Humans are prone to cancer…this is not a secret, However larger mammals, like whales, are no where near as prone to cancer as humans are. If cancer is essentially a negative outcome lottery at cell levels, and larger organisms have more cells, and thus more potentially cancerous cell divisions, one would expect larger organisms to be more predisposed to cancer. But this is not the case.

1. PETO’SPARADOX
AnnThomas

2. Theevolutionofmulticellularity requiredthesuppressionofcancer.Ifevery
cellhassomechanceofbecomingcancerous,large,long-livedorganismsshould
haveanincreased riskofdevelopingcancercomparedtosmall,short-lived
organisms.Thelackofcorrelationbetween bodysizeandcancer riskisknownas
Peto’sParadox.
Beforetalkingaboutthisparadox,weneedtofirstunderstand howthe
mechanismofcancertakesplaceinanorganism.

3. MECHANISMOFCANCER
Inthesimplestsense,ourbodiesaremadeupofcells.Andtypically thesecellswillbedividing.Itisnotunusualforacelltodivide
andsometimesdieandreplacethemselveswithmorecells.Butwhathappenstocanceristhatyougetsomekindofamutation tothedna
ofthecellandyougetunregulatedcellproliferation.Thecellwillstarttodivideuncontrollablyandovertimeyouwillendupwith
thisuncontrolledcellmassgrowth anditmightbesomethinglikeatumour.
MUTATION
Thetheoryofcancerinitiation andprogressionisdeeplyrootedinevolutionaryandecologicalconcepts.Cancerdevelopsthrough
somaticevolution,withgeneticandepigeneticinstability generatingfitnessvariationamongthecellsofabody

4. TWOTYPESOFGENES
1. Oncogenes
Theyareinvolvedinnormalcellgrowthandproliferation.Theyarenormalgenesandarenotinherentlybad.Buttheproblemarises
whenamutationoccursinoneofthesegenes.Ifyouweretoincreasetheactivityofoncogenes,therewouldbetoomuchcell growth
andcellactivity,andthatcanledtoarealproblem.
2.Tumoursuppressors
Duringcellcycle,itisnormalforcellstoslowdownitsnormalactivitieslikeproteinproduction,etc.,inordertodivide.When
thesecellsgetsmutated,thereisadecreaseinactivityofthesesuppressorsandslowsdowncellcycle.
Hence,boththesegeneswhenmutated, resultsintonsandtonsofcellgrowthandactivity,buttheyworkindifferentways.

5. Howdoesourbodyreacttocancer:
Thesimplest wayourbodycandealwiththeproblemisbyidentifying thecellthathasundergoneaproblematicmutation.Andonceit
does,itessentiallysendsthatcelltoitsdeathinaprocesscalledasAPOPTOSIS(CELLDEATH).Itisaverybasicbutpowerfulwaytodeal
withcancer.
APOPTOSIS(CELLDEATH)
Butwhenyouhaveamutation inyouroncogenesortumoursuppressorgene,itisverylikelytoendupwiththiscellmass.
Selectionattheleveloforganismshasledtotheevolutionoftumorsuppressormechanisms,suchascellcyclecheckpoints and
apoptosis,whichactassafe-guardstopreventsomaticmutations frompropagatinginthecellpopulation.Nonetheless,canceroccurs
atastonishinglyhighratesandcanberesponsiblefor20–46%oftotaldeathsinmulticellular animalsrangingfrommollusksto
mammals

6. Somaticevolutionandthedevelopment ofcancer
Somaticcellsintumourssatisfythethreenecessaryandsufficientconditionsfornatural selection:
1. Theremustbeavariationwithinapopulation.Atumourisaheterogenouspopulationofcellswithsomatic
geneticandepigeneticalterations.
2. Thevariationsmustbeheritable.Geneticandepigeneticalterationsareinheritedbybothdaughtercellswhena
celldivides.
3. Theremustbedifferentialsurvivalandreproduction.Insomecases,thegeneticandepigeneticmutationsprovide
cellswithsurvivaland?orreproductiveadvantagesoverothercells.

