Cancer is a Disease of Abnormal Growth Regulation

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Cancer is a Disease of Abnormal Growth Regulation
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Regulation of Cell Growth

• In normal tissue, cell numbers are precisely
  controlled by balancing cell proliferation, with
  differentiation and death (apoptosis).
• All of these processes are affected in during
  carcinogenesis.

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Regulation of Cell Growth

• Normal cell growth occurs in response to soluble
  peptide growth factors. (mostly stimulatory).
• Normal cell growth is inhibited by interaction
  with neighboring cells (contact inhibition).
• Normal cell growth requires contact with
  substratum (anchorage-dependent).

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Cancer Cell Growth

• Tumor cells have reduced requirement for growth
  factors.
• Lack sensitivity to growth inhibitors
• Resistance to programmed cell death (apoptosis)

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Growth Factors

• Soluble peptides that interact with cells via
  specific receptors located in the cell membrane.
• Autocrine
• Paracrine
• Endocrine

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Growth Factors
TyK
TyK
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Growth Factor Receptors
TyK
TyK
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Tyrosine Phosphorylation
TyK
TyK
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Tyrosine phosphorylation recruits and activates
signaling proteins
TyK
TyK
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Phosphatidyl Inositol-3 Kinase
PI-3K
TyK
PI-3K
TyK
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Phosphatidyl Inositol-3 Kinase
PI-3K
TyK
PI-3K
TyK
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Recruitment of AKT and PDK1
PDK1
PI-3K
AKT/PKB
TyK
PI-3K
TyK
AKT/PKB
PDK1
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Activation of AKT and PDK1
PDK1
PI-3K
AKT/PKB
TyK
PI-3K
TyK
AKT/PKB
PDK1
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PDK1 Substrates
PDK1
PI-3K
AKT/PKB
TyK
PI-3K
TyK
PKC?
AKT/PKB
S6K
PKC?
PDK1
S6K
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AKT/PKB Substrates
PDK1
PI-3K
AKT/PKB
TyK
PI-3K
TyK
BAD Caspase 9
AKT/PKB
GSK3
PDK1
BAD Caspase 9
Cyclin D
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PTEN Inhibition of PI-3K
PTEN
PI-3K
TyK
PI-3K
TyK
PDK1
PTEN
AKT/PKB
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MAP kinase signaling
TyK
TyK
shc
shc
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Recruitment of GTPGDP Exchange Factor (GEF)
SOS
TyK
Grb2
TyK
shc
SOS
shc
Grb2
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Activation of RAS
RAS
GTP
SOS
GDP
TyK
Grb2
TyK
shc
SOS
shc
Grb2
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Inhibition of RAS
RAS
NF-1
GDP
SOS
TyK
Grb2
TyK
shc
SOS
shc
Grb2
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Activation of RAF
RAS
RAF
GTP
SOS
TyK
Grb2
TyK
shc
SOS
shc
Grb2
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RAF Substrates
RAS
RAF
GTP
SOS
MEK1, MEK2
TyK
Grb2
TyK
shc
SOS
shc
Grb2
ERK1/2
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Erk1/2 Substrates
RAS
RAF
GTP
SOS
Paxillin
TyK
RSK1-4, MSK1,2, MNK1,2
Grb2
TyK
shc
SOS
shc
Grb2
ERK1/2
c-jun c-fos
Bad GSK3 4EBP1 eIF4E et al
c-fos c-myc
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Activation of PLC?
TyK
PLC?
IP3 DAG
TyK
PLC?
PKC Ca
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Cell Adhesion molecules
Integrins
FAK
PI3K others
Actin Cytoskeleton
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Cell signaling and cancers

• Activating mutations in RTKs
• Activating mutations in RAS (reduced GTPase
  activity)
• Activating mutations in AKT or inactivating
  mutations in PTEN
• Mutations in more distal components are infrequent

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Cell Cycle Progression

• The cell cycle is the orderly progression of
  events that occurs following growth stimulation
  and results in the generation of 2 daughter
  cells.
• Cell cycle progression is regulated at specific
  checkpoints.
• Checkpoint control is abnormal in cancer cells.

