49462942 Molecular Oncogenes Is (1)

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Molecular Perspectives In

Carcinogenesis


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INTRODUCTION

CANCER

Cancer is an overgrowth of cells bearing

cumulative genetic injuries that confergrowthadvantage over the normal cells [Nowells

Law]

Cancer cells can be characterized as

antisocial, fairly autonomous units thatappear to be indifferent to the constraints

and regulatory signals imposed on

normal cells [Robbins]


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CANCER CELLS AND NORMALCELLS

CANCER CELLS AND NORMALCELLS

CANCERCELLSCANCERCELLS NO RMAL CELLSNORMAL CELLS

Loss of contact inhibitionLoss of contact inhibition

Increase in growth factor secretionIncrease in growth factor secretion

Increase inIncrease in oncogeneoncogene expressionexpression

Loss of tumor suppressor genesLoss of tumor suppressor genes

OncogeneOncogene expression is rareexpression is rare

Intermittent or coIntermittent or co--ordinatedordinated

growth factor secretiongrowth factor secretion

Presence of tumor suppressorPresence of tumor suppressor

genesgenes

NormalNormal

cellcell

FewFew

mitosesmitoses

FrequentFrequent

mitosesmitoses

NucleusNucleus

Blood vesselBlood vessel

AbnormalAbnormal

heterogeneous cellsheterogeneous cells


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CHARACTERISTICS OF

CANCER Clonality

Autonomy

Anaplasia

Metastasis


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CHARACTERISTICS OF CANCER

ClonalityClonality

Cancer is a genetic disease at the cellular level. Genetic mutations play a critical role in

pathogenesis of cancer.

Consequences of genetic instability: Phenotypic heterogeneity Tumor progression

Proto-oncogenes and oncogenes

Dominant mutations = mutation resulting fromconversion of protooncogenes to oncogenes

Recessive mutations = mutation resulting fromdamage or loss of tumor suppressor gene.


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Cancer Genetics

Tumors arise as clones from a singlecell. At the cellular level, cancer is a

genetic disease. The development of the malignant clone

is due to mutations in DNA due to:

Random replication errors Exposure to carcinogens

Faulty DNA repair process


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Evidence that Mutations Cause

Cancer Recurring sites of chromosome change are

observed in cancers at sites of genesinvolved in cellular growth control.

Most carcinogens are mutagens.

Defects in DNA repair systems increasethe possibility of cancer.


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Cancer cells are able to proliferate despiteregulatory influences.

Unrestricted proliferation results in tumorformation.

Mechanisms: Growth factor secretion

Increased number of cell receptors

Independent activation of key biochemicalprocess

Proliferation depends on the cell cycle.

CHARACTERISTICS OF CANCER

Autonomy


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AUTONOMY

Brought about by mutations in the cellsgenetic apparatus

Most common in tissues with rapidturnover, especially:- those exposed to environmental agents

- those whose proliferation is hormone-

dependent Proliferation is dependent on the cell

regeneration cycle


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DEATH

DIFFERENTIATION

DNADNA content = 2n= 2n

MitosisMitosis

MM

SSDNA synthesisDNA synthesis

GG22 GG11

G0


The Cell Cycle

G1/S checkpoint

G2/M checkpoint


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CYCLIN, CDK,CDKI:

PHOSPHORYLATION


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Cell Cycle Regulation Process assures that cell accurately

duplicates its contents.

Important checkpoints are present atG1 and G2 and are regulated byprotein kinases called cyclins (cdk).

Checkpoints determine whether thecell proceeds to next phase of thecycle.


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G2/M Checkpoint Regulated by the cyclin B/cdc2

(mitosis promoting factor or MPF).

Activity of this cyclin with itssubstrate results in: Chromosome condensation

Nuclear membrane breakdown Spindle formation


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G1/S Checkpoint Area most often disrupted in cancer.

