HallmarksofCancerHayleyAffrontiPhDStudent

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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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