Cancer

SBL101
JamesGomes
SchoolofBiologicalSciences
IndianInstituteofTechnologyDelhi

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
3. Constructed

OR

Basic property of cancer cells

Cancercellspossesstwo
heritableproperties
Reproduceindefianceto

normalconstraintson
growthandproliferation
Invadeandcolonize
territoriesreservedfor
othercells

Theabnormalcellsgive
risetoatumoror
neoplasm
Benign
Malignant

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Metastases

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Metastasis in Non-Hodgkin
Lymphoma.
Fluorodeoxyglucose shows up as
yellow in regions of high glucose
activity typical of tumor cells.

Cancer originates from a single

abnormal cell

Cancerdevelopsfromasinglecellthathas
acquiredaheritablechange
Thisispassedontoitsdescendentsallowing

themtooutgrow,outdivideandoutlivetheir
neighbors
Bythetimethesecellsaredetected,thereare
aboutabillionofthem
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Causes of Cancer
GeneticandEpigeneticchanges
Carcinogenesis
ChemicalCarcinogenesis
RadiationCarcinogenesis

GeneticdefectinDNArepair
mechanisms
Peoplewithxeroderma pigmintosum aremore
pronetocancer
MicelackingcertainDNArepairgenesare
abnormallypronetocancer

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Mutations and Cancer

Itisestimatedthat1016 cell
divisionsoccurinahuman
bodyinonelifetime
ErrorrateofDNAcoding106

Everygeneislikelytohave
undergone1010 mutations

Sowhydoescanceroccurso
Infrequently?

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Itmeansthatanumberofrare
genetic accidentsmustoccurin
thelineageofonecelli.e.
progressiveaccumulationof
randommutationsinasingle
lineageofcells
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Progression of cervical cancer

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Tumor progression
Involvessuccessionof
randominheritedchanges
followedbynaturalselection
Ateachstagethecellsacquirea
mutationorepigeneticchange
Theenvironmentinsideatumoris
harshandinhibitsthegrowthof
normalcells

Isthisexpected?
Higherorganismshavestringent
generegulation
Thecellshavetocrosstheselevels
ofregulation

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Epigenetic Changes: Inherited

chromatin structure
Cellsareidentifiedbyabnormal
appearanceintumorbiopsies
Containunusualamountofheterochromatin
Associatedwithgenesilencing
Genesareswitchedoffinacelltocellinherited
manner

Inrealitythisisthesameprincipleby

whichfetusgrowsinhigheranimals

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Genetic & Epigentic changes

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Defective Control of
Programmed Cell Death

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Escapes limits of replication

Normalprimary cellsproliferateinculture,but
soonstopdividingafteranumberofdividingcycles
replicative senescence
Celldivisioncountingmechanismdependsonthe
shorteningoftelomeres
Cellshavetheenzymetelomerase, thepromotedthe
formationofproteincapstoprotecttheendsofthe
chromosomes
Manyproliferationcells(withtheexceptionofstemcells)
aredeficientintelomeraseandsoitultimatelyresultsinthe
cellcyclearrestofthecell

Cancercellseither
Blockthecontrolpointsothatcellcyclecontinuesinthe
absenceoftelomeres
Acquire/maintaintelomeraseactivitytocontinueindefinite
celldividion

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Tumors induce angiogenesis

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Viruses can cause cancer

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Analysis of stable states in Apoptotic pathways dependent

upon the presence or absence of heat shock proteins for
predicting drug targets

Cell death
Death
signal

Apoptotic
state
HSPs

Cell Survival

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Hypothesis
(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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Stable states

Transient
Survival
7025
1186675
7027
1309567
1833855

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9117412091391
9122532091389
129917
654205
129919
654207

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Death
2091901
2090140
2090142
2091903

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Node Mutation

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HSPs

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Experimental methods

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Differences between 2-D and 3D cultures

Phenotypeandmorphology
Metabolicandgeneexpressionpattern
Tumorcellsgrownin3Dshow

pronouncedresistancetodrugsasobserved
invivo
Alterspluripotency ofstemcells
Responsiblefordevelopmentalchanges
(whichmeansthisareaofresearchcannot
becarriedoutin2D)
Spatiotemporalconsistencyofinformation
andheirarchy
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Variability in 2-D & 3-D

cultures

Rolereversal:unlikein2Dcultures,breast
tumour cellsin3Dculture(left)thatbecome
malignant(centre)canbemadetoreverttotheir
originalstate(right)whenanantibody
against 1integrinisaddedtothesystem.
M.BISSELL,theLawrenceBerkeleyNationalLaboratoryinCalifornia

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Testing Cancer drugs

Receptorsforgrowthfactorsplay
akeyroleintheinitial
developmentoftumours

themigrationofcellsawayfrom
primarytumours tocause
secondarycancersaroundthe
body

Cancercellsundergoing
metastasisnormallycut
themselvesfreefromatumours
ECMusingproteindigesting
enzymes

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Joined up: a cell in a 3-D culture

forming links by means of 1-integrin
(orange) with the scaffolding.

formationofamoebalikecells
dependsonaparticularsignalling
pathwayinarangeofdifferent
tumour celllines

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Changes in Morphology :
Metastatis
Theinvasionand
migrationoftumor
cellsinvolves
coordinatedadhesion
aswellasproteolytic
interactionwiththe
ECMsubstrate,
resultinginthe
degradationand
remodelingof
interstitialtissue
barriers
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Transition of spindle-shaped (mesenchymal) to

more spherical (amoeboid) migration in
HT1080/MT1 and MDA-MB-231 cells for migration
(metastatis) Wolf et al. JCB 2003 160 (2): 267

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Change in Morphology of HT 1080 in

Hollow Fiber Reactor

Trajectories showing the course of physiological

states during the external modulation of HFR for
urokinase production

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

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