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Katherine M. Hyland, PhD,
71
Tumor Suppressor Genes and Oncogenes:
Genes that Prevent and Cause Cancer(Biochemistry/Molecular Biology Lecture)
OBJECTIVES Describethenormalcellularfunctionsoftumorsuppressorgenesandproto-oncogenes
andexplaintheirrolesincancer.
DescribeKnudsonstwo-hithypothesisforthepathogenesisofretinoblastoma.
Listthecommonclinicalfeatures,evolutionandtreatmentforretinoblastoma.
Explainwhyloss-of-heterozygosityofaparticularchromosome/chromosomalregionin
tumorDNAsuggeststheexistenceofatumorsuppressorgeneinthatregion.
ExplainwhylossofeitherRborp16drivesacelltoproliferate.
ExplainhowtheproteinsencodedbytheE6andE7genesoftheoncogenichuman
papillomavirusesfunctiontopromotetumorformation.
DescribehowtheHER2/neuoncogeneisactivatedinbreastcancer.
DescribethenormalfunctionofRasproteinsandthemolecularmechanismbywhich
mutationsinRasgenesleadtocancer. DescribethreepathwaysbywhichthecyclinDgeneisactivatedintumors.
ExplainwhyactivationoftheBcl-2genepromotescancer.
Describethemoleculareventsassociatedwithdifferentstagesinthedevelopmentof
coloncancer.
Describethesixhallmarkfeaturesofcancercellsandthemolecularbasisofeach.
KEY WORDS
Adenomatouspolyposiscoli(APC) multi-steptumorgenesis
Bcl2 mutatorphenotype
caretaker myc
chromosomalinversion neurobromatosis(NF1)chromosometranslocation oncogene
cyclinD promoters
E6protein p16
E7protein p53
EMSY promoters
gain-of-function proto-oncogene
geneamplication Rasprotein
HER2/neu Rbgene
humanpapillomavirus(HPV) retinoblastoma
loss-of-function tumorsuppressorgene
loss-of-heterozygosity(LOH) two-hithypothesis
Li-Fraumenisyndrome
OPTIONAL READING
Albertsetal.Molecular Biology of the Cell;5thEdition,GarlandScience,2008
Chapter20;Cancer,pp.1230-1256
KumarV,AbbasA,FaustoN:Robbins and Cotran Pathologic Basis of Disease7thed,Elsevier/
Saunders,2005;Chapter7:OncogenesandTumorSuppressorGenespp.292-306
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Tumor Suppressor Genes and Oncogenes
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I. INTRODUCTION : TYPES OF GENES INVOLVED IN CANCER
Canceriscausedbytheaccumulationofgeneticandepigeneticmutationsingenesthatnormally
playaroleintheregulationofcellproliferation(asdescribedintheCellProliferationlecture),
thusleadingtouncontrolledcellgrowth.Cellsacquiremutationsinthesegenesasaresultof
spontaneousandenvironmentally-inducedDNAdamage.Thosecellswithmutationsthatpromote
agrowthandsurvivaladvantageovernormalcellsareselectedforthroughaDarwinianprocess,
leadingtotheevolutionofatumor.Genesinvolvedintumorigenesisincludethosewhoseprod-
ucts:1)directlyregulatecellproliferation(eitherpromotingorinhibiting),2)controlprogrammed
celldeathorapoptosis,and3)areinvolvedintherepairofdamagedDNA.Dependingonhow
theyaffecteachprocess,thesegenescanbegroupedintotwogeneralcategories:tumor suppres-
sor genes(growthinhibitory)andproto-oncogenes(growthpromoting).
Mutantallelesofproto-oncogenesarecalledoncogenes.Sincemutationinasinglealleleofa
proto-oncogenecanleadtocellulartransformation,suchmutationsareconsidereddominant.In
contrast,typicallybothallelesofatumorsuppressorgenemustbealteredfortransformationto
occur.Genesthatregulateapoptosismaybedominant,aswithproto-oncogenes,ortheymaybe-
haveastumorsuppressorgenes.Tumorsuppressorgenesmaybedividedintotwogeneralgroups:
promotersandcaretakers.Promotersarethetraditionaltumorsuppressors,likep53andRB.
Mutationofthesegenesleadstotransformationbydirectlyreleasingthebrakesoncellularpro-liferation.Caretakergenesareresponsibleforprocessesthatensuretheintegrityofthegenome,
suchasthoseinvolvedinDNArepair.Althoughtheydonotdirectlycontrolcellproliferation,
cellswithmutationsinthesegenesarecompromisedintheirabilitytorepairDNAdamageand
thuscanacquiremutationsinothergenes,includingproto-oncogenes,tumorsuppressorgenes
andgenesthatcontrolapoptosis.AdisabilityinDNArepaircanpredisposecellstowidespread
mutationsinthegenome,andthustoneoplastictransformation.Cellswithmutationsincaretaker
genesarethereforesaidtohaveamutator phenotype.Thefactthatpatientswithdefectsin
DNArepairarecancerproneprovidesoneofthemoststrikingpiecesofevidencethatmutations
inDNAlieattheheartoftheneoplasticprocess.(Moreaboutgeneswhoseproductsareinvolved
inDNArepairintheMutationandCancerlecture.)
II. TUMOR SUPPRESSOR GENESTumorsuppressorgenescanbedenedasgeneswhichencodeproteinsthatnormally
inhibittheformationoftumors.Theirnormalfunctionistoinhibitcellproliferation,oract
asthebrakesforthecellcycle.Mutationsintumorsuppressorgenescontributetothe
developmentofcancerbyinactivatingthatinhibitoryfunction.Mutationsofthistypeare
termedloss-of-functionmutations.Aslongasthecellcontainsonefunctionalcopyofagiven
tumorsuppressorgene(expressingenoughproteintocontrolcellproliferation),thatgene
caninhibittheformationoftumors.Inactivationofbothcopiesofatumorsuppressorgene
isrequiredbeforetheirfunctioncanbeeliminated.Therefore,mutationsintumorsuppressor
genesarerecessiveatthelevelofanindividualcell.Aswewillsee,theinactivationoftumor
suppressorgenesplaysamajorroleincancer.