7. Thegeneticandepigeneticchangesinsomaticcellscanresultinthesix‘hallmarksofcancer’,allofwhich
provideafitnessadvantagetosomaticcells:
1. Selfsufficiencyofgrowthsignals
2. Insensitivitytoanti-growthsignals
3. Evasionofapoptosis
4. Sustainedangiogenesis
5. Limitlessreplicativepotential(stabilizationoftelomeres)
6. Theabilitytoinvadetissueandmetastasize

8. THEPARADOX
Thechallengeofsuppressingsomaticevolutiondramaticallyincreaseswithlargerbodiesandlongerlifespans.Becausecancer developsthroughtheaccumulation
ofmutations,eachproliferatingcellisatriskofmalignanttransformation,assumingallproliferatingcellshavesimilarprobabilitiesofmutation.
Therefore,ifanorganismhasmorecells,i.e.morechancestoinitiateatumor,theprobabilityofgettingcancershouldincrease.Similarly,ifanorganismhasan
extendedlifespan,itscellshavemoretimetoaccumulatemutations.Becausetheprobabilityofcarcinogenesisisanincreasingfunctionofage,anorganism’s
lifetimeriskofcancershouldalsoscalewithitslifespan.Itiswellknownthatlargerorganismsgenerallyhavelongerlifespanswhichexacerbatesthisproblem.
Lifespan
Size
Thereappearstobenocorrelationbetweenbodysize,longevityandcanceracrossspeciesandtheabsenceofsucha
relationshipisreferredtoasPETO’SPARADOX.

9. CalabreseandShibatadevisedasimplemathematicalequationtoexpresstheprobabilityofahumandevelopingcolorectalcancer.Their
equationproducesresultswhichcloselymatchdatafromtheSEERProgram.Theprobabilityofanindividualdevelopingcancerwasgivenby
P=1-(1-(1-(1-u)d)k)Nm
Whereuisthemutationratepergeneperdivision,disthenumberofstemcelldivisionssincebirth,kisthenumberofrate
limitingmutationsrequired forcancertooccur,Nisthenumberofeffectivestemcellspercryptandmisthenumberofper
colon.
Usingthisrationale,theyincreasedtheparameterm from1.5x103to1.5x1010toseehowthetotalnumberofstem
cellsinthecolonchangesthelifetimeriskofdevelopingcancer.Whenbluewhalethatis1,000timesthesizeofhuman, was
usedasanexample,wherem equaledto1.5x1010cryts.theanalysisrevealedthatover50%ofbluewhaleswoulddevelopcancer
byage50andallwouldhavecancerbyage80.Thechanceofahumangettingcancerbyage90isonlyabout2.5%.Itis
implausiblethat100%ofbluewhalesactuallygetcancerbyage80.Thoughwedon’tknowhowoftentheygetcancer,theyhave
beenreportedtooccasionallyhaveothercancersandliveover100years.Thismodelsuggeststhatthereissomething
fundamentallydifferentintheinitiationandprogressionofcancerinlarge,long-livedanimals,likewhales,comparedto
humans.

10. Interestingly,withinaspecies,sizeisassociatedwithanincreasedcancerrisk.Inhumans,3–4mmabovetheaverage
leglengthresultsinan80%higherriskofnonsmoking-relatedcancers.Also,childrenwithbonecancerstendtobe
tallerandosteosarcomasoccurinlargedogs200timesmorefrequentlythansmallandmediumbreeds.Therehaslikely
notbeenenoughtimetoevolveadditionalmechanismstoprotectthemfromthisincreasedriskandcounteractthe
extremeartificialselectionforsize.
Thissuggeststhatanimalswhichevolvedtobelarger asaspeciesdevelopedmechanismstooffsetthisincreased
cancerrisk;whileaboveaverageindividualsdonotpossessadditionaldefensescomparedtosmallerorganismswithin
theirspecies,andthereforefallvictimtocancerwithgreaterprobability.Thisdivergenttrendwithinversusbetween
speciesisanexampleofSimpson’sparadox.

11. HypothesestoresolvePeto’sParadox
LimitedresearcheffortshavebeenfocusedonresolvingPeto’sParadox.However,therearemanyhypothesesthatmight explain
howorganismscouldovercometheburdenofcancerdespiteanincreasednumberofcellsandextendedlifespan.Somehavebeen
previouslyproposedandothersarerelativelynew.Largebodiesevolvedindependentlyalongmultiple lineages;therefore,we wouldnot
expectthatalllarge,long-livedanimalshaveevolvedthesamemechanismstosuppresscancer,unlessthesuppressionstemsfrom an
innatecharacteristiccommontoalllargerorganisms.Differencesindietandcarcinogenicexposures(including pathogens,which
areonlyassociatedwith15%ofhumancancers)areunlikelyexplanationsbecausetherearemany-folddifferencesinsizebetween
organismswithsimilarenvironments(e.g.,dolphinsandwhales)andsimilardiets(e.g.,elephantsandmicearebothherbivores).

