Académique Documents
Professionnel Documents
Culture Documents
Oncogenesis
Felina R. Masadao-Adefuin, MD
CHEMICAL
CHEMICAL
S
S ACCUMULATIO
ACCUMULATIO
1. SELF-SUFFICIENCY
N
N OF
OF GENETIC
GENETIC IN GROWTH SIGNALS
&
& EPIGENETIC
EPIGENETIC
ONCOGENES CHANGES
CHANGES
2. INSENSITIVITY TO
ANTI-GROWTH SIGNALS
INFECTIOU
INFECTIOU INACTIVATED
S
S TUMOUR SUPPRESSOR 3. EVASION OF APOPTOSIS
AGENTS
AGENTS GENES
4. LIMITLESS REPLICATIVE
HEREDITY
HEREDITY POTENTIAL
additional mutations
5. SUSTAINED ANGIOGENESIS
GENETIC
GENETIC 6. TISSUE INVASION
INSTABILIT
INSTABILIT AND METASTASIS
Y
Y
??? INFLAMMATION
7 Hallmark?
th
INITIATION
Initiated cells
CARCINOGEN
PROMOTION
Tumour cells
Inactive metabolite
Clones
X
TUMOURS
X
TUMOUR
S
X
NO TUMOURS
NO TUMOURS
X Initiator
Promoter
Knudsons Two-Hit Hypothesis
2nd
mutation
Uncontrolled proliferation;
Cancer formation
1st
mutation
Controlled growth;
No cancer
Cancer Mutations
Sporadic : majority of cancers; acquired
during ones lifetime; incidence increases
with age; due to environmental causes;
not passed on to offspring
Hereditary : less than 10% of cancers;
germline mutation (present in reproductive
cells) can be passed on to next
generation(s); cancers usually occur at
younger ages
ONCOGENES
Definitions
Proto-oncogenes : genes that
encode proteins that regulate normal
cell proliferation or apoptosis
Abnormal
(hyperactive)
GENE
GENE protein
AMPLIFICATIO
AMPLIFICATIO CHROMOSOMAL
CHROMOSOMAL
POINT
POINT N
N TRANSLOCATION
TRANSLOCATION
MUTATION
MUTATION
DNA
LOCAL
LOCAL DNA
DNA proto-oncogene INSERTIONAL
INSERTIONAL
REARRANGEMENT
REARRANGEMENT MUTAGENESIS
MUTAGENESIS
S
S
Insertion or
Viral DNA
Insertion Deletion Transposition
Excess normal
protein
Abnormal
(hyperactive)
protein
Functions of Cellular Proto-oncogenes
4. Nuclear
Proteins:
Transcription
3. Cytoplasmic Factors
Signal Transduction
Proteins
Cell Growth
Genes
Oncogenes : Growth Factors
sis : PDGF B chain
transduced by retrovirus
autocrine loop in some glioblastomas
int-2 : FGF-related growth factor
activated by integration of retrovirus
Oncogenes : Growth Factor
Receptors
ErbB/B2 : EGF receptor family
truncated erbB is transduced by retrovirus
overexpression is due to increased transcription or gene
amplification (CAs of breast, ovary, stomach)
Src : membrane-associated nonreceptor PTK
transduced by retrovirus
deleted regulatory domain so constitutively active
mas : angiotensin receptor
transduced by retrovirus
RET : involved in thyroid CA
Oncogenes : Signal Transduction
Proteins
abl : nonreceptor PTK; detects DNA
damage
translocation-fusion w/ BCR in CML
ras family : monomeric GTP-binding
proteins
aa substitutions reduce GTPase activity or
increase rate of exchange of GDP for GTP so it
remains active
raf : MAPKKK Ser/Thr kinase
Mutated/rearranged in stomach cancers
Oncogenes : Transcription Factors
9
9
h
h
1
1
0
0
h
h
4
4
h
h
1
1
h
h
Rao & Johnson :
cell fusion experiments
G1-phase cells + S-phase cells = DNA
REPLICATION IN HYBRID CELL
G2-phase cells + S-phase cells = NO DNA
REPLICATION
G1-phase cells + M-phase cells =
PREMATURE CHROMOSOMAL COMPACTION
G2-phase cells + M-phase cells =
PREMATURE CHROMOSOMAL COMPACTION
S-phase cells + M-phase cells =
CHROMATIN COMPACTION
Cell Cycle Regulation : Importance
cdc25
A
Cyclin E1, E2
+
CDK 2
Role of Rb/E2F in cell cycle
M G1
G2 E2F
Rb/p107/
p130
S
SWI/
SNF METHYLASE
S
HDAC
s
E2F
E2F E2F E2F E2F E2F E2F
6 5 4 1 2 3
TRANSCRIPTIONAL WEAK TRANSCRIPTIONAL STRONG TRANSCRIPTIONAL
REPRESSOR ACTIVATORS ACTIVATORS
Role of Rb/E2F in cell cycle
M G1 Cyclin
Cyclin
D1,2,3
D1,2,3
++
CDK4,6
CDK4,6
G2 E2F
P Rb/p107/
p130
P P Cyclin
Cyclin
P E E
E2F
S ++
P CDK2
CDK2
P
Cyclin A,
DNApolDHFR, E; CDK2, c-myc, c-
TK, TS E2F1 jun, c-fos
Cyclin B,
+
CDK1
Cyclin A
+ G0
CDK1
M
G2
Cyclin D1,
D2,
D3
+
CDK 4, 6
G1
Cyclin A S
+
CDK2
p15ink4b
ink4b
p16ink4
ink4
p21waf1/cip
waf1/cip p18ink4c
ink4c
1
1 p19ink4d
ink4d
p27kip1
kip1 Cyclin E1, E2 p21waf1/cip1
waf1/cip1
+
p57kip2
kip2
CDK 2
p27kip1
kip1
p130 p57kip2
kip2
p107
CELL CYCLE CHECKPOINTS
G1S
Are we ready to replicate our DNA?
