Endothelial Cell Development, Vasculogenesis, Angiogenesis, and Tumor Neovascularization: An Update

In the embryo, blood vessel formation de novo (vasculogenesis) and from existing vessels (angiogenesis) results in blood vessels lined by endothelial cells (ECs). The relationship between ECs and blood cells suggested by their physical closeness was recently confirmed with the demonstration of progenitors that give rise to both cell types. In tumors, new blood vessel formation has been thought to occur primarily via angiogenesis. Recent evidence, however, suggests that postnatal vasculogenesis also contributes to tumor neovascularization. In this article, we provide an update on EC development, including early lineage specification, morphogenesis or differentiation to form functional blood vessels, and regulation of EC survival and senescence. Furthermore, we review the latest findings on tumor neovascularization and therapeutic potentials of molecules critical to this process.

Vasculogenesis - embryo - angiogenesis - angiogenesis - cancer

REFERENCES

• 1 Baron M H. Induction of embryonic hematopoietic and endothelial stem/progenitor cells by hedgehog-mediated signals.  Differentiation. 2001;  68 175-185
• 2 Choi K. The hemangioblast: a common progenitor of hematopoietic and endothelial cells.  J Hematother Stem Cell Res. 2002;  11 91-101
• 3 Fujimoto T, Ogawa M, Minegishi N et al.. Step-wise divergence of primitive and definitive haematopoietic and endothelial cell lineage during embryonic stem cell differentiation.  Genes Cells. 2001;  6 1113-1127
• 4 Shalaby F, Rossant J, Yamaguchi T P et al.. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice.  Nature. 1995;  376 62-66
• 5 Yamashita J, Itoh H, Hirashima M et al.. Flk-1-positive cells derived from embryonic stem cells serve as vascular progenitors.  Nature. 2000;  408 92-96
• 6 Choi K, Kennedy M, Kazarov A, Papadimitriou J C, Keller G. A common precursor for hematopoietic and endothelial cells.  Development. 1998;  125 725-732
• 7 Asahara T, Murohara T, Sullivan A et al.. Isolation of putative progenitor endothelial cells for angiogenesis.  Science. 1997;  275 964-967
• 8 Takakura N, Watanabe T, Suenobu S et al.. A role for hematopoietic stem cells in promoting angiogenesis.  Cell. 2000;  102 199-209
• 9 Jiang Y, Jahagirgar B N, Rieinhardt R L et al.. Pluripotency of mesenchymal stem cells derived from adult marrow.  Nature. 2002;  418 41-49
• 10 Ohneda O, Ohneda K, Arai F et al.. ALCAM (CD166): its role in hematopoietic and endothelial development.  Blood. 2001;  98 2134-2142
• 11 Dyer M A, Farrington S M, Mohn D, Munday J R, Baron M H. Indian hedgehog activates hematopoiesis and vasculogenesis and can respecify prospective neuroectodermal cell fate in the mouse embryo.  Development. 2001;  128 1717-1730
• 12 Byrd N, Becker S, Maye P et al.. Hedgehog is required for murine yolk sac angiogenesis.  Development. 2002;  129 361-372
• 13 Scappaticci F A. Mechanisms and future directions for angiogenesis-based cancer therapies.  J Clin Oncol. 2002;  20 3906-3927
• 14 Fong G H, Rossant J, Gertsenstein M, Breitman M L. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium.  Nature. 1995;  376 66-70
• 15 Kearney J B, Ambler C A, Monaco K A, Johnson N, Rapport R G, Bautch V L. Vascular endothelial growth factor receptor Flt-1 negatively regulates developmental blood vessel formation by modeling endothelial cell division.  Blood. 2002;  99 2397-2407
• 16 Segura I, Serrano A, De Buitrago G G et al.. Inhibition of programmed cell death impairs in vitro vascular-like structure formation and reduces in vivo angiogenesis.  FASEB J. 2002;  16 833-841
• 17 Alon T, Hemo I, Itin A, Pe'er J, Stone J, Keshet E. Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity.  Nat Med. 1995;  1 1024-1028
• 18 Carmeliet P, Ferreira V, Breier G et al.. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele.  Nature. 1996;  380 435-439
