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odmorning
odmorning
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Carcinogenesis
Dr. MeghaDr. Megha
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ndexndexod
uctionoductioninologyinologyal growth regulational growth regulation
Hal
lmarks of cancer Chromosomal basis Genetic basis Protein basis
Proto-oncogenes
Tumorsuppressor
gene
Theories Process of
carcinogenesis Factors influencing cancer development
Cellula
r defense me Recent advances
Carcinogens
PartPartII PartPart
IIII
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among fatal diseases in the indu
.hird fatal disease in India
ted that in the next quarter ofcancer cases globally is going
in the developing countries
ntroduction
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ntroduction
.
lignant diseases
of uncontrolled cell proliferat
.ion in form of cancer genes,ratus betraying ell only w( , )obel Prize Winner 1989
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istorical perspective
ippocrates arkinosaleno
Neoplasi
ercivall pott himney workersamagiwa
abbit sar
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ime line
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ime line
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erminologiesGenotype -genetic make upor constitution of an individualorganism.Phenotype - form and
,functioning of an individualto the extent that it may&encompass metabolism behaviour
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erminologies, Gene Exons n
introns
Allele, ,LOH SNP
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erminologiesMutations -changes in the DNA
&sequence of a cell's genome,are caused by radiation viruses
& ,mutagenic chemicals as well aserrors that occur during meiosis
or DNA replication
http://en.wikipedia.org/wiki/File:Chromosomes_mutations-en.svghttp://en.wikipedia.org/wiki/File:Chromosomes_mutations-en.svghttp://en.wikipedia.org/wiki/File:Chromosomes_mutations-en.svghttp://en.wikipedia.org/wiki/File:Chromosomes_mutations-en.svghttp://en.wikipedia.org/wiki/File:Chromosomes_mutations-en.svghttp://en.wikipedia.org/wiki/File:Chromosomes_mutations-en.svghttp://en.wikipedia.org/wiki/File:Chromosomes_mutations-en.svghttp://en.wikipedia.org/wiki/File:Chromosomes_mutations-en.svg8/6/2019 carcinogenesis 1
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&with that of normal tissues per
lls by causing permanent genetic a
erminologies
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ormal cell cycleOrderly progression of cellsthrough the various phases of cell
cycle is mediated by
Cyclins synthesized during,specific phases of cell cycle
activate CDKs
Cyclin dependent kinases drivecell cycle by phosphorylating,target proteins present in
inactive form
.Their inhibitors
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ormal cell cycleCyclinDfirstonetoincreaseince
llcy
appearsinmidG1
absentinSphase
bindsto&activateCDK4
Phosp
horylat
ion
of
Retin
oblastoma
susceptib
ility
protein
mole
cular
on/
off
switc
hfo
rcell
cycle
.
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ormal cell cycleHypophosphory
latedRB-bindstoE2F
&asubuni
DP1
E2Ffamilyoftranscrip
tionfactors
Complexbinds-promoter
sofE2Fresponsivegen
Thesegenesaresilent
recruithistone
deacetylase
Compactionofchromatin
&inhibitionof
transcription
DNA
repli
catio
n&synthesis
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ormal cell cycle
Transition is initiated by E2F mediated transcripComplex cyclin A-CDK2Regulates events at mitotic prophase
G 2 -M
Beyond prophase cyclin B CDK1 is responsibleCauses breakdown of nuclear envelope & initiates mitosis
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ell cycle inhibitors
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ell cycle check points
cle checkpoint components is a major cause of genetic instabili
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l alterations for malignant transforSelf sufficiency in growth signals
Insensitivity to growth inhibitory signalsEvasion of apoptosis
Defects in DNA repair
Limitless replication
Sustained angiogenesis
Invasion & metastasi
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hal genetic damagenalexpansion of genetically damaged cellFour classes of normal regulatory genesDNA repair genesCarcinogenesis multistep process at phe
Fundamental principles of carcinogenesisFundamental principles of carcinogenesis
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hromosomal basis of cancerhromosomal basis of cancer
.e.e
well as structural chromosomal changes were revealed in humwell as structural chromosomal changes were revealed in hum
neoplasm was suggested when specific chromosomal aberrationeoplasm was suggested when specific chromosomal aberration
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enetic basis of cancer
e clear ine clear in 1980s980s hrough the discovery thathrough the discovery that foreigoreig:man gene classes :man gene classes - & -roto oncogenes tumor suppres& -roto oncogenes tumor suppres
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enetic basis of cancer
.ring systems.ring systems:rous behaviour either by :rous behaviour either by ) ectopic expression oectopic expression o
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rotein basis of cancer
-or proteins through processes transcription &-ption factors wo types .
