PROSTHODONTICS - American College of Prosthodontists
PROSTHODONTICS - American College of Prosthodontists
PROSTHODONTICS - American College of Prosthodontists
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Apoptosisoccursinacarefully‐scriptedmannerthatresultsinloss<strong>of</strong>cellmembraneintegrityandnucleardisruptionasaprecursortoprocessing<strong>of</strong>breakdownproductsbyadjacentcells.Apoptosiscanbeinducedbyexternalfactorsthatuponbindingtospecificcellsurfacereceptorsactivatepro‐apoptoticsignaltransductionpathways.Inmostcells,apoptosisoccursviatwomainsignalingpathways.Theextrinsicpathwayinvolvestheactivation<strong>of</strong>thedeathreceptors,Fasandtumournecrosisfactorreceptors,whiletheintrinsicpathwayinvolvestheactivation<strong>of</strong>severalprocaspasesandthemitochondrialrelease<strong>of</strong>apoptogenicfactorssuchascytochromecandapoptosis‐inducingfactor(AIF)intothecytoplasm.Subsequently,acascade<strong>of</strong>eventsdrivenprimarilybytheactivation<strong>of</strong>proteolyticcaspasesresultsintheprocessing<strong>of</strong>intracellularstructuralproteinsandregulatoryenzymesthatculminatesinapoptoticcelldeath.Thesomewhatfamousp53tumoursuppressorprotein,themyconcogene,theretinoblastomaproteinandtheBcl‐2family<strong>of</strong>proteinsareallproposedtobeinvolvedinapoptosisregulationwiththeformerconsideredaneffectivesensor<strong>of</strong>DNAdamageandintracellularhypoxia.Forexample,somecancercellsappeartohavelostadegree<strong>of</strong>p53‐inducedapoptosis.Indeedsomecancertherapiesareaimedattrickingcancercellsintoinitiatingapoptoticeventsandthisisnotsurprisinggiventhegoal<strong>of</strong>radiationtherapyandchemotherapytocauseDNAdamage.4.LimitlessreplicativepotentialItispostulatedthatallcellshaveafinitenumber<strong>of</strong>celldivisionsafterwhichacellwilleitherdieorbecomesenescentandthisappearstobetrueformostcells.One<strong>of</strong>tenhears<strong>of</strong>“Hayflick’sLimit”inscientificcircles,atermbornfromobservationsthatincellculture,fibroblastscannotreplicateadinfinitumandseemtoonlybeabletodoubleaspecificnumber<strong>of</strong>timeswithfiftytosixtytimes<strong>of</strong>tenproposedasanaveragenumber.However,acancercell,withitsabilitytoreplicateseeminglyout<strong>of</strong>control,overcomesthisbiologicallimitation<strong>of</strong>replicativesenescencebydisablingtheretinoblastomaproteinandthep53family<strong>of</strong>proteins.Replicationscontinueuntilthecellreachesastage<strong>of</strong>“crisis”inwhichalmostallcellsdie.Yet,thereareexceptionsalbeitrare(1in10million)thatsurvive“crisis”andbecome“immortal”,i.e.thecellshavelimitlessreplicativepotential.Itisthesespecialsurvivors,whohavesomehowevadedtwomajorimpedancestotheirsurvival,thatcanmultiplyandpromotetumorgrowth.Whencellsdivide,telomeres,arepetitivesegment<strong>of</strong>DNAlocatedattheterminalend<strong>of</strong>chromosomes,protectschromosomesfromdestructionordamage.Duringmultiplecelldivisions,telomeresbecomeprogressivelyshortenedandultimatelytheyarenolongerabletoprovidethechromosomalprotectionthatisneededt<strong>of</strong>acilitateadditionalreplicationsandpreventcellsfromentering“crisis”.Cancercellsappearareabletomaintaintelomereseitherbyupregulation<strong>of</strong>thetelomeraseenzyme(seeninapproximately90%<strong>of</strong>cancers)orelsebyinter‐chromosomalDNAexchanges,aprocessreferredtoas“alternativelengthening<strong>of</strong>telomeres”orALTthatisobservedinapproximately10%<strong>of</strong>cancers.Regardless<strong>of</strong>themechanismsemployedbyanygiventype<strong>of</strong>cancer,theneteffectistopreventcellsfromreachingcrisiswhichinturnsprovidesforalargerpool<strong>of</strong>cellsfromwhichimmortalizedcellsmayemerge.5.SustainedangiogenesisClearlyacadre<strong>of</strong>cellsthatformsamalignanttumorneedsnutrientstosustainitselfandtoexpand.Theanalogywouldbetoaninvadingarmythatcannotmoveorpushforwardwithoutapropersupply<strong>of</strong>resourcesintheshape<strong>of</strong>foodandfuel.Simply,physicochemicallimitationsmeanthatcapillariesmustlieincloseproximitytotumorcellsandsomecancercells,even 182010 CDEL Re-recognition <strong>of</strong> the Specialty Report 202 <strong>of</strong> 279