carcinogenesis 1

8/6/2019 carcinogenesis 1

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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.svg


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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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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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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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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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carcinogenesis 1