n g r ni mo ood

Carcinogenesis
Dr. Megha
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Index
Part I
Part II

roduction minology mal growth

Hallmarks of cancer Theories Chromosomal basis Cellular defense mec Process of carcinogenesis Genetic basis Factors influencing cancer development regulation Recent advances Protein basis
s oncogene Protone essor ge ppr Tumor su
ns Carcinoge

Introduction

among fatal diseases in the indus third fatal disease in India.

ated that in the next quarter of a w cancer cases globally is going t in the developing countries
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Introduction

ction in form of cancer genes . C paratus betraying cell only wh alignant, diseases.
( Nobel Prize Winner , 1989 )

y of uncontrolled cell proliferati

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Historical perspective

Yamagiwa Galeno Percivall pott Hippocrates

Chimney workers

Karkinos Neoplasi a

Rabbit s ear

Time line

Time line

Terminologies
Genotype genetic make-up

or constitution of an individual organism. Phenotype - form and functioning of an individual, to the extent that it may encompass metabolism & behaviour
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Terminologies
Gene ,Exons n introns Allele ,LOH ,SNP

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Terminologies
Mutations -changes in the DNA sequence of a cell's genome & are caused by radiation, viruses & mutagenic chemicals, as well as errors that occur during meiosis or DNA replication

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Terminologies

d with that of normal tissues & pers

ells by causing

permanent genetic al

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Normal cell cycle

Orderly progression of cells through the various phases of cell cycle is mediated by Cyclins synthesized during specific phases of cell cycle , activate CDKs Cyclin dependent kinases drive cell cycle by phosphorylating target proteins , present in inactive form Their inhibitors.

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Normal cell cycle

Cy c l in Df

t ili b ti f p o f ce o f s n io su on/ t la ma lar e. ry to cu cl o s ph bla ole ll cy s ho ino m ce P t e tein for R o h pr itc sw

irst on e app e t abs ars in o incr eas ent m id e in bin in S G1 ds cel pha to l cy se &a cl c ti v ate CD K4

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Normal cell cycle2F & a subunit

N A

re pl ic

at io n

&

sy nt he si s

s to E d RB - bind rylate ypophospho H ors DP1 ription fact ransc ene family of t esponsive g E2F E2F r moters of ds-pro ne omplex bin C cruit histo nt re nes are sile These ge e of deacetylas & inhibition m atin ion of chro Compact n transcriptio

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Normal cell cycle

G2-M

Transition is initiated by E2F mediated transcript Complex cyclin A-CDK2 Regulates events at mitotic prophase

Beyond prophase cyclin B CDK1 is responsible Causes breakdown of nuclear envelope & initiates mitosis
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Cell cycle inhibitors

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Cell cycle check points

ycle checkpoint components is a major cause of genetic instabilit

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ial alterations for malignant transform

Self sufficiency in growth signals Insensitivity to growth inhibitory signals Evasion of apoptosis Defects in DNA repair Limitless replication Sustained angiogenesis

Invasion & metastasis 19

Fundamental principles of carcinogenesis

Carcinogenesis multistep process at phen onalexpansion Four classes ofdamaged cell of genetically normal regulatory genes thal genetic damage DNA repair genes

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Chromosomal basis of cancer

ve. well as structural chromosomal changes were revealed in huma

h neoplasm was suggested when specific chromosomal aberrations aberration

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Genetic basis of cancer

ame clear in 1980s through the discovery that foreign foreig

human gene classes : proto - oncogenes & tumor - suppres

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Genetic basis of cancer

airing systems .

cerous behaviour either by : 1 ) ectopic expression of

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Protein basis of cancer

The first category - general transcription factors that form part of a multi - protein e complex ( i . e . the RNA polymerase - II initiation & t for proteins through processes transcription complex ). iption factors - two types . This complex recognizes specific DNA sequences immediately adjacent to a transcriptional start site . Binding of this multi - protein complex usually results in the active transcription of the24

Protein basis of cancer

ors recognize & bind specific DNA motifs , present in

omains, the RNA polymerase II activity by direct or

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ial alterations for malignant transform

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f sufficiency in growth signals : Oncoge

genes that promote autonomous cell growth in cancer cells es - their normal cellular counterparts. es are physiologic regulators of cell proliferation & differ ability to promote cell growth in the absence of normal mitog

