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Chapter 25: Cancer

Cancers
Cause 1/5
th
of the deaths in the US per year
Number 3 cause of deaths worldwide
Malignant neoplasm
Terminology: proto-oncogenes
proto-oncogenes =
activate to become
oncogene
Increase gene
expression
Produce more
hyperactive product
Mutation
! excessive growth
Mutation
Normal
! regular growth
Normal
Oncogene = gain-of-function
Point mutation ! hyperactive/constitutive
active protein
Chromosomal translocation ! chimeric
gene ! chimeric hyperactive/constitutive
active protein
Chromosomal translocation ! new
promoter
Amplication = numerous copy
proto-oncogenes to oncogenes
Gain of function
Point mutation: switch a single base pair to make
the gene constitutively active
Normal
Mutant
Constitutive
att gcg ata ATG TTT TCT TAT
Met Phe Ser Tyr
att gcg ata ATG CTT TCT TAT
Met Leu Ser Tyr
proto-oncogenes to oncogenes
Gain of function
Chromosomal
translocation:
bring two genes
together to produce
hybrid gene that is
hyperactive
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proto-oncogenes to oncogenes
Gain of function
Chromosomal
translocation:
bring a
hyperactive
promoter close by
a proto-oncogene
P* proto-oncogene
P* oncogene
proto-oncogenes to oncogenes
Gain of function
Amplication: make multiple copies of the
proto-oncogene
1 copy = normal expression
1 copy = normal expression
3 copies = over-expression
Terminology: Tumor suppressor genes
Tumor suppressor
genes = normally
restraint growth
Mutation !
inappropriate growth
restraint
Inappropriate growth
Tumor suppressor = loss-of-function
Loss regulator of cell cycle: Rb
Loss receptor or signal transduce: TGF"
Loss checkpoints: AMT
Loss control of apoptosis: p53
Loss DNA repair enzymes
"
"
"
"
Terminology: caretaker genes
Caretaker genes involed in:
Cell birth
Cell death = Apoptosis
Repairing damaged DNA
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Terminology
Carcinogens
Chemicals
Radiations
Terminology
Germ cell = a precursor cell that gives rise
to gametes (haploid cells, e.g., sperm/egg)
thus participates in formation of next
generation
Somatic cell = not germ cell
Stem cell = a self-renewing cell that divides
to give rise to a cell with an identical
developmental potential
Tumors
Mutations of proliferating somatic cells
Proliferation for cancer to pass on
More than one mutation
Tumor cells = on-set of cancer
Cancers
Losses of cell regulation
Grow and divide in an unregulated fashion
Descendants inherit the propensity to
proliferate without regulation
Arise with great frequency in old animals
Multiple mutations
Theory: 5-6 hits
Low incident with low #
hits at younger age
Cancer
To pass on, want dividing cells
Stem cells = proliferating & differentiating
Ex: blood, bone, intestine, skin
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Tumors
Benign = moles and warts
Tumors
Malignant
Cells grow and divide more rapidly
Liver Lung
Cells fail to die at normal rate
Tumors
Malignant
Characteristics of rapid growth:
High nucleus to cytoplasm ratio
Prominent nucleoli
Leukemia
Cancer
Normal
endoderm
gut
Neural
tube
ectoderm
mesoderm
muscle Connective
tissue
Blood
leukemia
skin
Carcinoma
Sarcoma
Classes of cancers More common
Tumors
Malignant
Invade surrounding tissues
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Normal vs. malignant cells
Normal
Physical barrier
= basal lamina
Malignant
Overcome physical constraint
Angiogenesis = formation of new blood vessels

Breakdown of basal lamina
Plasminogen activator
Plasmin/protease
Digest basal lamina
Fig. 25.3
Metastasis
Spread of tumor cells to secondary areas
(migrate & overtake secondary areas)
Movie: metastasis
http://uwp.edu/%7Epham/bios301/
L26A0006801.mov
Angiogenesis
Require more blood vessels for growth
Breakdown of the basal lamina of nearby
capillaries
Invasion Angiogenesis
Angiogenesis
Induce synthesis or secretion of growth factors:
Basic broblast growth factor (bFGF)
Transforming growth factor (TGF#/") "
Vascular endothelial growth factor (VEGF)
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Brain tumor
Rabbit
Normal Angiogenesis
Medical relevance
Avastin inhibit VEGF
http://www.gene.com/gene/products/
information/oncology/avastin/
Techniques
DNA isolation
Transfection: introduce DNA into cells
Liposomes
DNA
Fusion
Fig. 25.6 =
transformation
DNA from human
transformed cells
= cancer cells
transfection
Cultured cells
Extract DNA
Amplifying DNA
= phage or bacteria
Identify DNA
Amplify clone
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DNA from tumor cells can transform
normal cells
Normal cells stop growing on contact
DNA from tumor cells ! signal for
continuous growth
Fig. 25.5
Normal Transformed with ras
D

