Host-derived tumor endothelial marker 8 promotes the growth of melanoma.

Abstract Tumor endothelial marker 8 (TEM8) wasinitially identified asageneoverexpressedinthevasculatureofhumantumorsandwas subsequently identified as an anthrax toxin receptor.To assess the functional role of TEM8, we disrupted theTEM8 gene in mice by targeted homologous recombination.TEM8 / mice were viable and reached adulthood withoutdefects in physiologic angiogenesis. However, histopathologicanalysis revealed an excess of extracellular matrix in severaltissues, including the ovaries, uterus, skin, and periodontalligament of the incisors, the latter resulting in dentaldysplasia. When challenged with B16 melanoma, tumorgrowth was delayed in TEM8 / mice, whereas the growth ofother tumors, such as Lewis lung carcinoma, was unaltered.These studies show that host-derived TEM8 promotes thegrowth of certain tumors and suggest that TEM8 antagonistsmay have utility in the development of new anticancertherapies. [CancerRes2009;69(15):6021–6] Introduction Thevascularizationofsolidtumorsprovidestumorcellswithanessential supply of oxygen and nutrients and is considered aprerequisiteforthesustainedgrowthandspreadofcancer(1).Thesuccessfuldesignofrationalnewagentsthatcaninhibittumorgrowthbydestroyingorpreventingthegrowthoftumorbloodvesselsdependsonanintimatemolecularunderstandingoftumorangiogenesis.Global analysesofgeneexpressionofendothelialcellsliningthetumorbloodvesselsofhumancolorectalcancerhaveledtotheidentificationofaseriesofgenescalledtumorendothelialmarkers(TEM;ref.2).Ofthese,TEM8isofparticularinterestbecauseofitsoverexpressionintumorvesselsofmultipletumortypes,cellsurfacelocalization,highconservationamongspecies,andlackofdetectableexpressionintheangiogenicvesselsofthecorpusluteum(2–4).ThepredominantformofTEM8isa single-pass transmembrane glycoprotein of approximately 80to 85 kDa containing an extracellular von Willebrand type Adomainandalargecytoplasmictail.In vitro TEM8hasbeenfoundtobindcollagentypesIandVI(3,5,6).BothTEM8andcapillarymorphogenesisprotein2(CMG2),itsclosesthomologue,havebeenidentifiedasanthraxtoxinreceptorsandarethereforealsoknownasANTXR1andANTXR2,respectively(7,8).Interestingly,anthraxlethal toxin, composed of lethal toxin and protective antigen,displayedpotentantitumoractivityinpreclinicaltumormodelswhenjudiciouslyadministeredtomiceatnontoxicdoses(9–13).Up-regulationofTEM8intumorvesselsmayhelptoexplainthetumoricidalactivityofanthraxlethaltoxinin vivo,butCMG2,alsoexpressedinendothelialcells,couldpotentiallyplayarole.Tobetter understand the normal functional role of TEM8, wedisruptedtheTEM8 geneinmicebyhomologousrecombination.ThesestudiesshowthatTEM8playsanimportantroleinnormalextracellularmatrix(ECM)homeostasisandthegrowthofcertaintumortypes,suchasmelanoma.