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Sequential steps showing normal cel l proliferation

Oncogenes

eir role in growth factor-mediated signal s such as ras based on the virus or tumor

transduction cascad in which they were

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n ncoge O

es

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Oncogenes

r c ell s sal acq so uir exp e ion res abi of s r lit gro ece y t wth pto o s rs ynt fac for hes tor ize sam gen e g gro es, row wth lar th fac ge 2 m fac tor amo ech tor s t unt ani & o w s o sm hic f g hen h t row ce hey th res fac pon are tor siv s a e t re o a sec u ret ed.

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Oncogenes
A : Normal Rs show activity when GF is bound . B : Rs with permanent GF activity . C : Normal Rs but in excess leading to Amplified RS .

Normal receptor

Mutated

receptor

Amplified

receptor

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Oncogenes

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ial alterations for malignant transform

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Tumor suppressor genes

are a distinct class of genes which promote neoplasi

akes to cell proliferation are the products of tumor

ction of these genes is to regulate cell growth , not

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Subcellular Location Cell surface Inner aspect of plasma membrane Cytoskeleton Cytosol

Gene

Function

Tumors

TGF - b Carcinomas colon Tumorreceptor Growth inhibition genes suppressor E - cadherin Cell adhesion Carcinoma stomach NF - 1 Inhibition of RAS signal Neuroblastomas transduction , p21 cell cycle inhibitor Cytoskeletal stability Inhibition of signal transduction PI - 3 kinase signal transduction Schwannomas meningiomas Carcinoma stomach , colon Endometrial and prostate cancers

NF - 2 APC / b - catenin PTEN RB

osis etc .
Nucleus

rs , signal p53 transduction molecules , cell surface rec Cell - cycle Most human cancers
arrest , apoptosis in response to DNA damage p16 ( INK4a ) Regulation of cell cycle Pancreatic , by inhibition of cyclin esophageal cancers dependent Kinases DNA repair Unknown
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Regulation of cell cycle Retinoblastoma ; osteosarcoma

BRCA - 1 , BRCA - 2

Role of RB as a cell cycle regulator

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p53 : guardian of the genome

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In oral cancer

s detected in 1 / 3 rd of tobacco related ca & 4 % in EGF receptors is increased , increased expression of

1 , int - 2 , K - ras , N - ras , c - myc , N - myc - 40 % of oral cancer utations oral ca specially in smokers .

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ial alterations for malignant transform

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Evading apoptosis

p53

lated process that eliminates senescent or altered c

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DNA repair defects

but their abnormalities allow mutations in other ge

eotide excision repair and recombination repair .

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DNA repair defects

has a defect , the other strand can be used as a temp

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DNA repair defects

ents . Three mechanisms exist to repair DSBs : non - homo

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ial alterations for malignant transform

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Limitless replicativepotential Telomerase

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Limitless replicativepotential Telomerase

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Development of sustained angiogenesis

Polypeptide growth factors Insulin like growth factor , PDGF

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Development of sustained angiogenesis

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Invasion and metastasis

Biologic hallmarks of malignant tumors . 4 models were given D

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Invasion and metastasis

etastatic cascade is divided into 2 phases : 1 ) invasion of extracellular matrix 2 ) Vascular dissemination & homing of tumor cells
Metastatic cascade

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Invasion

ECM is an active process that can be resolved into s

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Molecular genetics of metastasis development

r genes that elicit metastasis as their principal or

23 M KA

-1 I K SS i
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Stromal microenvironme

&

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Acquired (environmental) DNA damaging agents: Chemicals Radiation viruses

Normal cell Successful DNA repair

To conclude
DNA Damage

Failure of DNA repair Inherited mutations in: Genes affecting DNA Mutations in the genome repair of somatic cells Activation of growthpromoting oncogenes Alterations of genes that regulate apoptosis Inactivation of cancer suppressor genes

Expression of altered gene products and loss of regulatory gene products

Clonal expansion Additional mutations (progression)

Malignant neoplasm

Heterogeneity

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Next week
Part II
Theories Process of carcinogenesis Cellular defense mechanism Factors influencing canceradvances Recent development

ns Carcinoge
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