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        Molecular Characterisation of Angiogenesis


        Definition

           Angiogenesis (angio'gen'esis) - sprouting of new capillaries from pre-existing vessels characterized by expansion of the endothelium by proliferation, migration and remodeling. Angiogenesis is a dynamic multistep process, which involves retraction of pericytes from the abluminal surface of the capillary, release of proteases from the activated endothelial cells, degradation of the ECM surrounding the pre-existing vessels, endothelial cell migration toward an angiogenic stimulus and their proliferation, formation of tube-like structures, fusion of the formed vessels and initiation of blood flow. Growth of the vascular system is primarily a developmental process occuring during embryogenesis and only to a limited extend in postnatal life. In the adult, endothelial cells are among those exhibiting the lowest replication level in the body (0.01% engaged in cell division) with angiogenesis being almost completely downregulated, except for the female reproductive system, and during pathological tissue growth (wound healing, tumor growth, diabetic retinopathy, rheumatoid arthritis, psoriasis, and more than 70 other conditions). The soluble mediators from the surrounding tissues induce the switch from the quiescent to an activated endothelial cell. The following construction of a vascular network is organized in several steps of the angiogenic cascade: induction of proteases, degradation of the basement membrane, migration of the endothelial cells into the interstitial space, endothelial cell proliferation, lumen formation, generation of new basement membrane with the recruitment of pericytes, fusion of the newly formed vessels, initiation of blood flow.


        Tumor-associated Angiogenesis


           The theory that tumors lay dormant yet viable, unable to grow beyond 2 to 3 mm3 in size in the absence of neovascularization was put forth by Judah Folkman (Folkman J, 1971, N Engl J Med 258:1182). In accordance with the latter, the progressive growth of tumors has been shown to be angiogenesis-dependent in various systems. Consequently the process of tumor angiogenesis gained importance as a potential target of anti-cancer therapies. The latter would be crucially dependent on determining and exploiting the distinctions of tumor versus normal endothelium. Several differences between tumor-associated and normal endothelium have established in the past by studies on their structure and function:
        • Pericytes surrounding normal capillaries are reduced in number or absent from tumor capillaries. Pericytes are thought to be involved in the maturation of vessels and the inhibition of endothelial proliferation.
        • The extracellular matrix of tumor vessels is different. The basement membrane surrounding the vessels is reduced, there are higher concentrations of hyaluronic acid and lower concentrations of sulfated proteoglycans.
        Tumor Angiogenesis

        Molecular Mechanisms

           Considerable insight in the molecular and cellular biology of angiogenesis has been obtained by in vitro studies using endothelial cells, isolated from capillaries or large vessels. Angiogenic factors (heparin binding peptide growth factors: VEGF, FGF-1, FGF-2, PDGF, HGF/SF; non-heparin binding peptide growth factors: EGF, TGF-alpha, TGF-beta; oligosaccharides; inflammatory mediators: TNF-alpha, ILs, Prostaglandins; hormones: Oestrogens, Proliferin; cell adhesion molecules: VCAM-1, E-selectin (Klagsbrun et al, 1999)) are able to mimic in vitro all the steps of the angiogenic cascade, including endothelial cell proliferation, migration and differentiation (Daniel et al).

         
        Tumor Angiogenesis
         
        Angiogenic endothelial cells show a distinct genetic expression repertoir leading to modification of the principal cellular functions involved in angiogenesis. These are thought to fall into the following categories: a) regulation of the proteolytic balance leading to localized pericellular matrix degradation during cell migration, and protection against excessive extracellular matrix destruction. b) extracellular matrix (ECM) synthesis with preferentially expression of basement membrane components such as tenascin, type IV collagen, laminin, nidogen/entactin, and proteoglycans. c) synthesis of adhesion molecules involved in extracellular matrix interaction. d) cytoskeletal reorganization involved in cell migration. e,f) growth factors and their receptors. Indeed, our sequence analysis of a published angiogenesis expression profile experiment (St Croix B et al. Science. 2000 Aug 18;289(5482):1197-202) supports such a view.

        Antiangiogenic therapies

           Antiangiogenic therapies have the following advantages that make the study of tumor angiogensis of practical interest:

        • As an oncofetal mechanism that is mostly downregulated in the healthy adult, targeting of angiogenesis should lead to minimal side effects even after prolonged treatment.
        • tumor-associated angiogenesis is a physiological host mechanism and its pharmacological inhibition should, consequently, not lead to the development of resistance
        • each tumor capillary potentially supplies hundreds of tumor cells and the targeting of the tumor vasculature should, thus, lead to a potentiation of the antitumorigenic effect
        • in contrast to the interstitial location of tumor cells, direct contact of the vasculature to the circulation allows efficient access of therapeutic agents.

        Functional Genomics Approaches in Angiogenesis

        PubMed: 10947988 Genes expressed in human tumor endothelium
        St Croix B, Rago C, Velculescu V, Traverso G, Romans KE, Montgomery E, Lal A, Riggins GJ, Lengauer C, Vogelstein B, Kinzler KW.
        Science. 2000 Aug 18;289(5482):1197-202.
        PubMed: 10854212 Gene expression profiling in an in vitro model of angiogenesis.
        Kahn J, Mehraban F, Ingle G, Xin X, Bryant JE, Vehar G, Schoenfeld J, Grimaldi CJ, Peale F, Draksharapu A,Lewin DA, Gerritsen ME.
        Am J Pathol. 2000 Jun;156(6):1887-900.
        PubMed: 10792972 Identification of tumor angiogenesis-related genes by subtractive hybridization.
        Wang JL, Liu YH, Lee MC, Nguyen TM, Lee C, Kim A, Nguyen M
        Microvasc Res 2000 May;59(3):394-7
        PubMed: 10769617 Gene targeting and gene transfer to unravel the molecular basis of the formation and disorders of blood vessels.
        Carmeliet P.
        Verh K Acad Geneeskd Belg. 2000;62(1):31-68. Review.


        Author: Maria Novatchkova (novatchkova@imp.ac.at)
        Last modified: Jan 2001