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
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Tumor progressionTumor progression
Involvessuccessionofrandominheritedchangesfollowedbynaturalselection
Ateachstagethecellsacquireamutationorepigeneticchange
Theenvironmentinsideatumoris
harshandinhibitsthegrowthofnormalcells
Isthisexpected?Higherorganismshavestringent
generegulation
Thecellshavetocrosstheselevels
ofregulation
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Epigenetic Changes: InheritedEpigenetic Changes: Inherited
chromatin structurechromatin structureCellsareidentifiedbyabnormal
appearancein
tumor
biopsies
Containunusualamountofheterochromatin
Associatedwithgenesilencing
Genesareswitchedoffinacelltocellinheritedmanner
Inrealitythisisthesameprinciplebywhichfetusgrowsinhigheranimals
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Genetic &Genetic & EpigenticEpigentic changeschanges
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Defective Control ofDefective Control of
Programmed Cell DeathProgrammed Cell Death
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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
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Tumors induce angiogenesisTumors induce angiogenesis
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Viruses can cause cancerViruses can cause cancer
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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
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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.
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7025
1186675
7027
1309567
1833855
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1186675
7027
13095671833855
2091901
2090140
2090142
2091903
2091901
2090140
2090142
2091903
911741 2091391
912253 2091389
129917
654205129919
654207
Transient
Survival Death
Stable states
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Node Mutation
HSPHSP
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HSPsHSPs
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Experimental methodsExperimental methods
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Differences between 2Differences between 2--D and 3D and 3--
D culturesD culturesPhenotypeandmorphology
Metabolicand
gene
expression
pattern
Tumorcellsgrownin3Dshowpronouncedresistancetodrugsasobserved
invivo
Alterspluripotency ofstemcells
Responsiblefordevelopmentalchanges(whichmeansthisareaofresearchcannotbecarriedoutin2D)
Spatiotemporalconsistencyofinformationandheirarchy
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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
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