• 19 Ferrara N, Carver-Moore K, Chen H et al.. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene.  Nature. 1996;  380 439-442
• 20 Sato T N, Tozawa Y, Deutsch U et al.. Distinct roles of the receptor tyrosine kinase Tie-1 and Tie-2 in blood vessel formation.  Nature. 1995;  376 70-74
• 21 Puri M C, Rossant J, Alitalo K, Bernstein A, Partanen J. The receptor tyrosine kinase TIE is required for integrity and survival of vascular endothelial cells.  EMBO J. 1995;  14 5884-5891
• 22 Suri C, Jones P F, Patan S et al.. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis.  Cell. 1996;  87 1171-1180
• 23 Maisonpierre P C, Suri C, Jones P F et al.. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis.  Science. 1997;  277 55-60
• 24 Yancopoulos G D, Davis S, Gale N W, Rudge J S, Wiegand S J, Holash J. Vascular-specific growth factors and blood vessel formation.  Nature. 2000;  407 242-248
• 25 Kontos C D, Cha E H, York J D, Peters K G. The endothelial receptor tyrosine kinase Tie1 activates phosphatidylinositol 3-kinase and Akt to inhibit apoptosis.  Mol Cell Biol. 2002;  22 1704-1713
• 26 Wang H U, Chen Z F, Anderson D J. Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4.  Cell. 1998;  93 741-753
• 27 Adams R H, Wilkinson G A, Weiss C et al.. Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis.  Genes Dev. 1999;  13 295-306
• 28 Zhang X Q, Takakura N, Oike Y et al.. Stromal cells expressing ephrin-B2 promote the growth and sprouting of ephrin-B2(+) endothelial cells.  Blood. 2001;  98 1028-1037
• 29 Chavakis E, Dimmeler S. Regulation of endothelial cell survival and apoptosis during angiogenesis.  Arterioscler Thromb Vasc Biol. 2002;  22 887-893
• 30 Velazquez O C, Snyder R, Liu Z J, Fairman R M, Herlyn M. Fibroblast-dependent differentiation of human microvascular endothelial cells into capillary-like 3-dimensional networks.  FASEB J. 2002;  16 1316-1318
• 31 Milner R, Campbell I. Developmental regulation of beta1 integrins during angiogenesis in the central nervous system.  Mol Cell Neurosci. 2002;  20 616-624
• 32 Francis S E, Goh K L, Hodivala-Dilke K et al.. Central roles of alpha5beta1 integrin and fibronectin in vascular development in mouse embryos and embryoid bodies.  Arterioscler Thromb Vasc Biol. 2002;  22 927-933
• 33 Zhu J, Motejlek K, Wang D, Zang K, Schmidt A, Reichardt L F. Beta8 integrins are required for vascular morphogenesis in mouse embryos.  Development. 2002;  129 2891-2903
• 34 Kosta G, Giltay R, Bloch W et al.. Perinatal lethality and endothelial cell abnormalities in several vessel compartments of fibulin-1-deficient mice.  Mol Cell Biol. 2001;  21 7025-7034
• 35 Griffin C T, Srinivasan Y, Zheng Y W, Huang W, Coughlin S R. A role for thrombin receptor signaling in endothelial cells during embryonic development.  Science. 2001;  293 1602-1604
• 36 Hosking B M, Wang S C, Chen S L, Penning S, Koopman P, Muscat G E. SOX18 directly interacts with MEF2C in endothelial cells.  Biochem Biophys Res Commun. 2001;  287 493-500
• 37 Taichman D B, Looms K M, Schachtner S K et al.. Notch1 and Jagged1 expression by the developing pulmonary vasculature.  Dev Dyn. 2002;  225 166-175
• 38 Salvucci O, Yao L, Villalba S, Sajewicz A, Pittaluga S, Tosato G. Regulation of endothelial cell branching morphogenesis by endogenous chemokine stromal-derived factor-1.  Blood. 2002;  99 2703-2711
• 39 Tsuda S, Ohtsuru A, Yamashita S, Kanetake H, Kanda S. Role of c-Fyn in FGF-2-mediated tube-like structure formation by murine brain capillary endothelial cells.  Biochem Biophys Res Commun. 2002;  290 1354-1360
• 40 Matsumoto T, Turesson I, Book M, Gerwins P, Claesson-Welsh L. p38 MAP kinase negatively regulates endothelial cell survival, proliferation, and differentiation in FGF-2-stimulated angiogenesis.  J Cell Biol. 2002;  156 149-160
• 41 Bayless K J, Davis G E. The Cdc42 and Rac1 GTPases are required for capillary lumen formation in three-dimensional extracellular matrices.  J Cell Sci. 2002;  115 1123-1136