Is the DNA repair machinery in place to
fix any mutations that are detected?
Are the DNA replicating enzymes
available? Is there an adequate supply
of nucleotides? Is there sufficient
energy?
DNA
DAMAGE
Ionizing radiation, ds DNA breaks UV, replication errors
ATM ATR
PS395 ATR
S15
mdm2 P
S20
p5
3 T68 P P
Chk
Chk Chk
Chk
2
2 1
1
p5
3
Cyclin
Cyclin
E E
GADD p2
++
mdm2 45 CDK2
1 CDK2
Cyclin
Cyclin
PCNA
D D
+ + G1
CDK4/6
CDK4/6 ARREST
DNA
DAMAGE
Ionizing radiation, ds DNA breaks UV, replication errors
ATM ATR
ATR
T68 P
Chk
Chk
2
2
BASC : BRCA1-associated genome surveillance
complex
NBS 1 : Nimejen Breakage Syndrome 1
BRCA 1 : breast cancer susceptibility gene 1
P SMC1 : structural maintenance of chromosome
protein 1
NBS1/BRCA
P
S123
1/SMC1
cdc25A
cdc25A
Cyclin E/A
Cyclin E/A
++
CDK2
CDK2
S-PHASE DELAY
G2M
Have all of the chromosomes been fully
duplicated?
Were any segments of DNA copied more
than once?
Do we have the right number of
chromosomes and the right amount of
DNA?
DNA
DAMAGE
Ionizing radiation, ds DNA breaks UV, replication errors
ATM ATR
ATR
P
p5
P P S216
P
3 T68
Chk
Chk Chk
Chk cdc25C
cdc25C
2
2 1
1
S216
P
p5
3 cdc25C
cdc25C
14-3-
3
p2
1
Cyclin
Cyclin
B1B1
++
GADD cdc2
cdc2
45
G2
ARREST
DNA
DAMAGE
Ionizing radiation, ds DNA breaks UV, replication errors
ATM ATR
P ATR
mdm2 P
p5
P P P
3
Chk
Chk Chk
Chk cdc25C
cdc25C
2
2 1
1
P
p5
3 cdc25C
cdc25C
NBS1/BRC
P
14-3-
A1/SMC1 3
cdc25A
cdc25A
GADD
P
p2
mdm2 45 1
Cyclin Cyclin
Cyclin
Cyclin Cyclin E/A
E E Cyclin E/A B1B1
++ ++
++
CDK2
CDK2 cdc2
cdc2
CDK2
CDK2
G1 G2
S-PHASE DELAY
ARREST ARREST
APOPTOSIS
Cell 100:5770, 2000
The Hallmarks of Cancer Review
Douglas Hanahan* and Robert A.