Mechanism of regulation is complexand involves the phosphorylation ofthe Rb gene. This results in: Activation of several genes needed for S

phase progression. Promotes differentiation through

association with transcription factors.


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Rb Gene Activation


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Cyclin Regulators Regulated by cdk inhibitors (cdki).

May be induced by growth inhibitorsand inhibited by positive growthfactors.

Genetic alterations in cdki occur with

high frequency in some cancers.


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Cyclin Regulators p 21: inhibits cell cycle progression and

permits DNA repair to take place.

P53: the guardian of the genome In the presence of DNA damage, influences

transcription to either: Halt cell cycle progression to facilitate DNA repair.

In cases of severe DNA damage, activates apoptosis. Mutations in p53 are the most common genetic

alterations found in human cancer.


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CHARACTERISTICS OF

CANCER: Anaplasia Loss of differentiated function

resulting to bizarre-looking cells

Large nuclei, prominent nucleoli,increased chromatin

Increased and/or abnormal mitosis

Aneuploidy Partial or complete loss of normal

architecture


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Invasion and Metastasis The defining characteristic of a

malignancy.

Invasion: active translocation ofneoplastic cells across tissuebarriers.

Critical pathologic point: local invasionand neovascularization. These eventsmay occur before clinical detection.


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ATTRIBUTES OF CANCER

Metastasis

Two basic steps:

Destruction of the BM

Attachment to the laminin of distant BM

Genes up-regulated among good metastasizers:

EDGF receptor

BasicF

ibroblastG

rowthF

actorType IV Collagenase

I-Cathepsin (under-expressed)

Cathepsin B (a lamininase)

Heparanase


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Angiogenesis Process of new blood vessel formation.

Clinical importance:

Tumor vessel number correlates positively withrisk and degree of dissemination.

Several cytokines that stimulate endothelialcell proliferation also stimulate proliferation of

malignant cells.


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INVASION AND METASTASISINVASION AND METASTASIS


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Triad of Invasion Adhesion with the basementmembrane

Local proteolysis

Mobility and ability to translocatethrough dents in bodys structuralbarriers


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MOLECULARCARCINOGENESIS

Mutation

the molecular hallmark of most forms of cancer

Gene Families in CancerDevelopment

1 - Oncogenes

2 - TumorSuppressor genes

3 - Mutator genes


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Cancer Genes Proto-oncogenes normally promote normal

cell growth; mutations convert them to

oncogenes. Tumor suppressor genes normally restrain

cell growth; loss of function results inunregulated growth.

Mutator or DNA repair genes whenfaulty, result in an accumulated rate ofmutations.


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ONCOGENE FAMILY

+ oncogenes

Oncogenes

promote cell proliferation

dominant & highly conserved

types: viral oncogenes [v-oncs]

cellular oncogenes [c-oncs]

Proto-oncogene Mutation Oncogene


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ONCOGENE FAMILY

Classification ofOncogenes

A. Secreted Growth Factors

B. Cell Surface Receptors

C. IntracellularTransducers

D. DNA-binding Nuclear Proteins

E. Regulators of the Cell Cycle

Components of

signal transduction

pathways

c-sis, hst

erb B, fms, ret, trk, fes, fms

c-src, c-abl, mst, ras

myc, jun, fos

bcl, bax, bad


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SIGNAL TRANSDUCTION


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ONCOGENE FAMILY

Mechanisms ofOncogene Activation

1. Point Mutation

H-ras [codon 12]

Normal CGC p Gly

Bladder ca CTC p Val

H-ras

GTP

Perpetual cell division

2. Gene Amplification

Double minutes

HSRs

Homogenously

Staining regions Normal copy Multiple copies


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ONCOGENE FAMILY


3. Gene Translocation

Ex. Burkitts Lymphoma


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ONCOGENE FAMILY


3. Gene Translocation

Ex. Chronic Myelogenous Leukemia [CML]


