CellDeath&Differentiation(2019)26:690–702https://doi.org/10.1038/s41418-019-0292-yREVIEWARTICLEAutophagyandcancerstemcells:molecularmechanismsandtherapeuticapplicationsFrancescaNazio1●MatteoBordi1,2●ValentinaCianfanelli3●FrancoLocatelli1,4●FrancescoCecconi1,2,3Received:16November2018/Revised:15January2019/Accepted:16January2019/Publishedonline:6February2019©TheAuthor(s)2019.ThisarticleispublishedwithopenaccessAbstractAutophagyandmitophagyactincancerasbimodalprocesses,whosedifferentialfunctionsstrictlydependoncancerontogenesis,progression,andtype.Forinstance,theycanacttopromotecancerprogressionbyhelpingcancercellssurvivestressor,instead,whenmutatedorabnormal,toinducecarcinogenesisbyinfluencingcellsignalingorpromotingintracellulartoxicity.Forthisreason,thestudyofautophagyincanceristhemainfocusofmanyresearchersandseveralclinicaltrialsarealreadyongoingtomanipulateautophagyandbythiswaydeterminetheoutcomeofdiseasetherapy.Sincetheestablishmentofthecancerstemcell(CSC)theoryandthediscoveryofCSCsinindividualcancertypes,autophagyandmitophagyhavebeenproposedaskeymechanismsintheirhomeostasis,dismissalorspread,eventhoughwestillmissacomprehensiveviewofhowandbywhichregulatorymoleculesthesetwoprocessesdrivecellfate.Inthisreview,wewilldiveintothedeepwaterofautophagy,mitophagy,andCSCsandoffernovelviewpointsonpossibletherapeuticstrategies,basedonthemodulationofthesedegradativesystems.Facts●Autophagyplaysadualroleincancerasatumorsuppressorandpromoter.●CSCsareusuallycharacterizedbyadysregulationofautophagy/mitophagy.●Themodulationofautophagy/mitophagyimpactsonCSCgeneration,differentiation,plasticity,migration/invasionandpharmacological,viralandimmune-resistance.●Targetingautophagy/mitophagycouldpavethewayfornewtherapeuticstrategiestofightCSCaggressiveness.Openquestions●WhatarethekeysignalingpathwaysimpactedbyautophagyinCSCs?●WhichistheroleofmitophagyintheprofoundmetabolicreprogrammingofCSCs?●HowcouldwemanipulateautophagytodriveCSCfate?Autophagyincancer:anoverviewAutophagy...