• 42 Mukouyama Y S, Shin D, Britsch S, Taniguchi M, Anderson D J. Sensory nerves determine the pattern of arterial differentiation and blood vessel branching in the skin.  Cell. 2002;  109 693-705
• 43 Villars F, Guillotin B, Amedee T et al.. Effect of HUVEC on human osteoprogenitor cell differentiation needs heterotypic gap junction communication.  Am J Physiol Cell Physiol. 2002;  282 C775-C785
• 44 Hutley L J, Herington A C, Shurety W et al.. Human adipose tissue endothelial cells promote preadipocyte proliferation.  Am J Physiol Endocrinol Metab. 2001;  281 E1037-E1044
• 45 Chang E, Yang J, Nagavarapu U, Herron G S. Aging and survival of cutaneous microvasculature.  J Invest Dermatol. 2002;  118 752-758
• 46 Yang J, Chang E, Cherry A M et al.. Human endothelial cell life extension by telomerase expression.  J Biol Chem. 1999;  274 26141-26148
• 47 Tang J, Gordon G M, Nickoloff B J, Forman K E. The helix-loop-helix protein id-1 delays onset of replicative senescence in human endothelial cells.  Lab Invest. 2002;  82 1073-1079
• 48 Folkman J. Tumor angiogenesis: therapeutic implications.  N Engl J Med. 1971;  285 1182-1186
• 49 Conti C J. Vascular endothelial growth factor: regulation in the mouse skin carcinogenesis model and use in antiangiogenesis cancer therapy.  Oncologist. 2002;  7(suppl 3) 4-11
• 50 Holash J, Maisonpierre P C, Compton D et al.. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF.  Science. 1999;  284 1994-1998
• 51 Rubenstein J L, Kim J, Ozawa T et al.. Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption.  Neoplasia. 2000;  2 306-314
• 52 Kunkel P, Ulbricht U, Bohlen P et al.. Inhibition of glioma angiogenesis and growth in vivo by systemic treatment with a monoclonal antibody against vascular endothelial growth factor receptor-2.  Cancer Res. 2001;  61 6624-6628
• 53 Kim E S, Serur A, Huang J et al.. Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma.  Proc Natl Acad Sci USA. 2002;  99 11399-11404
• 54 Dachs G U, Tozer G M. Hypoxia modulated gene expression: angiogenesis, metastasis and therapeutic exploitation.  Eur J Cancer. 2000;  36 1649-1660
• 55 Larcher F, Robles A I, Duran H et al.. Up-regulation of vascular endothelial growth factor/vascular permeability factor in mouse skin carcinogenesis correlates malignant progression state and activated H-ras expression levels.  Cancer Res. 1996;  56 5391-5396
• 56 Kaelin W G, Iliopoulos O, Lonergan K M, Ohh M. Functions of the von Hippel-Lindau tumour suppressor protein.  J Intern Med. 1998;  243 535-539
• 57 Chiarugi V, Magnelli L, Gallo O. Cox-2, iNOS and p53 as play-makers of tumor angiogenesis [review].  Int J Mol Med. 1998;  2 715-719
• 58 Harada H, Nakagawa K, Iwata S et al.. Restoration of wild-type p16 down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in human gliomas.  Cancer Res. 1999;  59 3783-3789
• 59 Rak J, Filmus J, Finkenzeller G, Grugel S, Marme D, Kerbel R S. Oncogenes as inducers of tumor angiogenesis.  Cancer Metastasis Rev. 1995;  14 263-277
• 60 Petit A M, Rak J, Hung M C et al.. Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors.  Am J Pathol. 1997;  151 1523-1530
• 61 Risau W. Mechanisms of angiogenesis.  Nature. 1997;  386 671-674
• 62 Asahara T, Takahashi T, Masuda H et al.. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells.  EMBO J. 1999;  18 3964-3972
• 63 Hattori K, Dias S, Heissig B et al.. Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells.  J Exp Med. 2001;  193 1005-1014
• 64 Asahara T, Masuda H, Takahashi T et al.. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization.  Circ Res. 1999;  85 221-228
• 65 Lyden D, Hattori K, Dias S et al.. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth.  Nat Med. 2001;  7 1194-1201
• 66 Bolontrade M F, Zhou R R, Kleinerman E S. Vasculogenesis plays a role in the growth of Ewing's sarcoma in vivo.  Clin Cancer Res. 2002;  8 3622-3627
