OBJECTIVES1. Listthemajorhallmarksofcancer

2. Relatespecificgenes/proteinstoindividualhallmarks

3. Explainhowhallmarksofcancerleadtocancerdevelopment

Source:www.123rf.com

CaseStudy• 60yearoldfemale

• Previouslytreatedforbreastcancer(5yearsprior);norecurrence

• Presentswithpersistentcough,shortnessofbreath,fatigue

• X-rayrevealssmallmassinleftlung

• Abiopsyisperformed

think-discuss-shareAphysicianmeetswiththispatient.Whatisthefirst questionsheasksaboutthepatient’slifestyle?

www.lung.org

www.lung.org

brainstormingApathologistanalyzesthebiopsysample.Whatdoesshelookfor?,i.e.Whatinformationisgainedfromtheanalysisofthebiopsy?

www.lung.org

TYPESOFLUNGCANCER

Biopsyresultsindicatethatpatienthasametastatictumorofbreastcancerorigininlung.Tumorisacarcinoma.

Biopsyresultsindicatethatpatienthasametastatictumorofbreastcancerorigininlung.Tumorisacarcinoma.

QUESTION – Whatchangesoccurredtoabreastepithelialcellthatledtotheformationofametastatictumorinthelung?

DouglasHanahan

RobertWeinberg

Hanahan andWeinberg(2000)Cell,100:57– 70.

CELLDIVISION

GROWTHFACTOR(GF)

RECEPTOR

INTRACELLULARSIGNALINGPATHWAY

CELLDIVISION

GROWTHFACTOR(GF)

RECEPTOR

INTRACELLULARSIGNALINGPATHWAY

Ras

CELLDIVISION

RECEPTOR

INTRACELLULARSIGNALINGPATHWAY

HyperactiveMutantRas inCancers

Ras

GROWTHFACTOR(GF)

INTRACELLULARSIGNALINGPATHWAY

CELLDIVISION

AmplifiedEGFReceptorsinCancer

Source:Cheng,L.etal.(2012)ModernPathology,25:347– 369.

CLASSESOFLUNGADENOCARCINOMA

Ras

www.tarceva.com

www.lifewithlungcancer.org

TARCEVA – ADRUGWHICHTARGETSEGFRECEPTORINLUNGCANCER

Hanahan andWeinberg(2000)Cell,100:57– 70.

EUKARYOTICCELLCYCLE

G0

RECEPTOR

INTRACELLULARSIGNALINGPATHWAY

Rb

RECEPTOR

INTRACELLULARSIGNALINGPATHWAY

Rb-P

CELLDIVISION

GROWTHFACTOR(GF)

ModifiedandInactiveRb

RECEPTOR

INTRACELLULARSIGNALINGPATHWAY

Rb

CELLDIVISION

InactiveMutantRb

inCancer

p53’sNORMALROLEISTOINHIBITCELLDIVISIONINRESPONSETOCELLULARSTRESSESLIKEDNADAMAGE

TUMORCELLSLACKINGp53DONOT ARRESTCELLCYCLE

Source:MolecularBiologyoftheCell,Alberts etal.

Hanahan andWeinberg(2000)Cell,100:57– 70.

APOPTOSIS– PROGRAMMEDCELLDEATH

Source:MolecularBiologyoftheCell,Alberts etal.

CELLDIVISION

INSULIN-LIKEGROWTHFACTOR(IGF-1)

IGF-1R

INTRACELLULARSIGNALINGPATHWAY

Ras

CELLSURVIVAL

CELLDIVISION

INSULIN-LIKEGROWTHFACTOR(IGF-1)

IGF-1R

INTRACELLULARSIGNALINGPATHWAY

Ras

CELLSURVIVAL

SOMECANCERCELLSUPREGULATECELLSURVIVALPATHWAYSTOEVADEAPOPTOSIS

Hanahan andWeinberg(2000)Cell,100:57– 70.

TELOMERES ARECHROMOSOMEENDS

TELOMERESAREMADEBYTELOMERASE EARLYINDEVELOPMENT;THENTELOMERASEACTIVITYISNORMALLYTURNEDOFF

TELOMERESSHORTENWITHEACHCELLDIVISION,ULTIMATELYLEADINGTOSENESCENCE

CANCERCELLSREACTIVATE TELOMERASE

Biopsyresultsindicatethatpatienthasametastatictumorofbreastcancerorigininlung.Tumorisacarcinoma.

Hanahan andWeinberg(2000)Cell,100:57– 70.

Theformationofnewbloodvesselsfrompre-existingbloodvessels.

VEGF=VascularEndothelialGrowthFactor

Biopsyresultsindicatethatpatienthasametastatictumorofbreastcancerorigininlung.Tumorisacarcinoma.

Hanahan andWeinberg(2000)Cell,100:57– 70.

brainstormingWhathastohappentoabreastcarcinomacelltoallowittometastasizetothelung?

PRIMARYBREASTCARCINOMA

METASTATICTUMORINLUNG

METASTASIS

CELLSOFPRIMARYTUMORREDUCEEXPRESSIONOFINTERCELLULARCONNECTIONS(E-CADHERINS)ANDCONNECTIONSTOTHEEXTRACELLULARMATRIX(INTEGRINS)TOALLOWMETASTASIS

Hanahan andWeinberg(2000)Cell,100:57– 70.

CANCERDEVELOPMENTISAMULTI-STEPPROCESS.

INDIVIDUALSTEPSCANOCCURISDIFFERENTORDER.

Ras,EGFReceptor

Rb,p53

IGF-1,IGF-1R

Telomerase

VEGF

E-cadherin

THEHALLMARKSOFCANCER

Youshouldbeableto...1. Listthemajorhallmarksofcancer

2. Relatespecificgenes/proteinstoindividualhallmarks

3. Explainhowhallmarksofcancerleadtocancerdevelopment