Cancer%stem%cells,%reason%of%the%failure%of% conven6onal%cancer%treatments Anna!Pérez!Mar+n.!Grau!de!Biotecnologia.!Universitat!Autònoma!de!Barcelona!!
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Cancer%stem%cells,%reason%of%the%failure%of% conven6onal%cancer%treatments! Anna!Pérez!Mar+n.!Grau!de!Biotecnologia.!Universitat!Autònoma!de!Barcelona!! • To!understand!the!properAes!and!the!role!within!tumors!of!cancer!stem!cells! • To!know!cancer!stem!cells!origin! • To!study!different!signalling!pathways!implied!in!cancer!stem!cells!maintenance! • To!understand!why!current!therapies!fail!in!front!of!cancer!stem!cells! ! Cancer! stem! cells% (CSCs)! are! cancer! pluripotent! Defini6on% Cancer%stem%cell%model% iniAaAng!cells!that!are!present!within!tumors!in!a!low!percentage.! a Only!CSCs!have!the!ability!to! generate!the!tumor,!being! progenitors!cells!unable!to!!! generate!it! ! CSCs! have! been! defined! on! the! basis! of! their! ability! Proper6es% to! selfHrenew! (dividing! itself! into! two! idenAcal! daughter! CSCs),! to! expand! the! tumor,! to! migrate! and! form! new! tumors,! to! avoid! anAgrowth!signals,!to!evade!apoptosis,!to!replicate!limitless!and!to! Cancer!stem!cell! model! Clonal!evoluAon! model! ! resist!convenAonal!therapies.!! a! Because! of! their! high! resistance,! cancer! stem! cells! Inconvenient% Clonal%evolu6on%model% ! are!a!reason!of!the!failure!of!convenAonal!therapies,!which!are!not! targeAng!CSCs.!New!therapies!are!being!developed,!not!focused!on! ! ! All!tumor!cells!have!the!apAtude!to! form!new!tumors!! Interconversion%model% Interconversion! model! Cancer!cells!will!always!return!to!a! equilibrium!of!cellHstate!proporAons,! due!to!a!bidirecAonal!interconversion! between!CSC!and!nonHCSC!states! Models!are!not!mutually!exclusive!!! reducing!the!tumor!mass,!but!in!targeAng!CSCs.!! Shackleton,!M.!et!al!.'Semin.!Cancer!Biol.!20,!85–92!(2010)! ! ! Mutagenic%factors% ! Stem% cell% Asymetric!cell!division! Stem% cell% Diff.% cell% ic agen Mut ors% %fact Chemical!and!physical!carcinogens! InfecAous!agents!! EpigeneAc!changes! SomaAc!and!inherited!mutaAons! Microenvironment! Hedgehog% pathway% % % Stem!state!maintenance! Development! Metastasis!! SelfHrenewal! Notch% pathway% ! Hh! Hh Adjacent!! cell! DLL 1,3,4 Jag 1,2 CSC% Notch! Notch Ptch Asymetric!cell!division! Smo Gli 1,2 Diff.%% cancer%cell% CSC% CellHcell!communicaAon! Stem!state!maintenance! Adjacent Cell DifferenAaAon! ProliferaAon! Apoptosis!inhibiAon! γγ!Secretase! Secretase Signalling% pathways% deregula6on% NICD Circulatory% Circulatory System% System EMT EMT% Regulators Regulators% SNAI1 (Snail), SNAI2 (Slug), SNAI3, KLF8, Twist1, EpithelialAMesenchymal% Transi6on%(EMT)% FormaAon!of!a! !heterogeneous!tumor! !!Mesenchymal!markers:!! NHcadherin,!VimenAn,! Metastasis! FibronecAn,!Snail,!Slug,! Twist,!TGFHb1,!CD44! MesenchymalAEpithelial% " Epithelial!markers:!! Transi6on%(MET)% EHcadherin,!CD24! Diff.%% Loss!of!cellHcell!adhesion! cancer%cell% Migratory!capacity! Conven6onal%therapies%% Chemotherapy! !Radiotherapy!! Surgery!! CSC% NHcadherin,!VimenAn,! Twist2, Goosecoid, Foxc 1, 2, ZEB1, ZEB2 (SIP1) FibronecAn,!Snail,!Slug,! TGFHb1,!Twist1H2,!Foxc1H2,! micro RNA ZEB1H2! CSC% EMT EMT% Primary Tumor nonHCSCs!!!!!!!CSCs! Primary%Tumor% β catenin Fzd! APC! Fzd Wnt Wnt! E-cadherin EHcadherin! Vimentin Axl Smad 2/3, Stem!state!maintenance! 4 Wnt/βAcatenin% pathway%! ProliferaAon! TGFβR I/II SelfHrenewal! Apoptosis!inhibiAon! TGFβ Takebe,!N.!et!al.!Breast!Cancer!Res.!13,!211!(2011)! ! ! • Knowledge!of!cancer!stem!cells!leads!to!another! Cancer%stem%cells%therapies% point!of!view!against!the!treatment!of!cancer.!! A!successful!therapy!must!eliminate!the!tumor!bulk!cells!and! induce!the!differenAaAon!or!eliminaAon!of!CSCs!! • Cancer! stem! cells! properAes! help! us! to! Being!necessary!to!combine!tradiAonal!chemotherapy!and! radiotherapy!with!new!strategies!targeAng!CSCs!! • CombinaAon! therapies! are! needed! to! destroy! understand!convenAonal!therapies!failure.! CSCs,! through! differenAaAon! or! eliminaAon,! but! CSCs!present!geneAc!and!cellular!adaptaAons!! High%capacity%for%DNA%repair% High%resistance%to%drug%penetra6on%% Resistance%to%apoptosis%% Microenvironment!! Dormancy/Slow%cell%cycle%kine6cs%! High%metasta6c%poten6al% EpithelialAMesenchymal%transi6on! Therapy!failure!! Differen6a6on%therapy% Must!force!CSCs! to!differenAate!terminally!! to!lose!selfHrenewal!property! to!lose!progression!property!! ReAnoic!acids!! Drugs!targeAng!tumor! epigeneAc!changes!! also!to!avoid!EpithelialHmesenchymal!transiAon.! Elimina6on%therapy% TransplanAng!hematopoieAc!stem!cells! with!allogeneic!inserts! Therapies!against!the!selfHrenewal!! Modelling!the!mechanism!of!resistance! Therapies!based!in!anAgens! HypoxiaHinduced!anAHcancer!agents! EpigeneAc!therapies!! Nanomedicine! Gene!therapy! Drugs! a! • • • • Takebe,!N.,!Warren,!R.!Q.!&!Ivy,!S.!P.!Breast!cancer!growth!and! metastasis:! interplay! between! cancer! stem! cells,! embryonic! signalling! pathways! and! epithelialHtoHmesenchymal! transiAon.! Breast'Cancer'Res.!13,!211!(2011).! Han,! L.,! Shi,! S.,! Gong,! T.,! Zhang,! Z.! &! Sun,! X.! Cancer! stem! cells:! therapeuAc! implicaAons! and! perspecAves! in! cancer! therapy.! Acta'Pharm.'Sin.'B!3,!65–75!(2013).!! Zhao,! Y.,! Alakhova,D.Y.,.Can! nanomedicines! kill! cancer! stem! cells?!Adv.'Drug'Deliv.'Rev.!65,!1763H1783!(2013).!! Shackleton,!M.!Normal!stem!cells!and!cancer!stem!cells:!similar! and!different.!Semin.'Cancer'Biol.!20,!85–92!(2010).!