12. Somescientistshaveputforwardtheirtheoriestowhythisparadoxoccurs:
Oneofthepapersrelatedtheparadoxtowhattheycall the ‘GuardianoftheGenome’-TP53
TP53codesforaproteinP53whichplaysitsroleinconservingthestabilitybypreventinggenomemutation. HenceTP53 isclassifiedasatumor
suppressor gene.
p53hasmanymechanismsofanticancerfunction andplaysarole inapoptosis, genomic stability,andinhibitionof angiogenesis.In
itsanti-cancerrole,p53works through severalmechanisms:
ItcanactivateDNArepairproteinswhenDNAhassustaineddamage.Thus,itmaybeanimportantfactorin aging.
ItcanarrestgrowthbyholdingthecellcycleattheG1/SregulationpointonDNAdamagerecognition(ifitholdsthecellhereforlongenough,theDNA
repairproteinswillhavetimetofixthedamageandthecellwillbeallowedtocontinuethecellcycle).
Itcaninitiateapoptosis(i.e.,programmedcelldeath)ifDNAdamageprovestobeirreparable.
IftheTP53 geneisdamaged,tumorsuppressionisseverelycompromised.The TP53 genecanalsobemodifiedby mutagens,increasingthelikelihoodfor
uncontrolledcelldivision.Morethan50percentofhumantumorscontainamutationordeletionoftheTP53gene. Lossofp53createsgenomicinstabilitythat
mostoftenresultsinananeuploidyphenotype.

13. RelationofP53toPeto’sParadox
HumanshaveonecopyoftheP53gene,ie.,weinheritonecopyfromourparentseach.SowecansaywehavetwoallelesofP53.
SomepeoplearebornwithadiseasecalledaLiFraumeniSyndrome.SuchpeoplehaveonlyonefunctionalalleleoftheP53genome.And
thisresultsin90%lifetimeriskofcancer.Andforwomen,it’salmosta100%.
Nowtheresearchscientistsworkedwithelephantstofindouttherootcauseoftheparadox.
Itwasfoundthattheelephantshave20copiesofthisp53genome,ie.,40alleles.Andalso,theyfoundthatelephantshaveanincreased
sensitivitytoDNAdamage.Andonplotting agraphbetweenanelephant,ahealthyhumanandahumanwithLiFraumeniSyndrome and
thefrequencyofoccurrenceofapoptosis,itshowed:
apoptosis
LFS Humans Elephants
P53 1/2 1 20
Thisshowedthatitonlytookalittle bitofcelldamagetoactivatethep53pathway.Andthiswhyelephantsorallbig
animalsdon’tgetcancerattherateweexpect.

14. TumorSuppressionMechanisms thatmightvaryacrossLarge,Long-
livedSpecies
1. LowerSomaticMutationRates
Iflargeanimalshavelowersomaticmutationratespercellgeneration,thenmorecelldivisionswouldneedtooccur,comparedtosmaller
animals,inorderforacelltoacquirethenecessarymutationstobecomemalignant.Mutationrateisafunctionoftheerror rateandtherateatwhich
theseerrorsarerepaired.ThiscouldbeachievedthroughanumberofmechanismsincludingbetterDNAdamagedetectionandrepairmechanisms.However,
experimentaldataseemtosuggestthatmiceandhumanshavecomparablemutationrates,thoughbettermethodstomeasuresomaticmutationratesin
vivoareneededtoexplorethishypothesis.
2. RedundancyofTumorSuppressorGenes
Addedredundancyoftumorsuppressorgenescouldalsosuppresscancerinlargeanimals byrequiringmoremutationstooccur toproducea
malignantphenotype.Humancellsrequiremoremutationsthanmousecellstocreateimmortalizedcultures.BoththeRbandp53 pathwaysmustbeknocked
outtoimmortalizehumanfibroblastswhilemousecellsrequireonlythep53pathwaytobeinactivated.Micegeneticallyengineeredtohaveextracopies
ofTrp53 orCdkn2A haveincreasedtumorresistance.Interestingly,thecurrentbuildoftheelephantgenomehas12orthologsofthehumangene TP53,in
additiontoonecopyofthegenesthatencodep73andp63.Thehumangenomeonlyhasoneofeachofthesegenes(TP53,TP63,TP73)asdiscussedpreviously.