A. RetinoblastomaRetinoblastoma (RB) isararechildhoodtumoroftheeye(seeclinicalcorrelate).Most
cases(60-70%)aresporadic(asopposedtoinherited),occurunilaterally(affectingone
eye),andpresentinchildren1-4yearsofage.Theremaining30-40%ofpatientshavea
hereditaryformofretinoblastomaandthushaveinheritedagermlinecancerpredisposing
mutation(seebelow).Thesechildrentendtoacquiretumorsearlierthanthosewith
sporadicdiseaseandaremorelikelytohavemultipletumorsinone(unilateral)orboth
(bilateral)eyes.Infamilieswiththeinheritedformofretinoblastoma,thediseaseshows
anautosomaldominantinheritancepattern.
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Katherine M. Hyland, PhD,
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CLINICAL CORRELATION OF RETINOBLASTOMARetinoblastoma is a malignant tumor of immature neuroectodermal cells of the developing
retina that occurs almost exclusively in young children. Approximately 175 cases of
retinoblastoma are diagnosed in the US each year. It accounts for 3% of malignant disease in
children younger than age 15. It is the most common intraocular tumor in pediatric patients and
causes 5% of cases of childhood blindness.
Retinoblastoma may gradually fill the eye and extend through the optic nerve to the brain and
less commonly, along the emissary vessels and nerves in the sclera to the orbital tissues.
Occasionally, it grows diffusely in the retina, discharging malignant cells into the vitreous or
anterior chamber, thereby producing a pseudoinflammatory process that may mimic other
ocular inflammatory conditions.
Inheritance
Retinoblastoma occurs in retinal cells that have cancer-predisposing mutations in both copies of
theRB1 gene. About 60-70% of patients have the non-hereditary or sporadic form of the
disease, in which the initial mutation affecting one copy of the RB1 gene arises in a somatic
retinal cell (or a precursor of a retinal cell). The remaining 30-40% of patients have inherited a
cancer-predisposing mutation in one copy of theirRB1 gene from one parent, or have a new
germline mutation. Sporadic cases tend to be unilateral (one eye) and unifocal (one tumor), and
typically present by 24-30 months of age. Heritable cases tend to be bilateral (both eyes) andmultifocal (multiple tumors), and generally present earlier, in the first year of life. Second
primary malignant tumors, the most common of which is osteosarcoma, develop in large
numbers of survivors of the heritable form of retinoblastoma after a period of many years.
Clinical Presentation
The most common presenting sign is leukocoria (white pupillary reflex). A crossed eye or
strabismus is the second most common symptom of retinoblastoma. The child's eye may turn
towards the ear (exotropia) or towards the nose (esotropia). Other symptoms may include red
painful eye, glaucoma, pseudohypopyon (appearance of purulent material in the anterior
chamber of the eye), or poor vision.
Evaluation
The clinical diagnosis of retinoblastoma is usually established by examination of the fundus of
the eye using indirect ophthalmoscopy to directly visualize the intraocular tumor(s). Imagingstudies (CT or ultrasound) can be used to support the diagnosis by detecting intrinsic
calcification within the mass, a finding highly suggestive of retinoblastoma. High-resolution
MRI of the orbits can help to stage the tumor, and determine any extraocular spread.
Retinoblastoma usually remains unnoticed until it grows large enough to produce leukocoria or
strabismus (inflammation is a much rarer presentation orbital cellulitis represents about 1% of
all presentations of RB) with 90% of cases diagnosed before age 5. All children with poor
vision, strabismus, or intraocular inflammation should be evaluated for the presence of
retinoblastoma. The earlier the discovery and treatment of the tumor, the better the chance to
prevent spread through the optic nerve and orbital tissues. Retinoblastoma can lead to loss of
eyesight and, if not detected early enough, death, since systemic and CNS metastasis is almost
impossible to treat.
Individuals with a germline mutation inRB1 are also at increased risk of developing tumors
outside the eye over their lifetime. Most of the second primary cancers are osteosarcoma, soft
tissue sarcomas or melanomas. These tumors usually manifest in adolescence or adulthood. To
detect second non-ocular tumors in individuals with retinoblastoma, physicians and parents
should promptly evaluate complaints of bone pain or lumps because of the high risk of
sarcomas; however, no specific screening protocols currently exist.
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1. Two-hit hypothesis
Afterstatisticalanalysisofmanypatientswithretinoblastoma,Dr.AlfredKnuson
proposedin1971thatsporadiccasesofthisdiseaseinvolvetheinactivationofboth
copiesofaparticulargene,whichhecalledtheretinoblastomagene(RB1).He
proposedthatthisoccursintwosteps:ArsthitinactivatesoneofthetwocopiesofRB1inoneretinoblast.Laterasecondhitinactivatestheremainingfunctional
copyofRB1inthesamecelloroneofitsprogeny(Figure1).Toexplaintheinherited
formofthedisease,heproposedthattheaffectedpatientsinheritedonedefective
copyofRB1fromoneparentandafunctionalcopyfromtheotherparent.Because
thersthitisinheritedandispresentinallretinalcells,andinfactallofthecells
ofthebody,atumorariseswhenasecondhitoccursinanyretinoblast.Because
ittakesonlyoneadditionalmutational(orepigenetic)eventforanyofthesecellsto
developintoatumor,inheritedretinoblastomawouldbemorelikelytooccurearlier
Figure 1. Knudsons two-hit hypothesis for retinoblastoma.In sporadic Rb, both copies of RB1
(RB1) must be inactivated. This requires two mutational events hits which each inactivate one copy
of RB1. In inherited Rb, the rst hit is inherited.
Rb Rb Rb Rb Rb Rb
Rb Rb Rb Rb
rst hit second hit
second hit
X X X
X X X
Tumor
Tumor
Sporadic Rb: Two hits required
Inherited Rb: First hit is inherited; only one additional hit required
Treatment
Large tumors in eyes with no salvageable vision are often treated by enucleation (surgical
removal of the eye). Smaller tumors can be treated with plaque or external beam radiotherapy,
cryotherapy (use of liquid nitrogen to freeze and destroy a lesion or growth), or
photocoagulation (use of laser to destroy a small tumor). Chemotherapy can be used to reduce
initial tumor size prior to applying other modes of therapy. Combined therapy using
chemotherapy and coordinated laser treatment can often preserve vision and spare the patientenucleation and radiation that may lead to d isfigurement and the induction of secondary tumors.
Eradication of tumor before infiltration into the optic nerve or choroid carries an excellent
prognosis for survival.
Susan Hung, Curriculum Ambassador 2007
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Katherine M. Hyland, PhD,
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inchildhoodandmorelikelytocausebilateraldisease(multipleprimarytumors).