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Growth signals cause cell cycle progression
RB
G1
S
CDK/Cyclins
G0
G2
M
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G0 to G1 progression requires specific signals
Involves activation of a large number of genes
but regulation is not well Worked out. Likely
to involve events mediated by cell-cell and
cell-substratum interactions.
G1
G0
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G1 to S progression
RB
G1
S
CDK4/D Cyclins
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G1 to S progression
RB
G1
S
CDK4/D Cyclins
Phosphorylation of RB results in its dissociation
from E2F transcriptional complexes. E2F
regulates transcription of cyclin E, DNA
polymerases, thymidine kinase, dihydrofolate
reductase and others
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G1 to S progression
RB
G1
S
CDK4/D Cyclins
Inhibitors of Cdk4 p16INK4 p21 p27
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Regulation of G1 to S progression is frequently
abnormal in cancers.
RB
G1
S
CDK4/D Cyclins
-Cdk4 inhibitors are frequently mutated in human
cancers. -Cyclin expression is increased in some
cancers -Cdk4 is activated in some cancers
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S to G2 progression
S
CDK2/Cyclins A E
G2
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G2 to M progression
CDK1/Cyclins A/B
G2
M
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Checkpoint control - G1/S

• p53 - Activated by DNA damage. Allows repair
  prior to initiating new DNA synthesis - Guardian
  of Genome
• p53 - Effects mediated by p21
• p53 - Stabilized by p14Arf.

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Checkpoint control - G2/M

• ATM, RAD proteins - Activated by DS-DNA breaks.
• At G2/M, effects mediated by CDC25 phosphatase,
  which causes disruption of CDK2/Cyclin B complex.
  CHK kinases also required. BRCA1/2 may also
  function in DS repair.
• At G1/S, effects mediated by p53 (via p21).

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Checkpoint control

• Loss of checkpoint control is common in cancers.
• Loss of checkpoint control is a major cause of
  genetic instability in cancer cells.
• Inherited mutations in checkpoint proteins are
  associated with increase risk of cancer.

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Programmed Cell Death

• Apoptosis
• Characteristic morphologic changes
• Cell shrinkage
• Cytoplasmic blebs
• Chromatin condensation
• Death mediated by specific proteases (caspases)
• Phagocytosis by macrophages

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Extrinsic Pathway

• Receptor-Mediated
• FAS
• TNFR1
• Interaction with ligand results in clustering of
  caspase-8 and auto-cleavage
• Active caspase-8 activates downstream caspases,
  which ultimately leads to degradation of cellular
  contents.

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Intrinsic Pathway

• Mediated by increased mitochondrial permeability
• release of Cytochrome c from mitochondria to
  cytoplasm
• Cyto C interacts with Apaf-1, which then cleaves
  caspase-9
• Caspase-9 activates downstream caspases, which
  ultimately leads to degradation of cellular
  contents.

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Intrinsic Pathway

• Bcl family proteins mediate mitochondrial
  permeability
• Bcl-2 and Bcl-X inhibit permeability
• Bax, Bak, Bid and Bim promote permeability
• Mitochondrial permeability determined by the
  balance of pro- and inhibitory Bcl family members
  in mitochondrial membrane

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Regulation of Apoptosis

• Growth factors inhibit apoptosis
• AKT/PKB phosphorylates Bad and caspase-9,
  inhibiting their function
• Lack of growth factors results in death by
  neglect
• p53 promotes apoptosis in response to DNA damage

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p53 and Apoptosis

• p53 levels rapidly increase following exposure of
  cells to a variety of cell stressors
• DNA damage activates ATM, which phosphorylates
  p53.
• Phosphorylated p53 is a transcription factor
• p21
• Bax

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Apoptosis and Cancer

• p53 is mutated in over 50 of human cancers
• Decreased cell death in response to DNA damage
  (i.e., many chemotherapeutic agents)
• Increased mutability of DNA (lack of checkpoint
  and lack of cell death)
• Bcl-2 is overexpressed in a particular subtype of
  lymphoma
• Indolent disease characterized by accumulation of
  cells (lack of cell death), rather than rapid
  cell growth