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ONCOGENE FAMILY


4. Viral Gene Integration

promoter

Viral promoter


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TUMOR SUPPRESSORGENE FAMILY

TS Genes

inhibit growth and multiplication of mutated cells

prevent neoplastic transformation

recessive & highly conserved

Classification ofTS genes

A. Cell Adhesion Molecules

B. Regulators of the Cell Cycle

APC, DCC

RB1, Tp53


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KNUDSONS Two-Hit Hypothesis

1st Hit: TS mutation or Inherited mutation

2nd Hit: gross chromosomal loss


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Retinoblastoma gene [RB1 gene]

rare form of childhood malignancy

forms: hereditary & sporadic

pRb

105-KDa nuclear protein

inhibits E2F [prevents G1 p S transition]

inhibited by: phosphorylation

viral oncoproteins [E1A, HPV E7]


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Tp53 gene

location:17p13.1

product: p53 protein [53 KDa] function: induces DNA repair or apoptosis

mutation: point mutation > deletion

results to: loss of function & extended lifespan of p53

Clinical conditions: carcinomas, Li Fraumeni

Syndrome

p53 inhibited by:E1B, HPV E6, mdm2


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p53 protein


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p53 in action


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MUTATORGENE FAMILY

Mutator Genes

involved in ensuring the fidelity of replication

function: checks for & corrects mismatched pairs

mutation inefficient repair & replication leading

increased propensity of oncogenes and tumor

suppressor genes to undergo mutation

first described in Ecoli[Mut-HSL system]

Fischel, et al = Human homologs

leads to the formation ofMicrosatellite Instability

[MIN+]


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In summary ..

ONCOGENES TS GENES

MUTATORGENES


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Re-cap of Molecular Carcinogenesis

Proto-oncogene Gain-of-function

TS gene Loss-of-function

Mutator gene Loss-of-function

CANCER


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CARCINOGENS

Occupation related causes Lifestyle related causes

Tobacco

Diet Sexual practices

Multifactorial causes Viral carcinogens

Chemical carcinogens Ionizing radiation


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Sources of Free

Radicals

Smoking10 Quad Trillion free radicals per

cigarette!

y X-rays

y Stress

y Toxins

y Sunlight

y Solvents

y Pollution

y Cigarette

y Pesticides

y Herbicides

y Medications

y Airline travel

y Radioactivity

y Food additives

y Polluted Foods

y High heat cooking

y Synthetic materials

y Household cleaners

y EnvironmentalChemicals

MENUMENULots more

R.I.P

They only said itwas dangerous.

They didnt say

it could be

lethal.


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Occupational Risk FactorsEtiologyArsenic

AsbestosBenzene

Benzedine

Chromium cpds

Radiation (mining)

Mustard gasPolycyclic hydrocarbons

Vinyl Chloride

Site of MalignancyLung, skin, liver

Mesothelium, lungLeukemia

Bladder

Lung

Numerous locations

LungLung, skin

Angiosarcoma of liver


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Lifestyle Risk FactorsTobacco-related:

Lung cancer

Pancreatic cancer

Bladder cancer

Renal cancer Cervical cancer


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Diet-Related Risk FactorsNitrates

Salt

Low vitamins A, C, ELow consumption of

yellow-greenvegetables

Gastric CancerEsophageal

Cancer


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Diet-Related Risk FactorsHigh fatLow fiber

Low calciumHigh fried

foods

Colon Cancer

Pancreatic Cancer

Prostate CancerBreast Cancer

Uterine Cancer

Mycotoxins Liver Cancer


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Sexual Practices Risk Factors

Cervical Cancer

Sexual promiscuity

Multiple partnersUnsafe Sex

Human Papillomavirus


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Multifactorial FactorsTobacco + Alcohol Oral Cavity Cancer

Esophageal Cancer

Tobacco + Asbestos

Tobacco + miningTobacco + uranium +

radium

RespiratoryTract Cancer

Lung Cancer


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CARCINOGEN METABOLISM

Three Main Categories:

I. Chemical Carcinogens

II. Physical Carcinogens

III. Viral Agents

Carcinogens Mutations Cancer

Environmental

factors

?