SubsequentresearchidentiedRB1onchromosome13andconrmedKnudsons
hypothesis,thusmarkingthediscoveryofthersttumorsuppressorgene.
Inbothinheritedandsporadicretinoblastoma,thesecondalleleofRB1canbe
inactivatedbyseveralmechanisms.Inadditiontoepigeneticsilencing(seeMutation
andCancerlecture),thepossibilitiesincludepointmutation,largedeletionsthatremoveRB1andmanyadjacentgenes,orerrorsinchromosomesegregationleading
tolossoftheentirewild-typechromosome.Thelattertwomechanismsaremore
common.
2. Loss-of-heterozygosity (LOH)
Howaretumorsuppressorgenesfound?AsdiscussedintheGeneticslecturesin
Prologue,inthegenomethereareperiodicvariationsintheDNAsequencebetween
thetwohomologouschromosomes(oneinheritedfromeachparent).Variantsthat
arecommonlyusedasgeneticmarkersincludeshorttandemrepeatpolymorphisms
(STRPs)andsinglenucleotidepolymorphisms(SNPs).Thesevariantscanbe
visualizedbymoleculartechniques.Ifweexamineanyregionofthegenome,we
willndthatmostpeopleareheterozygousforcertainpolymorphicgeneticmarkers.
Althoughthesevariantsoftenoccurbetweengenesratherthaninthem,theycan
beusedtotrackthepresenceofadjacentgenes.(SeeGeneticVariationlecturein
PrologueandLinkageAnalysisILMinOrgansCV.)
AsshowninFigure2,tumorsuppressorgeneslikeRB1canbefoundbylooking
forloss-of-heterozygosity(LOH)inatumor.LOHmeansthatpre-tumor cellsare
heterozygousforallelesofatumorsuppressorgene(e.g.onenormalandonemutant
allele),orallelesofgeneticmarkersthatsurroundthetumorsuppressorgene,butthe
tumor cellshavelostthenormaltumorsuppressorallele(andthesurroundingmarker
Figure 2: Loss of heterozygosity.The diagram represents chromosome 13 homologs (circle = centro-mere). TheRB1 locus is indicated between two marker loci, with alleles A/a and B/b. Either a mutation in
RB1 is inherited, or a sporadic mutation occurs inactivating one copy of RB1 in a somatic cell. A second
mutation, in this case loss of the portion of chromosome 13 that contains RB1, occurs in the same cell,
resulting in complete lack of a functionalRB1, leading to tumorigenesis. Thus the pre-tumor cells areheterozygous for a mutation in RB1, but tumor cells are no longer heterozygous, having lost the functional
copy ofRB1.
Rb Rb
deletion removing
a, Rb, and B
X
Tumor Cells
A
RbX
Aa
b B b
Second hit:
Pre-Tumor Cells
alleles),sotheyarenolongerheterozygous.
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Tumor Suppressor Genes and Oncogenes
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TheexampleillustratedinFigure2involvesasporadiccaseofretinoblastoma.
Shownischromosome13aftertherstcopyofRB1hasbeeninactivated.Inthis
example,A(a)andB(b)representtwomarkerlocithatlieoneithersideofRB1.Each
hasoneoftwoalleles(e.g.,Aanda).TheRB1allelethatisinactivatedrstisanked
bytheAandballeles,whereastheremainingfunctionalcopyofRB1isankedby
theaandBalleles.ThesecondhitinRB1ofteninvolvesdeletionofalargeregionor
lossofanentirechromosome.Asaresult,thefunctionalcopyofRB1islostasaretheankingaandBmarkers.Consequently,onlytheAandballelesareleftandthe
cellisnolongerheterozygousforthesemarkers(i.e.onlyAexists,notA/aandonly
bexists,notB/b)inthetumor.Acellthatloosesbothcopiesofaparticulartumor
suppressorgenemayhaveaproliferativeadvantage,andthusbeselectedforduring
tumorprogression.Therefore,ifloss-of-heterozygosityisfrequentlyseeninaspecic
regionofthegenomeinaparticulartumortype,thissuggeststhatatumorsuppressor
genethatplaysanimportantroleindevelopmentofthattumormaybepresentinthatregion.
3. Mutation or loss ofRB1 removes a brake on the cell cycle
HowdoesthelossofRB1promotetumorformation?RecallthattheRbproteinplays
akeyroleinregulatingthecellcycle.Itisexpressedineverycelltype,whereit
existsinanactivehypophosphorylatedandinactivehyperphosphorylatedstate.In
itsactivestate,RbservesasabrakeontheadvancementofcellsfromtheG1tothe
S-phaseofthecellcycle.IfRbislostormadenonfunctionalthroughmutation,this
brakeonthecellcycleisreleasedandcellsmoveintoS-phaseunrestrained.Speci-
cally,RbnormallybindstoandinactivatestheE2Ftranscriptionfactor.LossofRb
resultsinactivationofE2F.E2FbindsthepromoterofthecyclinEgeneandinturn
causesincreasedexpressionofthecyclinEgeneandsynthesisofCdk2-cyclinE
complexes,whichthendrivesthecellcycle(Figure3).RecallthatCdk2-cyclinEac-
tivityrepresentsthetransitionfrommitogen-dependenttomitogen-independentcell
cycleprogression,soinactivationofRbcanlockcellsinaproliferatingstate.
