Ruhrberg, C

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Endogenous inhibitorsof angiogenesisChristiana RuhrbergEndothelial Cell Biology, Imperial Cancer ResearchFund, PO Box 123, 44 Lincoln’s Inn Fields, LondonWC2A 3PX, UK(e-mail: ruhrberg@icrf.icnet.uk)Journal of Cell Science 114, 3215-3216 (2001)© The Company of Biologists LtdIn the course of embryonicdevelopment, during some normalphysiological processes in the adult,such as the female reproductive cycle,and also in a variety of pathologies,including tumour growth, new bloodvessels develop from the pre-existingvascular network through endothelialcell sprouting, proliferation and fusion- a process termed angiogenesis (Risau,1997). Blocking tumour angiogenesishas become a promising approach inmanaging cancer: in recent years, alarge number of anti-angiogenic drugsand recombinant proteins have enteredclinical trials, and some are already inthe ﬁnal phase of testing (seehttp://cancertrials.nci.nih.gov). Research into tumour angiogenesis waskick-started by the realisation thattumours are not able to grow beyond asize of 1-2 mm3 without ﬁrst recruitingtheir own vascular supply to deliveroxygen and nutrients (Folkman, 1971).A wide variety of pro-angiogenicmolecules were subsequently found tobe released from cancerous cells, mostimportantly vascular endothelial growthfactor (VEGF) and basic ﬁbroblastgrowth factor (bFGF; step I; Kerbel,2000). Generally, angiogenesis can be inhibitedat any of a number of key steps in theendothelial growth cycle, in which aquiescent vessel becomes an activelygrowing and invading endothelial tube(Kerbel, 2000). The activation of restingvessels by tumour-derived angiogenicfactors such as VEGF can be blocked by,for example, neutralising antibodies orcompounds that impair downstreamsignalling (inhibition of step I).Degradation of the extracellular matrixby activated endothelial cells can also beprevented, which suppresses sproutingand invasion of growing capillaries intotheir surrounds (inhibition of step II).Alternatively, endothelial cellproliferation can be inhibited by agentsthat block signalling within the cell andarrest its division cycle (inhibition ofstep III) or by agents that prevent thematuration of nascent endothelial cellsinto functional tubes (inhibition of stepIV). Finally, endothelial cells can beforced to apoptose, which destroysexisting tumour vessels and therebyimpairs survival of large tumour massesand metastasis through the vascularroute (inhibition of step V). Excitingly,some inhibitors target the tumourvasculature at more than one of thesesteps, which should increase theirefficiency. For example, in addition tostimulating resting vessels, VEGFpromotes both proliferation and survivalof endothelial cells, and antibodiesagainst this endothelial cell-speciﬁcgrowth factor might therefore target bothquiescent and actively cyclingendothelial cells.Hijacking naturally occurring inhibitorsof angiogenesis to block tumourvascularisation might minimise sideeffects commonly associated with theuse of artiﬁcial compounds in cancerCELL SCIENCE AT A GLANCE 3215©J l f C ll S i 2001 (114 3215 3216)I Small tumour secretesangiogenic  factors Quiescent capillaryVEC apoptosisTumour growth and metastasisTumour cell apoptosisIIMatrix degradationVessel destabilisationSproutingIIIEC proliferationPericyteIVMigrationTissue  invasionLumen formationAngiostatinTSP1PF4METH1/2VasostatinAntithrombinAngiostatinTSP1EndostatinAntithrombinTSP1AngiostatinTSP1EndostatinThrombin Antithrombin1sNRP1Ang2Ang1HSPGTSP1CD36PlasminogenEndostatinCollagen  XVIIIAngiostatinbFGFThrombinPF4Microscopic tumourAntithrombinPF4VEGFbFGFVEGFMETH1/2Tie2FGFRECM LumenNRP1 + FLK NucleusEC(See poster insert)3216therapy. Experimental tests on tumourbearing animals are indeed promising:recombinant angiogenic inhibitors suchas endostatin can shrink tumours to abearable size and might be used to keepthem small indeﬁnitely, since resistancedoes not build up to these agents, andtheir toxicity is low. If these are used incombination with more traditionalcancer drugs, which target tumour cellsdirectly, cancers that are currentlyincurable might at least becomemanageable.Abbreviations/deﬁnitions: Ang1/2, angiopoetin 1/2- ligand for Tie-2 receptor; angiostatin - kringle-domain containing fragment of plasminogen (aprotein involved in the blood clotting/ﬁbrinolyticpathway); anti-thrombin - serpin-family memberinvolved in the blood clotting/ﬁbrinolytic pathway;endostatin - fragment of type XVIII collagen in theextracellular matrix; bFGF, basic ﬁbroblast growthfactor; FGFR, FGF receptor; FLK-1, fms-likekinase 1; VEGF receptor (also known as VEGFR2or KDR); HSPG, heparan sulphate proteoglycan inthe extracellular matrix; Meth1/2, proteincontaining metalloproteases and thrombospondindomains; PF4, fragment of platelet factor 4; NRP1,neuropilin 1 - FLK-1 co-receptor; sNRP1, secretedfragment of neuropilin 1; Tie-2, angiopoetinreceptor (also known as Tek); thrombin - proteinin the blood clotting/ﬁbrinolytic pathway thatupregulates VEGF receptors; TSP1,thrombospondin 1 - extracellular matrix protein;VEGF, vascular endothelial growth factor;vasostatin - fragment of calreticulin (a protein inthe endoplasmic reticulum involved in calciumsignalling).ReferencesRisau, W. (1997). Mechanisms of angiogenesis.Nature 386, 671-674.Folkman, J. (1971). Tumour angiogenesis:therapeutic implications. New Engl. J. Med. 285,1182-1186. Kerbel, R. S. (2000). Tumour angiogenesis: past,present and the near future. Carcinogenesis 21,505-515.JOURNAL OF CELL SCIENCE 114 (18)Cell Science at a Glance on the WebElectronic copies of the poster insert areavailable in the online version of this articleat jcs.biologists.org. JPEG and PDF ﬁles(see supplemental material) can bedownloaded for printing or use as slides.Year 2001 Travelling FellowshipsJCS offers fellowships of up to US$4000 to graduate students and post-docs wishing tomake collaborative visits to other laboratories. These are designed to cover the cost oftravel and other expenses, and there is no restriction on nationality. Applicants shouldbe working in the ﬁeld of cell biology and intend to visit a laboratory in another country.Each application is judged on the excellence of the candidate, and the importance andinnovative quality of the work to be done.Application forms can be downloaded from our Web site at http://jcs.biologists.org.Please send the completed application form, together with a copy of your CV, an accountof the work to be done and a breakdown of the costs involved, as well as letters ofrecommendation from the heads of the laboratory in which you currently work and thelaboratory you hope to visit, to the Production Editor at the address below.Journal of Cell Science Editorial Office,The Company of Biologists Limited,Bidder Building, 140 Cowley Road, Cambridge CB4 0DL, UKDeadline: 31 December

Cell Science at a Glance on the Web Electronic copies of the poster insert are available in the online version of this article at jcs.biologists.org. JPEG and PDF ﬁles (see supplemental material) can be downloaded for printing or use as slides. Year

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