15. 3.Lowerselectiveadvantageofmutantcells
Ahaploinsufficientgeneinmicecouldbecompletelyrecessiveinalargeranimal,requiringmutationstooccuronbothallelesinorderto
gainaselectiveadvantageoverneighboringcellsduringcarcinogenesisinthelargerspecies.Thiswoulddecreasethepossibilitythatmutationsatthislocus
wouldcontributetoprogressiontowardscancer.Thishasbeenobservedinatissue-specificmanner.ThetumorsuppressorTrp53 usuallyrequiresbothallelesofthe
genetobenullinordertoseeamutantphenotype;however,insometissues,Trp53 ishaploinsufficientandlosingonlyonealleleproducesaphenotypeinmice
4.Differenttissuearchitecture
Changesintissuearchitecturecouldinfluencethefrequencyofcancersbyalteringthewaycellsarecompartmentalizedand/orthedynamicsof
thetissue.Mosttissuesarecomprisedofsmallproliferativeunits,forexamplethecryptsoftheintestines.Ithasbeenproposedthatthishierarchicalstructureis
acrucialcancerpreventionmechanism.Sincedifferentiatingcellsareevolutionarydead-ends,theeffectivepopulationsizeofasomatictissueprobably
dependsmainlyonthenumberanddynamicsofstemcells(thoughamutationwhichdisruptsdifferentiationinanon-stemcellmightalsogeneratea
carcinogeniccelllineage).Underamodelof“serialdifferentiation”itispossibletoincreasethenumberofcellsandthe amountofcellturnoverwithout
increasingthenumberorproliferativeactivityofsomaticstemcells,simplybyaddingnon-stemstages.Alteringthenumberofstemcells,thecryptdensityor
thedynamicsofdifferentiationanddivisioncouldenhancethetissue’sabilitytopreventmalignanttransformation.

16. 5.Increasedsensitivitytocontactinhibition
Selfishcellularproliferationcanalsobesuppressedbysignalsfromthemicroenvironment.Forexample,cellcontactinhibitionhasbeennoted
todifferbetweenhuman,mouseandnakedmole-rat(Heterocephalusglaber)cells.Inculture,nakedmole-ratcellsstopdividingatmuchlowerdensitiesthan
humanandmousecellsduetotheearlyactivationofthep16pathwaywhichresultsinhypersensitivitytocontactinhibition. Althoughnakedmole-ratsandmice
aresmallanimals,theformerlivesignificantlylongerthanthelatter(28years[46]versus4years[47]).Inall250necropsiesofnakedmole-ratsthatdiedin
captivity,nonehaddiedofcancer.Hypersensitivecontactinhibitionmighthaveevolvedtosuppresscancersothenakedmole-ratcanlivelonger,thoughithas
onlybeenverifiedinvitro.Signalsforearlycellsenescencecouldbetriggeredinlarge,long-livedorganismstoinhibituncontrolledproliferation.
6. ShorterTelomeres
Telomerelengthappearstobeafundamentalcheckontheproliferativecapacityofcells.Telomeresshortenwitheverycellcycleandwhenthey
becometooshorttoprotectthechromosomes’ends,thecellsensesthoseendsasDNAdoublestrandbreaks,usuallyleadingto apoptosis.Eventhoughstemcells
expresstelomerase,whichhelpstorebuildtelomeres,theygenerallydonotexpressenoughtopreventtelomereshorteningdue toproliferation.Wehypothesizethat
large,long-livedanimalsmighthaveshortertelomeres(orerodethemfaster)thansmalleranimals,limitingthenumberoftimes theircellscandivideand
reducingopportunitiestoaccumulatecarcinogenicmutations.

17. Peto’sParadoxAppearstobeReal
Cancerincidencerecordsforwildandcaptiveanimalsarenotwelldocumentedformostspecies,makingitdifficultto
directlycompareincidencerecordsofhumansandotheranimals.However,itisstillclearthatcancerincidencedoesnot
scalewithbodysizeacrossspecies.Ifbluewhalesgot1,000timesmorecancerthanhumans,theywouldlikelydiebefore
theywereabletoreproduceandthespecieswouldquicklygoextinct.Themereexistenceofwhalessuggeststhatisit
possibletosuppresscancermany-foldbetterthanhumans.

18. Theexactfunctionalrelationshipbetweenbodysizeandexpectedcancerriskisunclear;
however itisassumedtobeanincreasingfunction.Incomparinglaboratoryrodentsandhumans,
whichdifferinlifespanbyafactorof40andsizebythreeordersofmagnitude,about30%ofboth
rodentsandhumanshavecancerbytheendoftheirlife.Thegeneralexplanationforthisisthat
large,long-livedanimalsaremoreresistanttocarcinogenesisthansmall,short-lived animals;
however,howtheyaccomplishthisresistancehasyettobeestablished.Understandingthisresistance
canleadtonewmethodsofcancerpreventioninhumans

19. TheEnd