Aspreviouslymentioned,individualswithgermlinemutationofRB1areatincreased
riskofdevelopingsecondprimarynon-oculartumorsovertheirlifetime-mostoften
osteoscercomas,softtissuesarcomas,ormelanomas.Inaddition,somaticallyac-
quiredmutationsinRB1 havebeendescribedinbreastcancers,glioblastomas,small
celllungcancers,andbladdercancers.SinceRbispresentineverycellandplays
animportantroleincellcyclecontrol,acouplequestionscometomind.First,why
dopatientswithgermlinemutationofRB1developprimarilyretinoblastomas?Itis
notcompletelyclearwhytumorsaretypicallyrestrictedtotheretinainpatientswho
inheritadefectivealleleofRB1,thoughevidencesuggeststhathomozygouslossof
RB1triggersapoptosis,andthatunrestrainedactionofE2Fproteins(aswouldoccur
withlossofbothRB1alleles)notonlydrivesthecellcycle,butalsotriggersapopto-
sis.Thereforeitisplausiblethatalthoughinmosttissues,homozygouslossofRB1inducescelldeath,theretinoblastsarerelativelyresistanttotheapoptosis-inducing
effect.Inthesecells,therefore,dysregulatedE2Fgivesrisetotumors.Inaddition,
therearelikelyparallelregulatorypathwaysindifferentcelltypes.Whilesomecell
types,e.g.breast,lungorbladderepithelialcells,requireadditionallossofother
tumorsuppressorgenesoractivationofoncogenes,theproliferationofretinoblasts
inearlychildhoodmaybeuniquelycontrolledbyRb,suchthatfewothergenetic
changesarerequiredfortumorformation.Thismaybebecauseretinoblaststermi-
nallydifferentiatebytheageofsixyears,andthusdonotneedextensivesafeguards
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Katherine M. Hyland, PhD,
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againstuncontrolledproliferation.Whereasinothercelltypes,manymoresafeguards
(includingtriggeringapoptosis)haveevolvedtoprotectagainstinappropriateprolif-
eration,andthesesafeguardsmustbeovercometodevelopcancer.
Asecondquestionthatcomestomind:WhyareinactivatingmutationsofRbnot
morecommonlyseeninhumancancer?Theanswertothisquestionismorestraight-
forward.MutationsinothergenesthatcontrolRbphosphorylationcanmimicthe
effectofRbloss.Suchgenesaremutatedinmanycancersthatseemtohavenormal
RB1genes.Thus,forexample,mutationalactivationofcyclinDorCDK4would
favorcellproliferationbyfacilitatingRbphosphorylation,thusmaintainingitinan
inactivatestate.Canyouthinkofotheranswerstothesequestions?
B. Genes encoding Cdk inhibitors are tumor suppressor genes
MutationalinactivationofCDKinhibitorsalsodrivesthecellcyclebyunregulated
activationofcyclinsandCDKs.Onesuchinhibitor,encodedbythep16gene,isa
commontargetofdeletionormutationalinactivationinhumantumors.Recallthatp16is
aninhibitorofCdk4-cyclinDcomplexes.Germlinemutationsofp16areassociatedwith
asubsetofhereditarymelanomas.Somaticallyacquireddeletionorinactivationofp16is
seenin75%ofpancreaticcancers;40-70%ofglioblastomas;50%ofesophagealcancers;
and20%ofnon-smallcelllungcancers,softtissuesarcomas,andbladdercancers.The
lossofp16leadstoincreasedCdk4-cyclinDactivity.ThisresultsinphosphorylationandinactivationofRb,leadingtoactivationofE2FandcyclinEtranscription.Infact,
incellsthatharbormutationsineitherp16,CDK4,orcyclinD,thefunctionofRB1is
disruptedevenifRB1itselfisnotmutated.
C. p53: a key tumor suppressor
p53,locatedonchromosome17p13.1,isthesinglemostcommontargetforgenetic
alterationinhumantumors.Infact,morethan50%ofhumantumorscontainmutations
inthisgene!Thusitisamongthemostimportantbrakesontumorformation.
Homozygouslossofthep53geneisfoundinvirtuallyeverytypeofcancer,including
carcinomasofthebreast,colon,andlungthethreeleadingcausesofcancerdeaths.In
mostcases,theinactivatingmutationsaffectingbothp53allelesareacquiredinsomatic
cells.Insomecases,althoughitisrare,individualsinheritamutantp53allele.AswithRB1,inheritanceofonemutantallelepredisposestheseindividualstodevelopmalignant
tumorsbecauseonlyoneadditionalhitisneededtoinactivatethesecond,normal,
allele.Inactivationofthesecondp53alleleleadstoincreasedcellproliferation,decreased
apoptosis,andtumordevelopment.Theseindividualshaveararecancerpredisposition
syndromecalledLi-Fraumeni syndrome,andhavea25-foldgreaterchanceof
developingamalignanttumorbyage50,comparedwiththegeneralpopulation.In
contrasttopatientswhoinheritamutantRB1allele,thespectrumoftumorsthatdevelop
inpatientswithLi-Fraumenisyndromeisquitevaried.Themostcommontypesoftumors
Cdk4-cyclin D Rb E2Fcyclin E
transcriptionCdk2-cyclin E proliferation
OFF ON ON ON ON
X
Figure 3. How inactivation of Rb leads to proliferation.Loss of both copies of Rb results in the
activation of E2F, increased cyclin E transcription, formation of the Cdk2-cyclin E complex and
thus cell proliferation (See Cell Proliferation lecture).
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Tumor Suppressor Genes and Oncogenes
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aresarcomas,breastcancer,leukemia,braintumors,andcarcinomasoftheadrenal
cortex.Ascomparedwithsporadictumors,thosethatafictpatientswithLi-Fraumeni
syndromeoccuratayoungerage,andagivenindividualmaydevelopmultipleprimary
tumors.
p53restrainstumorformationbytwodifferentmechanisms(Figure4).Intherst,p53
activatesthep21CdkinhibitorgeneinresponsetoDNAdamageandstress.Lossofp53
incellspreventsthep21genefrombeingtranscribed,leadingtotheincreasedactivityof
themultipleCdksnormallyturnedoffbyp21andresultinginincreasedcellproliferation.
Asecondwayinwhichp53restrainstumorformationisbyinducingapoptosis.
D. Caretaker Genes that Function as Tumor Suppressors
BRCA1,locatedon17q21,andBRCA2,locatedon13q12,aretumorsuppressorgenes
associatedwithbreastandovariancancer,alongwithseveralothercancers.About10%
ofallcasesofbreastandovariancancerarehereditarycancers,andmostofthesecases
areduetoinheritanceofagermlinemutationineitherBRCA1orBRCA2(see Familial
and Hereditary Cancer Syndromes lecture).Aswithothertumorsupporessorgenes,the
remainingalleleisinactivatedorlostduringthecourseoftumorformation(LOH).The
proteinsencodedbyBRCA1andBRCA2areexpressedinmosttissuesandcelltypes
(indicatingthatgeneexpressiondoesnotaccountfortherestrictedphenotypeofbreastandovariancancer),andshareanumberoffunctionalsimilarities.
BRCA1andBRCA2functionascaretakergenes,likep53,whichservetomaintain
genomicintegrity.ThegeneproductsencodedbyBRCA1andBRCA2arenuclearproteins
thatco-localizewithRAD-51atsitesofDNAdamage,andplayaroleinhomologous
recombinationrepairofdouble-strandedbreaks(see Mutation and Cancer lecture).