Weinberg
Definition
derived from greek word
meaning dropping off or
falling off of petals from the
trees
programmed cell death
Morphological Events
chromatin
condensation
DNA fragmentation
nuclear breakdown
membrane
"blebbing"
cell fragmentation
(apoptotic bodies)
phagocytosis
Apoptosis vs Necrosis
Internal / external
signals Ischemia/toxins/radn
Energy dependent
Single cells Non-energy dependent
The cell shrinks and is Groups of cells
engulfed by The cells swell and
macrophages or release their content
neighbouring cells into the surroundings
Normally, no and the circulation
inflammatory reaction Marked inflammatory
reaction
bcl-2 Family
PORE MEMBRANE
REGULATION FORMATION ANCHOR
Anti-apoptotic
BH BH BH BH
bcl-2, bcl-XL, bcl-w 4 3 1 2
TM
Pro-apoptotic
BH BH BH
Bax, Bak, Bok 3 1 2
TM
BH3-only Pro-apoptotic
BH
Bik, Blk, Hrk, Bnip3 3
TM
PROCASPASE
Proteolytic cleavage
CASPAS
E
Targets of Caspases
INACTIVATION OF FAK ->
DISRUPTION OF CELL ADHESION
DETACHMENT OF APOPTOTIC CELL
Protein kinases
IN INNER FROM
LININGNEIGHBOURING
OF NUCLEAR CELLS
ENVELOPE; CLEAVAGE
Lamins CLEAVAGE OFOF
DISASSEMBLY INTERM FILAMENTS,
NUCLEAR LAMINA &
ACTIN, GELSOLINOF
SHRINKAGE NUCLEUS
CHANGES IN
Proteins required for cell structure
CELL SHAPE
CASPASE-ACTIVATED
Endonuclease (CAD) DNAase ATTACKS DNA,
SEVERING IT INTO
Enzymes involved in DNA repairFRAGMENTS
DEATH SIGNALS
*EXTRINSIC FAS FasL (CD95L)
* TRAIL-R
TNF-R DISC
TNF
DR4, DR5 (TRAIL DEATH RECEPTORS
DD
DDDD
CELL MEMBRANE
FADD
CASPASE 10
CASPASE 8
INITIATOR
CASPASES
CASPASE 3
CASPASE 7
CASPASE 6
EXECUTIONER CASPASES
NUCLEUS
APOPTOSIS
INTERNAL STIMULI :
DNA DAMAGE 1. Cytochrome c
*INTRINSIC* ONCOGENE-INDUCED
release
PROLIFERATION
LOSS OF ATTACHMENT TO 2.
ECMBax translocation
CHEMOTHERAPY, RADIATION
THERAPY
to mitochondria
CELL MEMBRANE 3.*INTRINSIC*
Bax/Bak
PRO-APOPTOTIC oligomerization
PROTEINS :
Bak,Bax, Bad, Bid, Bik, MITOCHONDRIA
Bim, Puma, NOXA, BmftBID
CASPASE 8
CYTOCHROME C
INITIATOR
CASPASE
CASPASE 9
APAF-1
CASPASE 3
APOPTOSOME
CASPASE 7
CASPASE 6
EXECUTIONER CASPASES
NUCLEUS
APOPTOSIS
PRO-APOPTOTIC PROTEINS
REGULATION FAS
TRAIL ANTI-APOPTOTIC PROTEINS
TNF
DDDD
TRAF2
CELL MEMBRANE Ras
FADD
NFKB P13K
MITOCHONDRIA
PTEN Akt
CASPASE 10
Smac/Diabl
o IAP
FLIP CASPASE 8
CASPASE 9
APAF-1
CASPASE 3
CASPASE 7
CASPASE 6
CASPASE 2
EFFECTOR CASPASES
RAIDD
ICH1-CED3
NUCLEUS PIDD
p53 APOPTOSIS
Mdm2
Hypoxia, DNA damage (UV, gamma, chemotherapy),
ribonucleotide depletion, telomere shortening
P53 INDUCTION
Cell 100:5770, 2000
The Hallmarks of Cancer Review
Douglas Hanahan* and Robert A.
Weinberg
Guardian of the Genome
p5
3
1. DNA damage checkpoint p5 2. Oncogene checkpoint
P mdm2
3
T68 P P
Chk Chk
Chk
2
2
Chk
1
1 p14ARF
PIGF VEGF-A VEGF-B VEGF-C Ang-1 Ang-2 Ephrins ECM bFGF PDGF
DOWNSTREAM PATHWAYS
Ras/MAPK
PI3K/AKT
Rho/Rac/cdc42
NFB
VEGF
VEGF
VEGFR2 VEGFR2
Destabilizatio Tie 2
Ang
n Tie 2 v3
2 v3 v ECM
Tie 2
New sprout
Follows VEGF gradient to tumour
VEGFR1
Hematopoietic cell-derived leukocytes (HSC)
c-kit
NORMAL BLOOD TUMOR BLOOD
VESSEL VESSEL
Tortuous vessels
Hierarchical branching
Haphazard blood flow
Even blood distribution
High IP
Low IP
Hypoxemia
Normoxic
Acidosis
Physiologic pH
Loss of EC jxn
Tight jxns between EC
complexes
Well-formed BM
Absent or few
Pericyte coverage
pericytes
Normal permeability Increased permeability
METASTASIS
Major Features of Tissue Invasion
Tumor-associated fibroblast
Adherens
junction
E-cadherin
HGF
Twist
New integrin
expression C-Met