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CHEMICAL CARCINOGENESIS

Stages:

Initiation - primary exposure

Promotion - transformation

Progression - Cancer growth

Frank Cancer


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Initiation

normal cells are exposed to a carcinogen

not enough to cause malignant transformation

requires one round of cell division

normal cells are exposed to a carcinogen

1. Direct-acting carcinogens

2. Indirect

-acting carcinogens

procarcinogenCytochrome

P450

Ultimate

carcinogen


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Promotion

initiated cells are exposed to promoters

promoters are not carcinogens !

properties of promoters reversible

dose-dependent

time-dependent

Types ofCarcinogens ...

1. Direct carcinogens

2. Procarcinogens Ultimate carcinogens


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Direct-acting

Carcinogens

~ cyclophosphamide

~ chlorambucil

~ busulfan

~ melphalan

Procarcinogens

PAHs

Aromatic amines & Azo dyes

Aflatoxin B1

Nitrosamine & Amides

Asbestos

Vinyl chloride

Chromium, nickel, other metals

Arsenic

Promoters saccharine & cyclamates

Estrogen

Diesthystilbestrol [DES]


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Physical Carcinogenesis Radiation-induced mutation in the

host cell

Transmits irreversible changes ingene expression to cell progeny


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Sources of Potentially

Carcinogenic Radiation Sunlight

Artificial sources of UV light

X-rays

Radio-chemicals

Nuclear fission


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PHYSICAL CARCINOGENESIS

Ultraviolet Rays

UV-A = 320- 400 nm

UV-B = 280- 320 nm

UV-C = 200- 280 nm


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Ultraviolet Rays

UV-C filtered by ozone

UV-B

Inhibition of cell division

inactivation of enzymes

induction of mutations

cell death at high doses

Squamous cell cancer

Basal cell cancer

Melanocarcinoma


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Ionizing Radiation

includes electromagnetic rays & particulate matter

mechanism:o free radicals & mutations

pathology: leukemias > thyroid ca > lung & breast ca

resistant tissues: bone, skin and the GIT

PRE-IRRADIATION POST-IRRADIATION


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Viral Carcinogenesis

Viral carcinogens are classified intoViral carcinogens are classified intoRNA and DNA viruses.RNA and DNA viruses.

Most RNAMost RNA oncogeniconcogenic viruses belong toviruses belong tothe family of retroviruses thatthe family of retroviruses thatcontaincontain reverse transcriptase

mediates transfer of viral RNA intomediates transfer of viral RNA intovirus specific DNA.virus specific DNA.


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RETROVIRUSRETROVIRUS

OncogeneOncogene Viral RNAViral RNA

Viral DNAViral DNA

NUCLEUSNUCLEUS

DNADNA

OncogeneOncogene

REVERSETRANSCRIPTASEREVERSETRANSCRIPTASE

INSERTIONINSERTION

TRANSCRIPTIONTRANSCRIPTION

OncogeneOncogeneViral RNAViral RNA

CELLCELLMEMBRANEMEMBRANE CYTOPLASMCYTOPLASM

Viral genomeViral genome

RNA messengerRNA messenger TRANSCRIPTIONTRANSCRIPTION

OncogeneOncogeneproteinprotein

Viral Oncogenes


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Viruses Associated With TheDevelopment Of Human Neoplasia

VIRUSES NEOPLASMSDNA VIRUSES

Human papilloma virus Cervical Ca, warts, ano-

genital carcinomaHerpes simplex virus II Cervical carcinomaEpstein-Barr virus NPCa, African BurkittsHerpes simplex virus 8 Kaposis sarcomaHepatitis B virus Hepatocellular CaHerpes simplex virus 6 Certain B cell

(HBLV) lymphomas


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VIRUSES NEOPLASMS

RNA VIRUSES

Human THuman T--cell leukemia virus I Some Tcell leukemia virus I Some T--cell leukemia,cell leukemia,lymphomalymphoma

