2/Tek: adding to the complexity of cardiovascular development. Semin Cell Dev Biol 13:19–27

    Article  PubMed  Google Scholar 

  • Stoeltzing O, Ahmad SA, Liu W et al (2003) Angiopoietin-1 inhibits vascular permeability, angiogenesis, and growth of hepatic colon cancer tumors. Cancer Res 63:3370–3377

    PubMed  Google Scholar 

  • Hawighorst T, Skobe M, Streit M et al (2002) Activation of the tie2 receptor by angiopoietin-1 enhances tumor vessel maturation and impairs squamous cell carcinoma growth. Am J Pathol 160:1381–1392

    PubMed  Google Scholar 

  • Tian S, Hayes AJ, Metheny-Barlow LJ, Li LY (2002) Stabilization of breast cancer xenograft tumour neovasculature by angiopoietin-1. Br J Cancer 86:645–651

    Article  PubMed  Google Scholar 

  • Stoeltzing O, Ahmad SA, Liu W et al (2002) Angiopoietin-1 inhibits tumour growth and ascites formation in a murine model of peritoneal carcinomatosis. Br J Cancer 87:1182–1187

    Article  PubMed  Google Scholar 

  • Ahmad SA, Liu W, Jung YD et al (2001) The effects of angiopoietin-1 and -2 on tumor growth and angiogenesis in human colon cancer. Cancer Res 61:1255–1259

    PubMed  Google Scholar 

  • Yu Q, Stamenkovic I (2001) Angiopoietin-2 is implicated in the regulation of tumor angiogenesis. Am J Pathol 158:563–570

    PubMed  Google Scholar 

  • Hayes AJ, Huang WQ, Yu J et al (2000) Expression and function of angiopoietin-1 in breast cancer. Br J Cancer 83:1154–1160

    Article  PubMed  Google Scholar 

  • Shim WS, Teh M, Bapna A et al (2002) Angiopoietin 1 promotes tumor angiogenesis and tumor vessel plasticity of human cervical cancer in mice. Exp Cell Res 279:299–309

    Article  PubMed  Google Scholar 

  • Machein MR, Knedla A, Knoth R, Wagner S, Neuschl E, Plate KH (2004) Angiopoietin-1 promotes tumor angiogenesis in a rat glioma model. Am J Pathol 165:1557–1570

    PubMed  Google Scholar 

  • Cao Y, Sonveaux P, Liu S et al (2007) Systemic overexpression of angiopoietin-2 promotes tumor microvessel regression and inhibits angiogenesis and tumor growth. Cancer Res 67:3835–3844

    Article  PubMed  Google Scholar 

  • Zhang L, Yang N, Park JW et al (2003) Tumor-derived vascular endothelial growth factor up-regulates angiopoietin-2 in host endothelium and destabilizes host vasculature, supporting angiogenesis in ovarian cancer. Cancer Res 63:3403–3412

    PubMed  Google Scholar 

  • Hu B, Guo P, Fang Q et al (2003) Angiopoietin-2 induces human glioma invasion through the activation of matrix metalloprotease-2. Proc Natl Acad Sci U S A 100:8904–8909

    Article  PubMed  Google Scholar 

  • Etoh T, Inoue H, Tanaka S, Barnard GF, Kitano S, Mori M (2001) Angiopoietin-2 is related to tumor angiogenesis in gastric carcinoma: possible in vivo regulation via induction of proteases. Cancer Res 61:2145–2153

    PubMed  Google Scholar 

  • Tanaka S, Mori M, Sakamoto Y, Makuuchi M, Sugimachi K, Wands JR (1999) Biologic significance of angiopoietin-2 expression in human hepatocellular carcinoma. J Clin Invest 103:341–345

    Article  PubMed  Google Scholar 

  • Hashizume H, Baluk P, Morikawa S et al (2000) Openings between defective endothelial cells explain tumor vessel leakiness. Am J Pathol 156:1363–1380

    PubMed  Google Scholar 

  • Hegen A, Koidl S, Weindel K, Marme D, Augustin HG, Fiedler U (2004) Expression of angiopoietin-2 in endothelial cells is controlled by positive and negative regulatory promoter elements. Arterioscler Thromb Vasc Biol 24:1803–1809

    Article  PubMed  Google Scholar 

  • Ochiumi T, Tanaka S, Oka S et al (2004) Clinical significance of angiopoietin-2 expression at the deepest invasive tumor site of advanced colorectal carcinoma. Int J Oncol 24:539–547

    PubMed  Google Scholar 

  • Sfiligoi C, de Luca A, Cascone I et al (2003) Angiopoietin-2 expression in breast cancer correlates with lymph node invasion and short survival. Int J Cancer 103:466–474

    Article  PubMed  Google Scholar 

  • Siemeister G, Schirner M, Weindel K et al (1999) Two independent mechanisms essential for tumor angiogenesis: inhibition of human melanoma xenograft growth by interfering with either the vascular endothelial growth factor receptor pathway or the Tie-2 pathway. Cancer Res 59:3185–3191

    PubMed  Google Scholar 

  • Lin P, Buxton JA, Acheson A et al (1998) Antiangiogenic gene therapy targeting the endothelium-specific receptor tyrosine kinase Tie2. Proc Natl Acad Sci U S A 95:8829–8834