ThereisalsoevidencethatBRCA1andBRCA2interactwiththep53-mediatedDNA
damagecheckpoint(see Mutation and Cancer lecture).LossofBRCA1orBRCA2leads
totheaccumulationofothergeneticdefects,whichcanthenleadtocancerformation.
InadditiontotheirrolesinDNArepair,BRCA1andBRCA2havebeenimplicatedina
varietyofcellularprocesses,includingDNAsynthesis,regulationofgenetranscription
(similartop53,onetargetofBRCA1transcriptionalactivationistheCdkinhibitorp21),cellcyclecheckpointcontrol,centrosomeduplicationandubiquitination.
MostBRCA1andBRCA2mutationsleadtoframeshiftsresultinginmissingornon-
functionalprotein,or,inthecaseofBRCA2,tononsensemutationsleadingtopremature
truncationoftheprotein.Thesemutationsareallconsistentwiththelossoffunction
expectedwithtumorsuppressorgenes.
p53
transcription
factor
p21 Cdk inhibitor Cdk-cyclin
complexesproliferation
apoptosis
Figure 4. p53 tumor suppressor functions.p53 antagonizes tumor formation by activating the p21 Cdk
inhibitor (which blocks proliferation) and by promoting apoptosis.
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ApuzzleinbreastcancerhasbeenwhymutationsinBRCA1andBRCA2arenotfound
asofteninsporadic(i.e.non-familial)casesofbreastcancer.Recentstudiessuggest
partialanswer.AproteincalledEMSYhasbeenfoundthatbindsandinhibitsBRCA2.
Remarkably,EMSYisfrequentlyoverexpressedinsporadicbreastcancersduetogene
amplication,andthisisapparentlyamuchmorelikelyeventthatthelossofthetwo
normalcopiesofeithertheBRCA1ofBRCA2genes.IncreasedEMSYexpression
correlateswithpoorclinicaloutcome.
E. Regulators of Signal Transduction
Anotherpotentialwaythatproductsoftumorsuppressorgenesmayoperateisbydown
regulatinggrowth-promotingsignals.TheproductsoftheAPCgene(5q21)andtheNF1
gene(17q11.2)fallintothiscategory.Germlinemutationsofthesegenesareassociated
withbenigntumorsthatareprecursorsofcarcinomasthatdeveloplater.
InthecaseoftheAPC (adenomatous polyposis coli)gene,individualsbornwithone
mutantalleleinvariablydevelophundredsoreventhousandsofadenomatouspolypsin
thecolonduringtheirteensor20s(familialadenomatouspolyposis,orFAP;seeFamilial
andHereditaryCancerSyndromeslecture).Almostinvariably,oneormoreofthese
polypsundergomalignanttransformation,givingrisetocancer.Aswithothertumor
suppressorgenes,bothcopiesoftheAPCgenemustbelostfortumordevelopment.
Whenthisoccurs,adenomasformed.InadditiontocancersarisinginthesettingofFAP,
themajority(70-80%)ofnon-familialcolorectalcarcinomasandsporadicadenomas
alsoshowhomozygouslossoftheAPCgene,thusrmlyimplicatingAPClossinthe
pathogenesisofcolonictumors.(SeelectureonColonCancer.)AdescribedintheCell
Proliferationlecture,animportantfunctionoftheAPCproteinistocausedegradationof
beta-catenin,thusmaintaininglowlevelsinthecytoplasm.InactivationoftheAPCgene,
andconsequentlossoftheAPCprotein,increasesthecellularlevelsofbeta-catenin,
which,inturn,translocatestothenucleusandup-regulatescellularproliferation.Thus
APCisanegativeregulatorofbeta-cateninsignaling.Beta-cateninitselffunctionsasa
proto-oncogene(seebelow).Interestingly,casesofcolorectalcancerthatdonotshowlossofAPCmayinfacthaveactivatingmutationsinbeta-catenin.Dysregulationofthe
APC/beta-cateninpathwayisnotrestrictedtocoloncancer;mutationsineitherAPCor
beta-cateninhavealsobeenfoundinnearly30%ofmelanomacelllines.
TheNF1genebehavessimilartotheAPCgene.Individualswhoinheritonemutant
alleledevelopnumerousbenignneurobromas,presumablyasaresultoftheinactivation
ofthesecondcopyoftheNF1gene.Thisconditioniscalledneurobromatosistype
1,orNF1.Someoftheneurobromasmayundergomalignanttransformationinto
neurobrosarcomas.ChildrenwithNF1alsoareatincreasedriskfordevelopingacute
myeloidleukemia.Thefunctionofneurobromin,theproteinproductoftheNF1gene,is
toregulatesignaltransductionviatheRasprotein.NeurobrominisaGTP-aseactivating
proteinthatfacilitatesconversionofactiveRas(GTPfound)toinactiveRas(GDPbound).WithlossofNF1,Rasistrappedinanactive,signal-emittingstate.
III. VIRUSES AND CANCER
Virusesareinfectiousagentsthatmustreplicateinsideahostcell.Virusescontaintheirown
genome(whichcanbeeitherDNAorRNA)protectedbyacoatmadeupofproteinorprotein
pluslipid.Differentvirusesusethehostcellsmachineryindifferentways,butallviruses
requirethetranslationapparatus(e.g.ribosomes)ofthehostcellstotranslatetheirmRNAs.
Bacteria,incontrast,cangenerallygrowoutsidethehostandhavetheirowntranslation
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machinery.SomevirusespromotecancerinhumansincludingHIV,Epstein-BarrVirus
(EBV),andhuman papilloma viruses (HPVs).Thefundamentalsofviraltumorgenesis,
includingsomeofthehistory,werecoveredintheI3block.Herewewillmerelyreviewhow
HPVscausecancerinordertoconnecttotwoofthemaintumorsuppressorgenesdiscussed
inthissection.