Human THuman T--cell leukemia virus II Some cases of hairycell leukemia virus II Some cases of hairycell leukemiacell leukemia

Human immunodeficiency virus I Lymphoma; KaposisHuman immunodeficiency virus I Lymphoma; Kaposis

sarcomasarcoma

Viruses Associated With TheDevelopment Of Human Neoplasia


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VIRAL AGENTS: DNA viruses

Human Papillomavirus [HPV types 16, 18, 31, 33 & 35]

Interruption of the E1/E2ORF

E2 is not expressed

Over

-expression of

E6&

E7


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VIRAL AGENTS: DNA viruses

Epstein-Barr Virus [EBV]

in Burkitts, B-cell & Hodgkins lymphomas +NP ca

tropism: CD21+ cells [e.g., B cells, epithelial cells]

mechanism: viral entry episomal existence latency

(+) LMP-1, EBNA-1, EBNA-2 immortalization

Hepatitis B virus [HBV]

induction of chronic hepatocyte injury (+) HBx

HBx activates protein kinase c for transformation


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VIRAL AGENTS: RNA viruses

Human T-cell Leukemia Virus [HTLV]

a retrovirus

tropism: CD4+ cells

mechanism: Tax protein

o transcription o c-fos, c-sis, IL-1 and IL-2

Viral replication T cell proliferation


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Principal Pathways of

Malignancy

1. Proliferation

2. Cell-Cycle Progression

3. DNA Repair

4. Immortalization

5. Apoptosis6. Angiogenesis

7. Metastasis and Invasion


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SIGNAL TRANSDUCTION


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PROLIFERATION

(Growth Factor Signaling Pathway)

Uncontrolled and uncoordinatedproliferation

Uncontrolled growth stimulated by:1. Increased secretion of Growth Factors

(PDGF,EGF,FGF,VEGF,NGF)

2. Increased Growth Factor receptors

3. Independent activation of certain enzymeand protein production pathways


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PROLIFERATION

(Growth Factor Signaling Pathway) Receptor Tyrosine kinase Pathway

(RTK)-Main pathway

RTK ligands: NGF PDGF FGF EGF Functions of RTK:1. promotion of cell survival

2. regulation of cell proliferation anddifferentiation3. modulation of cellular metabolism


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PROLIFERATION

(Growth Factor Signaling Pathway)RTK SIGNALINGPATHWAYS

Ras-MAP Kinase Pathway- most

prominent PI3 kinase Pathway

Phospholipase C Pathway


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PROLIFERATION


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PROLIFERATION

(Growth Factor Signaling Pathway)Therapeutic implicationsBlocking of GF mitogenic signaling is achieved

by: Preventing binding of GF to receptor orreceptor dimerization with specific agent

Preventing receptor activation with small

molecule inhibitors Blocking cytoplasmic proteins downstream

of the activated receptor pathway


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DEATH

DIFFERENTIATION


MitosisMitosis

MM

SSDNA synthesisDNA synthesis

GG22 GG11

G0


The Cell Cycle

G1/S checkpoint

G2/M checkpoint


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Cell Cycle Regulation

Process assures that cell accuratelyduplicates its contents.

Important checkpoints are present at G1and G2 and are regulated by proteinsCyclins and Cyclin-dependent Kinases(CDKs).

Checkpoints determine whether the cellproceeds to next phase of the cycle.


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Cyclins and Cyclin-dependent

Kinases (CDKs) CYCLINS activate protein kinases CDKs protein enzymes which

selectively phosphorylate specificserine/threonine residues in theirsubstrates

Dimeric complex withcatalytic subunit (CDK 1-9)regulatory subunit (Cyclin A-H,T)


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G2/M Checkpoint

Regulated by the cyclin B/cdc2 (mitosis promotingfactor or MPF).