Review from Chapter 16
Ras protein
Control intracellular signaling
Inactive bound to GDP
Active bound to GTP
25 % breast cancer: amplication of
HER2 gene
HER2 protein = receptor tyrosine
kinase
Amplication of HER2 gene ! many
more receptors ! cells grow even at
low concentration of GF ! tumor
Medical relevance
Amplication of HER2 gene ! many
more receptors ! cells grow even at
low concentration of GF ! tumor
Anti-HER2 protein = block bind of GF
to HER2
Reduce recurrence in patients by 50%
Medical relevance
Medical relevance
Herceptin in inbihit HER2:
http://www.gene.com/gene/products/
information/oncology/herceptin/
Incidence & mortality rate of breast cancer
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Ras
D

Ras = proto-oncogene
Ras
D
= oncogene
Gly
12
to Val
12

Slow in GTP hydrolysis
= Cell proliferation
Ras
D

Dominant
ras
D
ras: problematic
Causes colon, bladder, breast, pancreatic, lung
and leukemic cancers
Why so many sites?
MAP kinase
cascade: Fig.
16-25 and -27
Different
cascades
Different targets
Given
Culture 3T3 cells = loss of function in the
p16 gene
Expression of Ras protein causes
transformation in 3T3 cells but not normal
cells
Why?
Fig. 25-8: synergistic effects of
multiple mutation
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Multi-hit model: Human colon
cancer
~100,000 new cases/yr
Fig. 25-9
Multi-hit model: Human colon cancer
Fig. 25-9
Most human
colon cancers
have mutations in:
APC
Ras
DCC
p53
Loss of APC
Loss of ras
Loss of DCC
Loss of p53
Proto-oncogenes to oncogenes
Viruses bring in an oncogene or activate
proto-oncogene
RNA
Rous Sarcoma Virus
RSV RSV
Can accidental
take host genome
with it
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RSV
Mistake made in excision
LTR
LTR
RSV: Fig. 25-19
Mistake made in excision
Host
Virus
missing C-terminus = phosporylation
(inactivation) site
RSV: Fig. 25-19
Host
With C-term
Phosphorylated
conformation ! no
easy access to kinase
activity
No easy access for
kinase activity
RSV: Fig. 25-19
Easy access for
kinase activity
Virus
Conformational change:
Missing C-terminus
Missing Tyr
527

RSV
Transformed host cells
Normal Transformed
Cancers from viruses
Viruses bring in:
Oncogene: Rous Sarcoma Virus
Tumor suppressor: Human Papilloma Virus
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REVIEW: HPV
E1 = replication factor
E2 = replication factor
Normal: shut down E6 and E7
E4 facilitates replication
E5 destabilizes membrane for
infection
If expressed, E7 inactivates
tumor suppressor gene Rb
If expressed, E6 inactivates
tumor suppressor gene p53
Oncogenes
Neoplasia
Fig. 25-16
RTK
Single amino acid mutation
Dimerization and activation of
receptor even w/out EGF ligand
REVIEW:
Retrovirus
Viruses
bring in an
oncogene or
activate
proto-
oncogene
Fig. 25-16: Erythroblatosis
Virus brings in ErB receptor
Lacks ligand binding domain
Constant on
Fig. 25-17: Colon carcinoma
Chromosomal translocation
Continous dimerization and activation
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Fig. 25-18:
Erytholeukemia
Viral protein
G55 from SFFV
Continuous binding
& activation
or E5
Carcinogen and caretaker genes
Mutagens
Cause DNA damage
Must
Overcome check points
Redirect blood vessels
Metastasize
Direct carcinogens
Reactive electrophiles react with O and N
on DNA
Direct carcinogens Direct carcinogens
Amino acids
from
red meat
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Homework
1: benign vs. malignant
3: gain-of-function
4: multi-hits
5: age
6: gain-of-function vs.
loss-of-function
12: c-src vs. v-src
16: p53
Analyze data: a & b