hallmarks of cancer · complementary capabilities that enable tumor growth and metastatic...
TRANSCRIPT
HallmarksofCancerHayleyAffrontiPhDStudent
9/6/16
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WhatisCancer?WhataretheHallmarks?
• Normalbodycellswhichbegintodividewithoutstoppingandcanspreadintosurroundingtissues
• Thehallmarksofcancerarethedistinctiveandcomplementarycapabilitiesthatenabletumorgrowthandmetastaticdissemination
• Inotherwords…Thecharacteristicsthatmakecancer,cancer.
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OncogeneandTumorSuppressorGenes
• Oncogene:mutatedformsofnormalcellulargenesgenerallyinvolvedinpromotingcellproliferation.Thesemutationsresultindominantgainoffunction.
• Tumorsuppressor:geneswhosenormalfunctioninregulatingproliferationistostopit.Mutationresultsinrecessivelossoffunction.
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TumorHeterogeneity
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SustainingProliferativeSignalling:MastersoftheirOwnDestinies!
• Normalcellscarefullycontrolgrowthanddivision• Cancercellsderegulatethesesignals• Howdotumorsderegulatethis?
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7NikiforovY.,NatureEndocrinology2011http://www.labbookpages.co.uk/research/bioNode.html
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EvadingGrowthSuppressors
• Circumventingprogramswhichnegativelyregulatecellproliferation
• Whataretheseprograms?– Apoptosis– Senescence– DNAdamageresponse– Cellcycleinhibition– Contactinhibition
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KeyPlayersinGrowthSuppression
• TP53:Sensestheneedtohaltcellcycleprogressionandcantriggerapoptosis– >50%oftumorshavemutation– Li-FraumeniSyndrome:~50%chanceofdevelopingcancerbyage30
• RB:Gatekeeperofcellcycleprogression
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ResistingCellDeath• Whatareformsofcelldeath?– Apoptosis– Autophagy– Necrosis
• Howdotumors resistcelldeath?– Lossofp53– Increaseanti-apoptotic– Decreasepro-apoptotic
12KulbackaJ.,Intech2012
AutophagyandNecrosis
• Autophagy:Enablescellstobreakdowncellularorganelles,andrecyclethemforbiosynthesisandenergymetabolism
• Necrosis:Releasecontentsintolocaltissuemicroenvironment(includingproinflammatorysignals)
13http://ds9.botanik.uni-bonn.de/zellbio/AG-Baluska-Volkmann/pdf/PCDU/09%20-%20Autophagy.pdf
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EnablingReplicativeImmortality
• Cancercellsmusthaveunlimitedreplicativepotential
• Normalcellspassthroughalimitednumberofsuccessivecellgrowth-and-divisioncycles
• Cellsmustovercomesenescenceandcrisis
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Telomeres:thegoodandthebad• Shorttandemrepeatswhichprotecttheendsofchromosomes,andareshorteneduponcelldivision
• TelomeraseaddstelomerestotheendsoftelomericDNA
16SahinE.andDePinhoR.,Nature2010
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InducingAngiogenesis
• Tumorsrequireoxygen,nutrients,andtheabilitytoevacuatemetabolicwastesandCO2
18EMDMillipore
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ActivatingInvasionandMetastasis
Step1:PhysicalDisseminationofcancercellsfromprimarytumortoDistantTissuesStep2:Adaptationofthesecellstoforeigntissuemicroenvironments,successfulcolonization
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ActivatingInvasionandMetastasis
21FranciaG.etal,NatureReviewsCancer2011
InterconnectionoftheHallmarks
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GenomeInstabilityandMutation
• Acquisitionofthehallmarksinpartdependsongenomicalterations
• Thismaybeacquiredthrough…– Clonalselection– DNAmethylation– Histonemodifications
• AlterationsinDNAmaintenancemachinery
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TumorPromotingInflammation• Immunecellsarepresentintumorsatvariousdensities
• Inflammationcancontributetomultiplehallmarksbysupplyingbioactivemoleculestothetumormicroenvironment,includinggrowthfactorsandsurvivalfactors
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ReprogrammingEnergyMetabolism
• TheWarburgEffect:Cancercellsreprogramtheirglucosemetabolism,bylimitingtheirenergyproductionlargelytoglycolysis
• Divertglycolyticintermediatestootherbiosyntheticpathwaystomakemacromoleculesandorganelles
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EvadingImmuneDestruction
• Cellsandtissuesareunderconstantsurveillancebytheimmunesystem
• MicelackingNKandTcellsweremoresusceptibletocancerdevelopment
• PatientswithhigherCTLsandNKcellshaveabetterprognosis
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TheHallmarksandTherapies
Doyoufeelthatonehallmarkismoreimportantthantheother?
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Thankyou!Comments/Questions?
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