Regulated mainly by intracellular signal

(Completion of DNA Synthesis) MPF is activated by dephosphorylation by cdc25 Cyclin B is degraded by Anaphase Promoting

Complex (APC)

Role of G2/M checkpoint: to prevent mitosis whenDNA is damaged and not yet repaired


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CYCLIN, CDK,CDKI:

PHOSPHORYLATION


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G1/S Checkpoint

Area most often disrupted in cancer. Mechanism of regulation is complex and

involves the phosphorylation of the Rbgene. Regulated by extracellular signals (e.g. GF) R point (restriction)- point late in G1

beyond which cell cycle progressionbecomes independent from external GF Regulated mainly by CDK4/cyclin D


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Rb Gene Activation


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Cyclin Regulators- CDK

Inhibitors CDK inhibitors inhibit the activity of CDK-cyclin

complex Two Groups:

1) INK4 family p15 16 18 192) CIP-KIP family p21 p27Actions:P15- change response to anti-mitogenic agentsP16- inhibits CDK4/cyclin D

P19- induces p53 stabilizationP21-induces cell cycle arrest via activation by p53P27- inhibits CDK2/cyclin E


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Cyclin Regulators

p 21: activated by p53 inhibiting cell cycleprogression and permitting DNA repair to

take place. P53: the guardian of the genome In the presence of DNA damage, influences

transcription to either:

Halt cell cycle progression to facilitate DNA repair. In cases of severe DNA damage, activates apoptosis.

Mutations in p53 are the most common geneticalterations found in human cancer.


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p53 in action


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CELL-CYCLE PROGRESSION


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Clinical Significance

Oncogenic alterations in cell cycle regulators: Loss of p53 and pRB function as tumor

suppressors

Increased expression of Cyclin D1(Mantle CellLymphoma) CDK4 amplification in sarcomas, glioma Mutations in p16-binding domain of CDK4(Familial

Melanoma)

Inactivation of INK4 Alterations in Cyclin D1,p16 Decreased levels of p27 (Breast Ca) Over expression of cdc25


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Therapeutic Implications

Approaches using Inhibitors of CDKsas therapeutic agents

Small molecules Protein therapy Antisense

Gene therapyMost cytotoxic agents block the cellcycle in the S/G2/M phases


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DNAREPAIRPATHWAYS

Cancer as Malady of Genes

Defects in the maintenance of genome

stability Repair Mechanisms:

1. Mismatch excision repair

2. Base excision repair

3. Nucleotide excision repair

4. Double strand base repair


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DNAREPAIRPATHWAYS


HNPCC mutations in genes involved in DNA

repair pathways (MSH1 MSH2) Somatic defects in repeated DNA

elements leading to Microsatelliteinstability (MSI)

Inactivation of TGF- (tumor suppressor) Inactivation of BAX gene


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IMMORTALIZATION


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Telomeres and Telomerase

Telomeres- specialized structures atchromosome ends generated andmaintained by telomerase

Telomerase- ribonucleoprotein enzyme whichpreserves the integrity of telomeres* key component in immortalization ofcancer cells

Telomere length- represents a molecularclock that determines the life span of thecell


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Telomeres and Telomerase

Clinical Significance Most normal adult tissues have NO telomerase

activity

Telomerase activity is present in 90% of tumorsTherapeutic ImplicationhTERT- protein identified to be catalytic subunit of

telomerase

limiting component of telomerase activity can be a target for small molecule inhibitor


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APOPTOSIS

APOPTOSIS programmed cell death Important in:

1. Steady-state kinetics of normal tissues2. Focal deletion of cells during normalembryonic development

3. Seen after chemotherapy and radiation

* Balance between proliferation andapoptosis is critical in determining growthor regression