• 67 Shirakawa K, Furuhata S, Watanabe I et al.. Induction of vasculogenesis in breast cancer models.  Br J Cancer. 2002;  87 1454-1461
• 68 Quirici N, Soligo D, Caneva L, Servida F, Bossolasco P, Deliliers G L. Differentiation and expansion of endothelial cells from human bone marrow CD133(+) cells.  Br J Haematol. 2001;  115 186-194
• 69 Shi Q, Rafii S, Wu M H et al.. Evidence for circulating bone marrow-derived endothelial cells.  Blood. 1998;  92 362-367
• 70 Lin Y, Weisdorf D J, Solovey A, Hebbel R P. Origins of circulating endothelial cells and endothelial outgrowth from blood.  J Clin Invest. 2000;  105 71-77
• 71 Peichev M, Naiyer A J, Pereira D et al.. Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors.  Blood. 2000;  95 952-958
• 72 Gunsilius E, Duba H C, Petzer A L et al.. Evidence from a leukemia model for maintenance of vascular endothelium by bone-marrow-derived endothelial cells.  Lancet. 2000;  355 1688-1691
• 73 Gehling U M, Ergun S, Schumacher U et al.. In vitro differentiation of endothelial cells from AC133-positive progenitor cells.  Blood. 2000;  95 3106-3112
• 74 Warren B A. The vascular morphology of tumors. In: Peterson H-I Tumor Blood Circulation: Angiogenesis, Vascular Morphology and Blood Flow of Experimental and Human Tumors. Boca Raton, FL; CRC Press Inc 1979: 1-48
• 75 Konerding M A, Steinberg F, Streffer C. The vasculature of xenotransplanted human melanomas and sarcomas on nude mice. II. Scanning and transmission electron microscopic studies.  Acta Anat (Basel). 1989;  136 27-33
• 76 Dvorak H F, Nagy J A, Dvorak J T, Dvorak A M. Identification and characterization of the blood vessels of solid tumors that are leaky to circulating macromolecules.  Am J Pathol. 1988;  133 95-109
• 77 Less J R, Skalak T C, Sevick E M, Jain R K. Microvascular architecture in a mammary carcinoma: branching patterns and vessel dimensions.  Cancer Res. 1991;  51 265-273
• 78 Kohn S, Nagy J A, Dvorak H F, Dvorak A M. Pathways of macromolecular tracer transport across venules and small veins. Structural basis for the hyperpermeability of tumor blood vessels.  Lab Invest. 1992;  67 596-607
• 79 Konerding M A, Miodonski A J, Lametschwandtner A. Microvascular corrosion casting in the study of tumor vascularity: a review.  Scanning Microsc. 1995;  9 1233-1244
• 80 Less J R, Posner M C, Skalak T C, Wolmark N, Jain R K. Geometric resistance and microvascular network architecture of human colorectal carcinoma.  Microcirculation. 1997;  4 25-33
• 81 Hashizume H, Baluk P, Morikawa S et al.. Openings between defective endothelial cells explain tumor vessel leakiness.  Am J Pathol. 2000;  156 1363-1380
• 82 McDonald D M, Baluk P. Significance of blood vessel leakiness in cancer.  Cancer Res. 2002;  62 5381-5385
• 83 Berger R, Albelda S M, Berd D, Ioffreda M, Whitaker D, Murphy G F. Expression of platelet-endothelial cell adhesion molecule-1 (PECAM-1) during melanoma-induced angiogenesis in vivo.  J Cutan Pathol. 1993;  20 399-406
• 84 Miettinen M, Lindenmayer A E, Chaubal A. Endothelial cell markers CD31, CD34, and BNH9 antibody to H- and Y-antigens-evaluation of their specificity and sensitivity in the diagnosis of vascular tumors and comparison with von Willebrand factor.  Mod Pathol. 1994;  7 82-90
• 85 DeYoung B R, Swanson P E, Argenyi Z B et al.. CD31 immunoreactivity in mesenchymal neoplasms of the skin and subcutis: report of 145 cases and review of putative immunohistologic markers of endothelial differentiation.  J Cutan Pathol. 1995;  22 215-222
• 86 Orchard G E, Zelger B, Jones E W, Jones R R. An immunocytochemical assessment of 19 cases of cutaneous angiosarcoma.  Histopathology. 1996;  28 235-240
• 87 Hellwig S M, Damen C A, van Adrichem N P, Blijham G H, Groenewegen G, Griffioen A W. Endothelial CD34 is suppressed in human malignancies: role of angiogenic factors.  Cancer Lett. 1997;  120 203-211
• 88 Kumar S, Ghellal A, Li C et al.. Breast carcinoma: vascular density determined using CD105 antibody correlates with tumor prognosis.  Cancer Res. 1999;  59 856-861