he first category - eneral transcriptionactors -hat form part of a multi protein( . .omplex i e the RNA polymerase II initiation
).omplexhis complex recognizes specific DNA sequences
mmediately adjacent to a transcriptional start.ite
-inding of this multi protein complex usuallyesults in the ctive transcription f the
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rs & ,ecognize bind specific DNA motifs present inmains , he RNA polymerase II activity by direct or
rotein basis of cancer
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l alterations for malignant transfor
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ncogenes
- ir role in growth factor mediated signal transduction casca-ir role in growth factor mediated signal transduction casca
such assuch as rasrasbased on the virus or tumor in which they werebased on the virus or tumor in which they were
Sequential steps showing normal cell proliferationSequential steps showing normal cell proliferation
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O nco ge nes
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Oncogenes
-
cells acquire ability to synthesize growthfactors to which they are
&
salso express receptors for same growth factor hence responsive to a
,
.
on of growth factor genes large amounts of growth factors are secreted
2 mechanism
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Oncogenes
Normal receptor Amplified receptorMutated receptor
: .Normal Rs show activity when GF is bound: .Rs with permanent GF activity: Normal Rs but in excess leading to
.mplified RS
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Oncogenes
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l alterations for malignant transfor
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umor suppressor genes
re a distinct class of genes which promote neoplases to cell proliferation are the products of tumor
,ion of these genes is to regulate cell growth not
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.is etc, ,signal transduction molecules cell surface re
umor suppressor genesubcellularLocation Gene Function Tumorsell surface -GF b receptor rowth inhibition arcinomas colon-cadherin ell adhesion arcinoma stomachnner aspectf plasmamembrane
-F 1 nhibition of RAS signal, -ransduction p21 cellycle inhibitorNeuroblastomas
Cytoskeleton -F 2 ytoskeletal stability chwannomasmeningiomasCytosol / -PC b catenin nhibition of signalransduction ,arcinoma stomachcolon
PTEN -I 3 kinase signalransduction ndometrial androstate cancersNucleus RB egulation of cell cycle ;etinoblastomaosteosarcoma
p53 -ell cycle,rrest apoptosis inesponse to DNA damage
ost human cancers( )16 INK4a egulation of cell cycley inhibition of cyclinependent Kinases
,ancreaticsophageal cancers- , -RCA 1 BRCA 2 NA repair Unknown
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ole of RB as a cell cycle regulator
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:53 guardian of the genome
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n oral cancer
/etected in 1 3rd & %f tobacco related ca 4 in,GF receptors is increased increased expression o, - , - , - , - , - - %nt 2 K ras N ras c myc N myc 40 of oral cance
.ations oral ca specially in smokers
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l alterations for malignant transfor
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vading apoptosis
ated process that eliminates senescent or alteredp53
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NA repair defects
ut their abnormalities allow mutations in other g.tide excision repair and recombination repair
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NA repair defects
,s a defect the other strand can be used as a temp
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NA repair defects
. :ts Three mechanisms exist to repair DSBs -on hom
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l alterations for malignant transfor
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mitless replicativepotential Telomerase
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mitless replicativepotential Telomerase
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evelopment of sustained angiogenesis
olypeptide growth factorsnsulin like growth,actor PDGF
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evelopment of sustained angiogenesis
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nvasion and metastasis
.iologic hallmarks of malignant tumors models were given
D
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:tastatic cascade is divided into 2 phases )invasion of extracellular matrix ) &Vascular dissemination homing of tumor cells
nvasion and metastasis
etastatic cascade
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nvasionM is an active process that can be resolved into
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lecular genetics of metastasis development
genes hat elicit metastasis as their rincipal o
NM 23-
KAI1
Ki SS
tromal microenvironm
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Acquired (environmental) Normal cell
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o concludeq ( )DNA damaging agents:ChemicalsRadiationviruses DNA Damage
Mutations in the genomeof somatic cells
Activation of growth-promoting oncogenes
Alterations of genesthat regulate apoptosis
Inactivation of cancersuppressor genes
Expression of altered gene products and
loss of regulatory gene products
Malignant neoplasm
Successful DNA repair
Failure of DNA repairInherited mutations in:Genes affecting DNArepair
Clonal expansion
Additionalmutations
(progression)
Heterogeneity
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Theories Process of carcinogenesis Factors influencing cancer development
Cellular defense mechanism Recent advances
Carcinogens
Part IIPart IINext weekNext week
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