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Components of Apoptotic

Pathway1) CASPASES (Cysteine-containing aspartate-

specific proteases) Initiator Caspases activated in response to cell

death signal Executioner or Effector Caspases- progress the

death signal activating cascade resulting to DNAfragmentation and cell death

Caspase prodomains DED CARDDeath ligands TNF- , Fas , TRAILSurvival Signals NF


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Components of Apoptotic

Pathway2) CYTOCHROME C component of mitochondria

released in response to apoptotic signals3) BCL-2 Family of Proteins- located upstream in the

pathway Provides pivotal decisional checkpoint in the fate

of the cell after a death stimulus Contains BH1-BH4 domains necessary for

interaction Anti-apoptotic BCL-2 BCL-xL Pro-apoptotic BAX BAD BAK BID


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APOPTOTIC PATHWAYS

1) FAS-mediated apoptosis FAS cell surface receptor of TNF family

which binds to FAS-L

Eliminates unwanted activated T cells Pathway for cytotoxic-mediated signaling2) P53-mediated apoptosis important after chemotherapy and radiation

Induction of BAX and downregulation of BCL-2 Induced expression of FAS and DR5


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Over expression of BCL-2 as a prognosticindicator

Mutations of BAX in GI Ca and leukemias P53 provides a link between cell

proliferation and apoptosis

Cell survival signals: NF BCL-2

P53 mutations confer chemoresistance


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EVADING APOPTOSIS


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Antisense oligonucleotide againstBCL-2 in the treatment of lymphoma

BCL-2 antisense as chemosensitizingagent in solid tumors

TRAIL ( TNF-related apoptosis

inducing ligand) to induce apoptosis


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ANGIOGENESIS

Formation of new blood vessels fromexisting vascular bed

Carried out by endothelial cells (EC) andextra cellular matrix (ECM)

Regulated by angiogenic factors (inducersand inhibitors)

* A tumor is unable to grow larger than 1mm3 w/o developing a new blood supply


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Components of Angiogenesis

1) ENDOTHELIAL CELLS Fenestrated

Increased cell adhesion molecules (E-selectin)

Increased integrins 3 essentialfor viability during growth

Activated ECs release: bFGF PDGFIGF-1


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2) INDUCERS OF ANGIOGENESIS VEGF main inducer

TGF- TNF- low concentration - inducerhigh concentration -

inhibitor

PDGF/thymidine phosphorylase TGF- EGF

IL-8


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3) CELL ADHESION MOLECULES (CAM) Mediate cell-cell adhesion processes Selectins

IG Supergene family- ICAM VCAM Cadherins Integrins- vitronectin receptor4) PROTEASES

Degrade ECM to provide suitableenvironment for EC migration thru adjacentstroma Ex: Metalloproteinases (MMP)


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Components of Angiogenesis5) ANGIOGENESIS INHIBITORS Interferon TSP-1

Angiostatin Endostatin VasostatinCLINI

CAL SIGNIFI

CAN

CE:Tumor angiogenesis switch is triggered as

a result of shift in the balance ofstimulators to inhibitors


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ANGIOGENESIS

Th ti I li ti s


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Metalloproteinase inhibitors (MMPI) block the degradation of basementmembrane

Inhibitors of endothelial function-thalidomide, TNP 470,endostatin Anti-angiogenic factors tyrosine

kinase inhibitors of VEGF bFGF PDGF Interferon angiogenic inhibitor COX-2 inhibitor thromboxane A2 as

critical intermediary of angiogenesis



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In si n nd M t st sis


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Invasion and Metastasis

The defining characteristic of amalignancy.

Invasion: active translocation ofneoplastic cells across tissuebarriers.

Critical pathologic point: local invasion

and neovascularization. These eventsmay occur before clinical detection.

PROCESS OF METASTASIS


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PROCESS OF METASTASIS


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Triad of Invasion

Adhesion with the basementmembrane.

Local proteolysis Mobility and ability to translocate

through rents in bodys structural

barriers.