Humanpapillomaviruses(transmittedthroughsexualcontact)playapathogenicrole
inmostcasesofcervicalcancer(seeinformationoncervicalcancerinthePathological
CharacteristicsofBenignandMalignantNeoplasmslab,theCancerScreeninglecture,
andtheClinicalandTranslationalResearchonlinemodule).Thereareatleast77subtypes
ofHPVthataredistinguishedbyvariationsintheirDNAsequences.HPV-16orHPV-18
DNAisfoundin70%ofcervicaltumors.Anadditional20%oftumorscontainHPVDNA
correspondingtooneof20othercancer-associatedsubtypes.HPVshaveadouble-stranded
DNAgenome.Thereare7viralgenesthatareexpressedearlyduringinfection(E1-E7)and2
genesthatareexpressedlate(L1-L2).
Twooftheearlygenes,E6andE7,promotetumorformation(Figure5).TheE6proteinas-
sociateswithacellularproteincalledE6AP(E6-AssociatedProtein).TheE6-E6APprotein
complexcatalyzescovalentattachmentofasmallproteincalledubiquitintop53.Theattach-mentofapolyubiquitinchaintoaproteintargetsittotheproteasomefordegradation.Thus,
E6inactivatesp53bycausingthedegradationoftheproteinviathecellsnormalprotein
degradationmachinery.TheproteinencodedbyE7directlybindstoRbandinactivatesit.
ThusRbcanbeinactivatedbylossofthegene(asinretinoblastomaandothertumors),by
mutationsingenesthatcontrolRbPhosphorylation,orbyinactivationoftheproteinbya
viralprotein.AsingeneticlossofRb,inactivationoftheRbproteinleadstotheactivationof
theE2FtranscriptionfactorandtranscriptionofthecyclinEgene.Withoutthesafeguardsof
bothp53andRb,thecellisstronglydriventowardcancer.
Figure 5. Inactivation of tumor suppressor genes by proteins encoded by Human Papilloma Virus.
The E6 protein of oncogenic HPVs binds to a cellular protein called E6-AP (E6 associated protein), which
is a ubiquitin ligase. The E6-E6AP protein complex catalyzes the attachment many copies of the small
protein ubiquitin to p53. This leads to the degradation of p53 by a large cytoplasmic protease called the
proteasome. The E7 protein promotes cancer by binding directly to the Rb protein, rendering it inactive.
p53
degradation viathe proteasome
E6 E6-AP
+ p53-Ub-Ub-Ub
ubiquitin (Ub)
+
activation
of E2F
and cyclin E
transcription
E7 + Rb
active
E7 Rb
inactive
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IV. ONCOGENES
Cellscontainmanynormalgenesthatareinvolvedinregulatingcellproliferation.Someof
thesegenescanbemutatedtoformsthatpromoteuncontrolledcellproliferation.Thenormal
formsofthesegenesarecalledproto-oncogenes, whilethemutated,cancer-causingforms
arecalledoncogenes.Incontrasttotumorsuppressorgenes,whichputthebrakesoncell
proliferation,oncogenesactivelypromoteproliferation(analogoustothegaspetalofthecell
cycle).Mutationsthatconvertproto-oncogenestooncogenestypicallyincreasetheactivity
oftheencodedproteinorincreasetheexpressionofthenormalgene.Suchmutationsare
dominantorgain-of-function mutations.Therefore,onlyonecopyofthegeneneedstobe
mutatedinordertopromotecancer.
Oncogeneswererstidentiedinoncogenicretrovirusesthathadpickedupacellular
oncogene(c-onc)andincorporateditintotheviralgenometoproduceaviraloncogene
(v-onc).J.MichaelBishopandHaroldVarmusofUCSFwereawardedthe1989NobelPrize
inMedicineforthediscoveryofthecellularoriginoftheviraloncogenes.
A. HER2/neu and breast cancer
TheHER2/neugeneencodesareceptortyrosinekinasecloselyrelatedtotheepidermal
growthfactor(EGF)receptor(theybothbelongtotheErbBfamilyofreceptors).This
geneisoverexpressedin~25%ofbreastcancers.BreastcancersthatoverexpressHER2/neutendtobemoreaggressiveclinically(moreonthisinupcominglecturesonBreast
CancerandCancerTreatment).ThemechanismbywhichHER2/neuisoverexpressedis
gene amplication,whichresultsinmultiplecopiesofthegeneaccumulatingintumor
cells.TheincreaseinthelevelsoftheHER2/neutyrosinekinasereceptorontumorcells
Sos
Ras-GDP Ras-GTP
GTP
GDP
inactive active
oncogenic mutations
block GTPase activiy
Figure 6. How mutations in the Ras
oncogenes promote cancer. Oncogenic
mutations in ras genes prevent the
protein from hydrolyzing GTP toGDP. As a result, the protein remains
always in its active GTP-bound form,
continually activating the MAP kinase
cascade, leading to proliferation.
resultsinincreasedsignalingviatheRas-MAPKpathway,drivingcellularproliferation.
ThediscoveryofHER2/neuamplicationinbreastcancerhasledtothedevelopment
oftheanticancerdrugHerceptin.Herceptinisamonoclonalantibodythatbindsto
HER2/neuonthecellsurfaceresultinginreceptordown-regulation(decreasednumbers
ofHER-2/neuatthecellsurface)andkillingofcellsbytheimmunesystem.Itwas
approvedin1998foruseintreatmentofbreastcancer(moreaboutHerceptinintheDrug
Developmentlecture).
B. Activation of Ras: the oncogene most commonly activated in human tumors
ThehumangenomeencodesthreeRas genes:H-ras,K-ras,N-ras.Alargefractionof
tumorscontainmutationsinoneofthesethreegenes.Forexample,70-90%ofpancreatic
carcinomascontainamutationintheK-rasgene.Rasoncogenesareactivatedbypoint
mutationsthatresultinproteinsunabletohydrolyzeGTP(Figure6).Thesemutant
RasproteinsarethereforelockedintheGTP-bound(active)form,whichtherefore
continuallyactivatestheMAPkinasepathway,whichinturnleadstocellproliferation.
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C. The Myc oncogene is often amplied or overexpressed in cancers
TheMycproteinactsinthenucleusasasignalforcellproliferationthroughseveral
mechanisms.Onemechanism,asdiscussedintheCellProliferationlecture,isasa
transcriptionfactorforthecyclinDgene.Mycisencodedbyaproto-oncogenethatis
overexpressedorampliedinmanycancers.ExcessquantitiesofMyccancausecells
toproliferateincircumstanceswherenormalcellswouldhalt.Insomecancers,rather
thanbeingamplied,Mycismadeactivebychromosomaltranslocation.(SeetheCancerCytogeneticssectionoftheMutationandCancerlectureforadescriptionofchromosome
abnormalitiesincancer.)Asaresultofthischromosomalrearrangement,astrong
promotersequenceisplacedinappropriatelynexttotheMycproteincodingsequence,
producingunusuallylargeamountsoftheMycmRNA.Forexample,asyouwilllearn
laterinthiscourse,inBurkittslymphomaatranslocationbringstheMycgeneunderthe
controlofsequencesthatnormallydrivetheexpressionoflargeamountsofantibodiesin
Bcells.Asaresult,mutantBcellsproducelargeamountsoftheMycprotein,proliferate
toexcess,andformatumor.
