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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
DNADNA content = 4n= 4n
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
Mechanisms ofOncogene Activation
3. Gene Translocation
Ex. Burkitts Lymphoma
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ONCOGENE FAMILY
Mechanisms ofOncogene Activation
3. Gene Translocation
Ex. Chronic Myelogenous Leukemia [CML]
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ONCOGENE FAMILY
Mechanisms ofOncogene Activation
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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TUMOR SUPPRESSORGENE FAMILY
KNUDSONS Two-Hit Hypothesis
1st Hit: TS mutation or Inherited mutation
2nd Hit: gross chromosomal loss
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TUMOR SUPPRESSORGENE FAMILY
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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TUMOR SUPPRESSORGENE FAMILY
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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TUMOR SUPPRESSORGENE FAMILY
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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CHEMICAL CARCINOGENESIS
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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CHEMICAL CARCINOGENESIS
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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CHEMICAL CARCINOGENESIS
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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PHYSICAL CARCINOGENESIS
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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PHYSICAL CARCINOGENESIS
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
DNADNA content = 2n= 2n
MitosisMitosis
MM
SSDNA synthesisDNA synthesis
GG22 GG11
G0
DNADNA content = 4n= 4n
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
Clinical Significance
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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Clinical Significance
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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Therapeutic Implications
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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Components of Angiogenesis
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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Components of Angiogenesis
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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Therapeutic Implications
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
INVASION AND METASTASISINVASION AND METASTASIS
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INVASION AND METASTASISINVASION AND METASTASIS
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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TRUE statements about
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
TRUE statements about
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TRUE statements about
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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This is not a characteristics of
cancerA. Loss of contact inhibition
B. Uncontrolled proliferation
C. Gain in function of mutator gene
D. Loss of differentiated function
This is not a characteristics of
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This is not a characteristics of
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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TRUE statements about RAS
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
TRUE statements about RAS
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TRUE statements about RAS
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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A biochemical change found in
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
A biochemical change found in
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A biochemical change found in
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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Any Questions ?
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