sbl101 jg cancer

8/10/2019 Sbl101 Jg Cancer

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CancerCancer

SBL101SBL101

JamesGomesSchoolofBiologicalSciencesIndianInstituteofTechnologyDelhi

All Figures in this Lecture are taken from

1. Molecular biology of the cell / Bruce Alberts et al., 5th ed.

2. Research papers as cited OR3. Constructed


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Basic property of cancer cellsBasic property of cancer cells

Cancercellspossesstwoheritableproperties Reproduceindefianceto

normalconstraints

on

growthandproliferation Invadeandcolonize

territoriesreservedfor

othercells Theabnormalcellsgive

risetoatumoror

neoplasm BenignMalignant

Metastases Metastasis in Non-HodgkinLymphoma.

Fluorodeoxyglucose shows up as

yellow in regions of high glucose

activity typical of tumor cells.


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Cancer originates from a singleCancer originates from a single

abnormal cellabnormal cell

Cancerdevelopsfromasinglecellthathasacquiredaheritablechange

Thisis

passed

on

to

its

descendents

allowing

themtooutgrow,outdivideandoutlivetheirneighbors

Bythetimethesecellsaredetected,thereare

aboutabillion

of

them


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Causes of CancerCauses of Cancer

GeneticandEpigeneticchanges

CarcinogenesisChemicalCarcinogenesis

RadiationCarcinogenesis

GeneticdefectinDNArepairmechanisms

Peoplewithxeroderma pigmintosumaremorepronetocancer

MicelackingcertainDNArepairgenesareabnormallypronetocancer


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Mutations and CancerMutations and Cancer

Itisestimatedthat1016 celldivisionsoccurinahumanbodyinonelifetime

ErrorrateofDNAcoding106

Everygeneislikelytohaveundergone1010 mutations

SowhydoescanceroccursoInfrequently?

Itmeansthatanumberofrare

geneticaccidentsmustoccurinthelineageofonecelli.e.progressiveaccumulationofrandommutationsinasingle

lineageofcells


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Progression of cervical cancerProgression of cervical cancer



Tumor progressionTumor progression

Involvessuccessionofrandominheritedchangesfollowedbynaturalselection

Ateachstagethecellsacquireamutationorepigeneticchange

Theenvironmentinsideatumoris

harshandinhibitsthegrowthofnormalcells

Isthisexpected?Higherorganismshavestringent

generegulation

Thecellshavetocrosstheselevels

ofregulation



Epigenetic Changes: InheritedEpigenetic Changes: Inherited

chromatin structurechromatin structureCellsareidentifiedbyabnormal

appearancein

tumor

biopsies

Containunusualamountofheterochromatin

Associatedwithgenesilencing

Genesareswitchedoffinacelltocellinheritedmanner

Inrealitythisisthesameprinciplebywhichfetusgrowsinhigheranimals



Genetic &Genetic & EpigenticEpigentic changeschanges



Defective Control ofDefective Control of

Programmed Cell DeathProgrammed Cell Death



Escapes limits of replicationEscapes limits of replication

Normalprimary cellsproliferateinculture,butsoonstopdividingafteranumberofdividingcycles

replicative senescence Celldivisioncountingmechanismdependsonthe

shorteningoftelomeres Cellshavetheenzymetelomerase,thepromotedthe

formationofproteincapstoprotecttheendsofthechromosomes

Manyproliferationcells(withtheexceptionofstemcells)aredeficientintelomeraseandsoitultimatelyresultsinthecellcyclearrestofthecell

Cancercellseither Blockthecontrolpointsothatcellcyclecontinuesinthe

absenceoftelomeres Acquire/maintaintelomeraseactivitytocontinueindefinite

celldividion



Tumors induce angiogenesisTumors induce angiogenesis



Viruses can cause cancerViruses can cause cancer



Analysis of stable states in Apoptotic pathways dependentAnalysis of stable states in Apoptotic pathways dependentupon the presence or absence of heat shock proteins forupon the presence or absence of heat shock proteins for

predicting drug targetspredicting drug targets

Apoptotic

state

Cell death

Cell Survival

HSPs

Death

signal



HypothesisHypothesis

(i) Apoptosis regulated at multiple steps, cFLIP is the

first level, IAP is second and Bcl2 at third level.

(ii)Inhibition of Bcl2 signaling induces apoptosis.(iii)Bcl2 should be constitutively activated concurrently

with p53 is essential for the long-term survival of cells

and to reproduce cancer phenotype.

(iv)Most stable state in pathway is where cFLIP, IAP, and

Bcl2 are ON.

(v) HSPs can prevent apoptotic pathway.



7025

1186675

7027

1309567

1833855

7025

1186675

7027

13095671833855

2091901

2090140

2090142

2091903

2091901

2090140

2090142

2091903

911741 2091391

912253 2091389

129917

654205129919

654207

Transient

Survival Death

Stable states



Node Mutation

HSPHSP



HSPsHSPs



Experimental methodsExperimental methods



Differences between 2Differences between 2--D and 3D and 3--

D culturesD culturesPhenotypeandmorphology

Metabolicand

gene

expression

pattern

Tumorcellsgrownin3Dshowpronouncedresistancetodrugsasobserved

invivo

Alterspluripotency ofstemcells

Responsiblefordevelopmentalchanges(whichmeansthisareaofresearchcannotbecarriedoutin2D)

Spatiotemporalconsistencyofinformationandheirarchy



Variability in 2Variability in 2--D & 3D & 3--DD

culturescultures

Rolereversal:unlikein2Dcultures,breasttumour

cellsin3Dculture(left)thatbecome

malignant

(centre)

can

be

made

to

revert

to

their

originalstate(right)whenanantibodyagainst

1integrinisaddedtothesystem.M.BISSELL,theLawrenceBerkeleyNationalLaboratoryinCalifornia


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Testing Cancer drugsTesting Cancer drugs

Receptorsforgrowthfactorsplayakeyroleintheinitialdevelopmentoftumours

themigrationofcellsawayfromprimarytumours tocausesecondarycancersaroundthe

body

Cancercells

undergoing

metastasisnormallycutthemselvesfreefromatumoursECMusingproteindigesting

enzymes formationofamoebalikecells

dependsonaparticularsignallingpathwayinarangeofdifferenttumour celllines

Joined up: a cell in a 3-D cultureforming links by means of 1-integrin(orange) with the scaffolding.


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Changes in Morphology :Changes in Morphology :

MetastatisMetastatis

Transition of spindle-shaped (mesenchymal) tomore spherical (amoeboid) migration inHT1080/MT1 and MDA-MB-231 cells for migration

(metastatis) Wolf et al. JCB 2003 160 (2): 267

Theinvasionandmigrationoftumor

cellsinvolvescoordinatedadhesionaswellasproteolytic

interactionwith

the

ECMsubstrate,resultinginthedegradationandremodelingofinterstitialtissuebarriers

C f


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Change in Morphology of HT 1080 inChange in Morphology of HT 1080 in

Hollow Fiber ReactorHollow Fiber Reactor

Adhered

cells

produce

urokinase Amoeboidal cellsmigrate

S. S. Khaparde, P. K.Roychoudhury, J. Gomes*, A.Mukhopdhyay, Biotechnol.Prog. 2008, 24, 1325

Trajectories showing the course of physiologicalstates during the external modulation of HFR forurokinase production

sbl101 jg cancer

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