• 89 de la Taille A, Katz A E, Bagiella E et al.. Microvessel density as a predictor of PSA recurrence after radical prostatectomy. A comparison of CD34 and CD31.  Am J Clin Pathol. 2000;  113 555-562
• 90 Maniotis A J, Folberg R, Hess A et al.. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry.  Am J Pathol. 1999;  155 739-752
• 91 Folberg R, Hendrix M J, Maniotis A J. Vasculogenic mimicry and tumor angiogenesis.  Am J Pathol. 2000;  156 361-381
• 92 Hendrix M J, Seftor E A, Meltzer P S et al.. Expression and functional significance of VE-cadherin in aggressive human melanoma cells: role in vasculogenic mimicry.  Proc Natl Acad Sci USA. 2001;  98 8018-8023
• 93 McDonald D M, Foss A J. Endothelial cells of tumor vessels: abnormal but not absent.  Cancer Metastasis Rev. 2000;  19 109-120
• 94 O'Reilly M S, Holmgren L, Shing Y et al.. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung.  Cell. 1994;  79 315-328
• 95 Giavazzi R, Nicoletti M I. Small molecules in anti-angiogenic therapy.  Curr Opin Investig Drugs. 2002;  3 482-491
• 96 Timar J, Dome B, Fazekas K, Janovics A, Paku S. Angiogenesis-dependent diseases and angiogenesis therapy.  Pathol Oncol Res. 2001;  7 85-94
• 97 Casanova M L, Larcher F, Casanova B et al.. A critical role for ras-mediated, epidermal growth factor receptor-dependent angiogenesis in mouse skin carcinogenesis.  Cancer Res. 2002;  62 3402-3407
• 98 Ogawa T, Takayama K, Takakura N, Kitano S, Ueno H. Anti-tumor angiogenesis therapy using soluble receptors: enhanced inhibition of tumor growth when soluble fibroblast growth factor receptor-1 is used with soluble vascular endothelial growth factor receptor.  Cancer Gene Ther. 2002;  9 633-640
• 99 McGary E C, Weber K, Mills L et al.. Inhibition of platelet-derived growth factor-mediated proliferation of osteosarcoma cells by the novel tyrosine kinase inhibitor STI571.  Clin Cancer Res. 2002;  8 3584-3591
• 100 Nowak A K, Lake R A, Kindler H L, Robinson B W. New approaches for mesothelioma: biologics, vaccines, gene therapy, and other novel agents.  Semin Oncol. 2002;  29 82-96
• 101 Shim W S, Teh M, Mack P O, Ge R. Inhibition of angiopoietin-1 expression in tumor cells by an antisense RNA approach inhibited xenograft tumor growth in immunodeficient mice.  Int J Cancer. 2001;  94 6-15
• 102 Brantley D M, Cheng N, Thompson E J et al.. Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo.  Oncogene. 2002;  21 7011-7026
• 103 Brooks P C, Stromblad S, Klemke R, Visscher D, Sarkar F H, Cheresh D A. Antiintegrin alpha v beta 3 blocks human breast cancer growth and angiogenesis in human skin.  J Clin Invest. 1995;  96 1815-1822
• 104 Gutheil J C, Campbell T N, Pierce P R et al.. Targeted antiangiogenic therapy for cancer using Vitaxin: a humanized monoclonal antibody to the integrin alphavbeta3.  Clin Cancer Res. 2000;  6 3056-3061
• 105 Kumar C C, Malkowski M, Yin Z et al.. Inhibition of angiogenesis and tumor growth by SCH221153, a dual alpha(v)beta3 and alpha(v)beta5 integrin receptor antagonist.  Cancer Res. 2001;  61 2232-2238
• 106 Janssen M L, Oyen W J, Dijkgraaf I et al.. Tumor targeting with radiolabeled alpha(v)beta(3) integrin binding peptides in a nude mouse model.  Cancer Res. 2002;  62 6146-6151
• 107 Raza S L, Cornelius L A. Matrix metalloproteinases: pro- and anti-angiogenic activities.  J Investig Dermatol Symp Proc. 2000;  5 47-54
• 108 Vihinen P, Kahari V M. Matrix metalloproteinases in cancer: prognostic markers and therapeutic targets.  Int J Cancer. 2002;  99 157-166
• 109 Katori H, Baba Y, Imagawa Y et al.. Reduction of in vivo tumor growth by MMI-166, a selective matrix metalloproteinase inhibitor, through inhibition of tumor angiogenesis in squamous cell carcinoma cell lines of head and neck.  Cancer Lett. 2002;  178 151-159
• 110 Jain R K. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy.  Nat Med. 2001;  7 987-989