    Article  PubMed  Google Scholar 

  • Lin P, Polverini P, Dewhirst M, Shan S, Rao PS, Peters K (1997) Inhibition of tumor angiogenesis using a soluble receptor establishes a role for Tie2 in pathologic vascular growth. J Clin Invest 100:2072–2078

    Article  PubMed  Google Scholar 

  • Oliner J, Min H, Leal J et al (2004) Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell 6:507–516

    Article  PubMed  Google Scholar 

  • McDonald DM, Thurston G, Baluk P (1999) Endothelial gaps as sites for plasma leakage in inflammation. Microcirculation 6:7–22

    PubMed  Google Scholar 

  • Gamble JR, Drew J, Trezise L et al (2000) Angiopoietin-1 is an antipermeability and anti-inflammatory agent in vitro and targets cell junctions. Circ Res 87:603–607

    PubMed  Google Scholar 

  • Wang Y, Pampou S, Fujikawa K, Varticovski L (2004) Opposing effect of angiopoietin-1 on VEGF-mediated disruption of endothelial cell-cell interactions requires activation of PKC beta. J Cell Physiol 198:53–61

    Article  PubMed  Google Scholar 

  • Gavard J, Patel V, Gutkind JS (2008) Angiopoietin-1 prevents VEGF-induced endothelial permeability by sequestering Src through mDia. Dev Cell 14:25–36

    Article  PubMed  Google Scholar 

  • Murdoch C, Muthana M, Coffelt SB, Lewis CE (2008) The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8:618–631

    Article  PubMed  Google Scholar 

  • Grunewald M, Avraham I, Dor Y et al (2006) VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 124:175–189

    Article  PubMed  Google Scholar 

  • De Palma M, Murdoch C, Venneri MA, Naldini L, Lewis CE (2007) Tie2-expressing monocytes: regulation of tumor angiogenesis and therapeutic implications. Trends Immunol 28:519–524

    Article  PubMed  Google Scholar 

  • De Palma M, Venneri MA, Roca C, Naldini L (2003) Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells. Nat Med 9: 789–795

    Article  PubMed  Google Scholar 

  • De Palma M, Venneri MA, Galli R et al (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

    Article  PubMed  Google Scholar 

  • Machein MR, Renninger S, de Lima-Hahn E, Plate KH (2003) Minor contribution of bone marrow-derived endothelial progenitors to the vascularization of murine gliomas. Brain Pathol 13:582–597

    Article  PubMed  Google Scholar 

  • Fiedler U, Reiss Y, Scharpfenecker M et al (2006) Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med 12:235–239

    Article  PubMed  Google Scholar 

  • Winkler F, Kozin SV, Tong RT 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

    PubMed  Google Scholar 

  • De Palma M, Mazzieri R, Politi LS et al (2008) Tumor-targeted interferon-alpha delivery by Tie2- expressing monocytes inhibits tumor growth and metastasis. Cancer Cell 14:299–311

    Article  PubMed  Google Scholar 

  • Thurston G, Suri C, Smith K et al (1999) Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 286:2511–2514

    Article  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  • Puri MC, Partanen J, Rossant J, Bernstein A (1999) Interaction of the TEK and TIE receptor tyrosine kinases during cardiovascular development. Development 126:4569–4580

    PubMed  Google Scholar 

  • Dumont DJ, Gradwohl G, Fong GH et al (1994) Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo. Genes Dev 8:1897–1909

    Article  PubMed  Google Scholar 

  • Puri MC, Bernstein A (2003) Requirement for the TIE family of receptor tyrosine kinases in adult but not fetal hematopoiesis. Proc Natl Acad Sci U S A 100:12753–12758

    Article  PubMed  Google Scholar 

  • Reiss Y, Knedla A, Tal AO et al (2009) Switching of vascular phenotypes within a murine breast cancer model induced by Angiopoietin-2. J Path 217 (4):571–580

    Article  PubMed  Google Scholar 

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Acknowledgment

I gratefully acknowledge Jutta Reiss for helping with the illustrations and cartoons, and Andrea Tal for confocal images. This work is supported by the SFB/TR23 – C1 and the Excellence Cluster Cardio-Pulmonary System (ECCPS).

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  1. Institute of Neurology/Edinger Institute, Frankfurt University Medical School, Heinrich-Hoffmann-Strasse, 760528, Frankfurt, Germany

    Yvonne Reiss

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  1. Yvonne Reiss
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Correspondence to Yvonne Reiss .

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  1. Medizinische Klinik und Poliklinik A, Universitätsklinikum Münster, Albert-Schweitzer-Str. 33, Münster, 48149, Germany

    Rüdiger Liersch

  2. Medizinische Klinik und Poliklinik, Universitätsklinikum Münster, Albert-Schweitzer-Str. 33, Münster, 48149, Germany

    Wolfgang E. Berdel

  3. Medizinische Klinik und Poliklinik A, Universitätsklinikum Münster, Albert-Schweitzer-Str. 33, Münster, 48149, Germany

    Torsten Kessler

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Reiss, Y. (2010). Angiopoietins. In: Liersch, R., Berdel, W., Kessler, T. (eds) Angiogenesis Inhibition. Recent Results in Cancer Research, vol 180. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-78281-0_2

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  • DOI: https://doi.org/10.1007/978-3-540-78281-0_2

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