HallmarksofCancer
HayleyAffronti
PhDStudent
9/6/16
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WhatisCancer?WhataretheHallmarks?
• Normalbodycellswhichbegintodivide
withoutstoppingandcanspreadinto
surroundingtissues
• Thehallmarksofcancerarethedistinctiveand
complementarycapabilitiesthatenabletumor
growthandmetastaticdissemination
• Inotherwords…Thecharacteristicsthatmake
cancer,cancer.
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OncogeneandTumorSuppressorGenes
• Oncogene:mutatedformsofnormalcellular
genesgenerallyinvolvedinpromotingcell
proliferation.Thesemutationsresultin
dominantgainoffunction.
• Tumorsuppressor:geneswhosenormal
functioninregulatingproliferationistostopit.
Mutationresultsinrecessivelossoffunction.
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TumorHeterogeneity
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SustainingProliferativeSignalling:Mastersof
theirOwnDestinies!
• Normalcellscarefullycontrolgrowthanddivision
• Cancercellsderegulatethesesignals
• Howdotumorsderegulatethis?
X
http://www.labbookpages.co.uk/research/bioNode.html
NikiforovY.,NatureEndocrinology2011
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EvadingGrowthSuppressors
• Circumventingprogramswhichnegatively
regulatecellproliferation
• Whataretheseprograms?
– Apoptosis
– Senescence
– DNAdamageresponse
– Cellcycleinhibition
– Contactinhibition
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KeyPlayersinGrowthSuppression
• TP53:Sensestheneedtohaltcellcycle
progressionandcantriggerapoptosis
– >50%oftumorshavemutation
– Li-FraumeniSyndrome:~50%chanceofdeveloping
cancerbyage30
• RB:Gatekeeperofcellcycleprogression
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ResistingCellDeath
• Whatareformsofcelldeath?
– Apoptosis
– Autophagy
– Necrosis
• Howdotumors
celldeath?
resist
– Lossofp53
– Increaseanti-apoptotic
– Decreasepro-apoptotic
KulbackaJ.,Intech2012
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AutophagyandNecrosis
• Autophagy:Enablescellstobreakdown
cellularorganelles,andrecyclethemfor
biosynthesisandenergymetabolism
• Necrosis:Releasecontentsintolocaltissue
microenvironment(includingproinflammatory
signals)
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http://ds9.botanik.uni-bonn.de/zellbio/AG-Baluska-Volkmann/pdf/PCDU/09%20-%20Autophagy.pdf
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EnablingReplicativeImmortality
• Cancercellsmusthaveunlimitedreplicative
potential
• Normalcellspassthroughalimitednumberof
successivecellgrowth-and-divisioncycles
• Cellsmustovercomesenescenceandcrisis
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Telomeres:thegoodandthebad
• Shorttandemrepeatswhichprotecttheendsof
chromosomes,andareshorteneduponcelldivision
• Telomeraseaddstelomerestotheendsoftelomeric
DNA
SahinE.andDePinhoR.,Nature2010
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InducingAngiogenesis
• Tumorsrequireoxygen,nutrients,andthe
abilitytoevacuatemetabolicwastesandCO2
EMDMillipore
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ActivatingInvasionandMetastasis
Step1:PhysicalDisseminationofcancercells
fromprimarytumortoDistantTissues
Step2:Adaptationofthesecellstoforeigntissue
microenvironments,successfulcolonization
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ActivatingInvasionandMetastasis
FranciaG.etal,NatureReviewsCancer2011
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InterconnectionoftheHallmarks
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GenomeInstabilityandMutation
• Acquisitionofthehallmarksinpartdependson
genomicalterations
• Thismaybeacquiredthrough…
– Clonalselection
– DNAmethylation
– Histonemodifications
• AlterationsinDNAmaintenancemachinery
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TumorPromotingInflammation
• Immunecellsarepresentintumorsatvarious
densities
• Inflammationcancontributetomultiplehallmarksby
supplyingbioactivemoleculestothetumor
microenvironment,includinggrowthfactorsand
survivalfactors
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ReprogrammingEnergyMetabolism
• TheWarburgEffect:Cancercellsreprogram
theirglucosemetabolism,bylimitingtheir
energyproductionlargelytoglycolysis
• Divertglycolyticintermediatestoother
biosyntheticpathwaystomake
macromoleculesandorganelles
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EvadingImmuneDestruction
• Cellsandtissuesareunderconstant
surveillancebytheimmunesystem
• MicelackingNKandTcellsweremore
susceptibletocancerdevelopment
• PatientswithhigherCTLsandNKcellshavea
betterprognosis
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TheHallmarksandTherapies
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Doyoufeelthatonehallmarkismore
importantthantheother?
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Thankyou!
Comments/Questions?
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