ADHESION


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ADHESION

De-regulated function of CAM (E-cadherin) Changes in catenin expression leads to loss

of cadherin function Integrin over expression in naturally

occurring cancers Downregulation of integrin in more advanced

stages of cancer Upregulation of ICAM-1 which enhances

extravasation Adhesion molecules on EC: E-selectin,VCAM

ICAM

LOCAL PROTEOLYSIS


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LOCAL PROTEOLYSIS

Degradation of basement membraneto traverse barriers Carried out by:1. Serine proteases -uPA elastase

plasmin cathepsin G2. Cysteine proteases- cathepsin B L3. Aspartate proteases cathepsin D

4. Matrix metalloproteinases-gelatinases interstitial collagenasesstromelysins matrilysins

MOTILITY


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MOTILITY

Tumor cells can move randomly ordirectionally toward attractants

Modulators of motility

GF, hyaluronases, components of ECM,tumor-secreted factors, host-derivedfactors

THERAPEUTIC IMPLICATIONS:

MMPI and monoclonal antibodiesagainst integrin

METASTASIS AND INVASION


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METASTASIS AND INVASION

Whi h f th f ll i i TRUE


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Which of the following isTRUE

of carcinogenesis?A. Carcinogenesis occurs as a result of

genetic mutation secondary to physical and

chemical agents onlyB. The ultimate carcinogens are usually

electrophiles which can readily attack NA

C. The most common base involved inmutagenesis is adenine

D. Tumorsuppressor gene is transformed to

oncogene

Whi h f th f ll i i TRUE


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Which of the following isTRUE

of carcinogenesis?A. Carcinogenesis occurs as a result of

genetic mutation secondary to physical and

chemical agents onlyB. The ultimate carcinogens are usually

electrophiles which can readily attack

NAC. The most common base involved in

mutagenesis is adenine

D.T

umorsuppr

essor g

ene

is

transform

ed to

Tumor p53 suppressor protein is


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reffered to as guardian of the

genome bec. it:A. Enhances thesurvival of tissues

B. Allows apoptosis to occur on seriously

damaged cells

C. Plays a key role in G2 checkpoint control

D. Arrests the cell cycle at Go phase

Tumor p53 suppressor protein is

ff d di f h


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reffered to as guardian of the

genome bec. it:A. Enhances thesurvival of tissues

B. Allows apoptosis to occur on seriously

damaged cells

C. Plays a key role in G2 checkpoint control

D. Arrests the cell cycle at Go phase

TRUE statements about


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oncogenes, EXCEPT:A. They positively affect cell proliferation

B. Single mutant allele isenough to cause

phenotypicC. They are mutant protooncegenes

D. Mutation involves a loss in function



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oncogenes, EXCEPT:A. They positively affect cell proliferation

B. Single mutant allele isenough to cause

phenotypicC. They are mutant protooncegenes

D. Mutation involves a loss in function

This is not a characteristics of


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cancerA. Loss of contact inhibition

B. Uncontrolled proliferation

C. Gain in function of mutator gene

D. Loss of differentiated function



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cancerA. Loss of contact inhibition

B. Uncontrolled proliferation

C. Gain in function of mutator gene

D. Loss of differentiated function

TRUE statements about RAS


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oncogene activation except:A. It involves a point mutation in codon 12

B. The mutated RAS results to increased

GTPase activityC. The mutated gene codes for valine instead

of glycine

D. It is over-expressed in bladder cancer



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oncogene activation except:A. It involves a point mutation in codon 12

B. The mutated RAS results to increased

GTPase activityC. The mutated gene codes for valine instead

of glycine

D. It is over-expressed in bladder cancer

A biochemical change found in


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fast growing tumor cells:A. Increased catabolism of nucleobases and

nucleotides

B. Inappropriatesynthesis of certain growthfactors and hormones

C. An adult pattern of isozymes

D. Markedly decreased glycolysis



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fast growing tumor cells:A. Increased catabolism of nucleobases and

nucleotides

B. Inappropriate synthesis of certaingrowth factors and hormones

C. An adult pattern of isozymes

D. Markedly decreased glycolysis


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