D. Cyclin D can be activated through several different mechanisms
AsdiscussedintheCellProliferationlecture,cyclinDformspartoftheG1-Cdk,which
normallyfunctionstoinactivetheRbtumorsuppressorproteinbyphosphorylatingit
(Figure7).CyclinDisoftenoverexpressedincancersleadingtoreducedactivityofRb.
Inbreastcancer,thecyclinDgeneisoftenamplied.AswithHER2/neuamplication,
thisresultsinmorecyclinEproteinbeingproduced.
CyclinDalsoplaysaroleinparathyroidadenomas,tumorsoftheparathyroidglandthat
resultinuncontrolledcalciummobilizationfrombones(Figure8).(Thenormalfunction
ofparathyroidhormoneistoinducecalciumreleasefrombones).Inthesetumors,cyclin
Dcanbeactivatedbyadifferentmechanism.Achromosome inversionplacesthestrong
transcriptionalcontrolregionoftheparathyroidhormonegeneadjacenttothecyclinD
geneonchromosome11q.ThisresultsinthecontinuousexpressionofthecyclinDgene,
whichinturnpromotesproliferation.
Inchroniclymphocyticleukemias,cyclinDisderegulatedbyyetanothermechanism.In
thesetumors,cyclinDisactivatedviaachromosometranslocationthatplacesthecyclin
Dgeneundercontroloftheimmunoglobulinheavychaintranscriptioncontrolregion.
(ChromosomerearrangementsaredescribedintheCancerCytogeneticssectionofthe
MutationandCancerlecture.)
Figure 7. How cyclin D gene amplication leads to proliferation.Increased numbers of cyclin D genes
leads to increased levels of Cdk4-cyclin D complexes which activate cyclin E transcription via the Rb-E2F
pathway.
Cdk4-cyclin D Rb E2Fcyclin E
transcriptionCdk2-cyclin E proliferation
OFF ON ON ON ON
cyclin D gene
amplication
ON
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E. Bcl-2: apoptosis proteins and cancer
Atranslocationbetweenchromosomes14and18(t(14:18)(q32;q21)isthemostcommon
translocationinhumanlymphoidmalignancies.Itisespeciallycommoninfollicularcelllymphomas(80-90%ofcaseshaveit).Thetranslocationresultsintheactivationof
Bcl-2becausethegeneisbroughtintoproximitywithpotenttranscriptionalregulatory
sequencesfromtheimmunoglobulinheavychaingene.Theantiapopototicactivity
ofBcl-2resultsintheincreasedsurvivalofthecellsthatoverexpressBcl-2.Thisin
turngivesthecellstheopportunitytoacquireadditionalmutationsthatleadtocancer.
Thus,programmedcelldeathisanimportantmechanismthatnormallyrestrictstumor
formation.
V. MULTISTEP TUMORIGENESIS: MOLECULAR EVENTS ASSOCIATED WITH
THE GENESIS OF COLON CANCER
Coloncancerisunusualinthattheprecancerouslesionscanbeidentiedearlyvia
colonoscopy.Molecularanalysisofthevariousstagesofcoloncanceristhereforepossible.Thesestudieshaveidentiedaroughsequenceofmoleculareventsthatcharacterizetumor
developmentincolorectalcancer(Figure9).Becausewenowknowthemolecularfunction
manytumorsuppressorgenesandoncogenes,wearebeginningtounderstandthegenetic
changesthatoccurduringcancerformation.
Theearlieststageofcoloncancerformationistheappearanceofahyperproliferative
epithelium(Figure9).ThisisassociatedwiththelossoftheAPCtumorsuppressor.Recall
thatAPClimitsWntsignalinginthegutepitheliumwhereitisexpressedathighlevelsin
non-dividingcellsandlowlevelsinthestemcellsofthecrypts.LossoftheAPCgeneresults
inhyperactiveWntsignalingandproliferationofcellsbeyondthecrypts.Subsequentto
lossofAPC,thereappearstobeaperiodofgenomicinstability,whichpermitsthecellsto
acquiremutationsmorerapidly.ProgressionofadenomasisassociatedwithactivationofthemitogenicRas-MAPKpathwaythroughtheacquisitionofactivatingmutationsinthe
K-rasoncogene.Later,afurtherblowtogrowthcontroloccursviathelossofaSMADgene
requiredforsignalingthroughthegrowthinhibitoryTGF-betasignalingpathway.Finally,the
progressionfromlateademonastomalignantcarcinomsisassociatedwiththelossofthep53
tumorsuppressor,whichreleasesthecellsfromDNAdamageandstressinducedapoptosis
andcellcyclearrest.(Fordescriptionofcancernomenclature,seetheIntroductiontoCancer
Pathologylecture.)
Figure 8. Activation of cyclin
D in parathyroid adenomas.In
parathyroid adenomas, the cyclin D
gene is activated by a DNA inversion.
The inversion places the promoter of
the parathyroid hormone gene (PTH
gene) next to the cyclin D codingregion.
PTH genepromoter
cyclin D gene
promotercyclin D genePTH gene
PTH gene
promoter
cyclin D gene
promoter
cyclin D genePTH gene
inversion of DNA segment
between cyclin D gene and PTH gene
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Thereareadditionalchangesintumorsuppressorgenesandoncogenesthatoccurduring
tumorprogressionthataredifferentindifferentcoloncancers,someofwhichhaveyettobeidentied.Nonetheless,thestudyofthemolecularbasisofcoloncancerhasgivenus
apictureofthemulti-stepevolutionofatumorandthegeneticchangesthatdrivethem.Importantly,anunderstandingofthespecicgeneticchangesthatoccurduringthismulti-
stepprocessallowsfortheidenticationofkeystepsforinterventionandthedevelopmentof
specictherapeuticstrategies
VI. THE HALLMARKS OF CANCER
Ifweconsiderthehallmarkfeaturesofcancercellsthatwereintroducedintheintroductory
lectureonCancerBiology,wecanbegintomapthemoleculardefectsinthegenesand
processeswevediscussedinthelasttwolecturestooneofthesixacquiredcapabilities
ofcancercells.Letsconsidertherstfouracquiredcapabilitieshere(thelasttwowillbe
coveredinlaterlectures).Acoupleexamplesofmoleculardefectsthatcanresultineach
acquiredcapabilityareincludedbelow.Canyouthinkofothers?
1. Self-Sufciency in Growth Signals
Normalcellscannotproliferateintheabsenceofstimulatorysignals,butcancercells
can.Manyoncogenesactbymimickingnormalgrowthsignalingthroughoneofseveral
mechanisms.
Whilemostmitogenicgrowthfactorsaremadebyonecelltypeinordertostimulate
Figure 9. Multistep model for colorectal cancer.
Shown is the sequence of pathological events that
take place during the development of sporadic
colon cancer and the genetic changes that occur
during this sequence. The sequence of events
is not absolute this diagram describes what
happens on average.
loss of APC
tumor suppresor
increased genetic
instability
activation of K-ras
loss of SMAD4 andother tumor suppressors
loss of p53
normal epithelium
hyperproliferative epithelium
early adenoma
intermediate adenoma
late ademoma
carcinoma
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Katherine M. Hyland, PhD,
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proliferationofanother(heterotypicsignaling),manycancercellsacquiretheability
tosynthesizetheirowngrowthfactors,creatingapositivefeedbacksignalingloop
(autocrinestimulation),andobviatingthedependenceongrowthfactorsfromother
cells.TheproductionofPDGF(plateletderivedgrowthfactor)andTGF-(tumor
growthfactor)byglioblastomasandsarcomasaretwoexamples.
Cellsurfacereceptorsthattransducegrowth-stimulatorysignalsintothecell,for
exampleEGFRandHER2/neu,maybeoverexpressedorstructurallyaltered,leadingtoligand-independentsignaling.
Downstreamtargetsofthesignalingpathwaycanalsobealtered.Forexample,Ras
isfoundmutatedabout25%ofhumantumors,thusleadingtoligand-independent
activationoftheRas-Raf-MAPKsignalingpathway.
2. Insensitivity to antigrowth signals
Antigrowthsignalscanblockproliferationbytwomechanisms:1)forcingcellsoutofthe
activeproliferativecycleintothequiescent(G0)state,untilappropriategrowthsignalsput
thembackintothecellcycle;or2)inducingdifferentiation,whichpermanentlyremoves
theirproliferativepotential.Cancercellsevadetheseantiproliferativesignals.Atthe
molecularlevel,manyandperhapsallanti-proliferativesignalsarefunneledthroughthe
Rbprotein(anditstworelatives,p107andp130).DisruptionoftheRbpathwayliberates
E2Fsandthusallowscellproliferation,renderingcellsinsensitivetoanti-growthfactors
thatnormallyblockadvancethroughG1.TheRbsignalingpathway(regulatedbyTGF-
anti-proliferativesignalingandotherextrinsicfactors)canbedisruptedinavarietyof
waysindifferenttypesofhumantumors,forexample:
LossofTGF(normallyactstopreventphosphorylationthatinactivatesRb)
LossofSmad4(normallytransducessignalsfromligand-activatedTGFreceptorsto
downstreamtargets)
LossofCDKinhibitorsp16,p21,p53
InactivationofRbdirectlybyhyperphosphorylationorinactivatingmutation
Tumorcellsalsousevariousstrategiestoavoidterminaldifferentiation.OverexpressionofcMycisonesuchstrategy.
3. Evading Apoptosis
Asdiscussedearlier,theabilityoftumorcellpopulationstoexpandinnumberis
determinednotonlybytherateofcellproliferationbutalsobytherateofcellattrition.
Programedcelldeath,orapoptosis,representsamajorsourceofthisattrition.Resistance
toapoptosisascanbeacquiredbycancercellsthroughavarietyofstrategies.Examples
include;
Lossofp53(normallyactivatespro-apoptoticproteins;representsthemostcommon
lossofaproapoptoticregulator)
Activationorupregulationofanti-apoptoticBcl2
4. Limitless Replicative Potential
Therstthreeacquiredcapabilitieslackofrequirementforgrowthsignals,insensitivity
toantigrowthsignals,andresistancetoapoptosisallleadtoanuncouplingofthecells
growthprogramfromsignalsinitsenvironment.However,ithasbeenshownthatthis
uncouplingalonedoesnotensureexpansivetumorgrowth.Mosttypesofmammalian
cellscarryanintrinsicmechanismthatlimitstheirproliferationbykeepingtrackofthe
numberofcellgenerations.Thismechanismusesthenumberoftelomererepeatsatthe
endsofchromosomes,whicherodethroughsuccessivecyclesofreplication-eventually
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leadingtocelldeath.Asmallpercentageoftumorcellsavoidthisbyobtainingamutation
thatupregulatesexpessionofthetelomeraseenzyme,thusacquiringlimitlessreplicative
potentialbymaintainingtheirtelomeres.(Moreontelomeresandtelomeraseinthe
MutationandCancerlecture.)
5and6.The5thand6thacquiredcapabilities,SustainedAngiogenesisandTissueInvasion
andMetastasis,willbecoveredindetailinlaterlectures.
References
Albertsetal.MolecularBiologyoftheCell;5thEdition,GarlandScience,2008.
GeneReviewsontheNCBIGeneTestswebsite:
http://www.ncbi.nlm.nih.gov/sites/GeneTests/?db=GeneTestsAndreferencestherein.
BRCA1andBRCA2HereditaryBreastandOvarianCancer
Retinoblastoma
Hanahan,D.andWeinberg,R.(2000).TheHallmarksofCancer.Cell100,57-70.
Mendelsohnetal.TheMolecularBasisofCancer,3rdEdition,Elsevier/Saunders,2008
OMIM(OnlineMendelianInheritanceinMan)http://www.ncbi.nlm.nih.gov/sites/
entrez?db=omimAndreferencestherein.
BRCA1,BRCA2
Acknowledgements:
Signicantcontributionstothislectureweremadeby
HitenMadhani,PhD,DepartmentofBiochemistryandBiophysics,whooriginallydevelopedthislecture
(lecturer20022006);