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Tumor genetics
Minna Thullberg
minna.thullberg@labmed.ki.se
08-585 87985
Basic concepts of carcinogenesis
Cancer is a disease of the genes
Phenotypes of cancer cells
What is an oncogene
What is a tumor suppressor gene
Inherited versus sporadic cancer
The molecular pathway concept
Discussion and microarray
Summary of the most important stuff
Break
Cells in arrest
G0 (t)
Terminally differentiated
G0 (i)
Latent ability to regenerate
Do not form tumors
Form tumors occasionally
nucleus
M
G2
cell
chromosomes
G1
X
S
Cells in the cell cycle
R
Dividing cells
Form tumors with highest frequency
Cancer is a geneticMultistep
disease
which develops stepwise
carcinogenesis
normal cells
genetic change
clonal expansion
genetic change
invasive tumor
clonal expansion
genetic change
Chromosome
5q
:
Alteration:
.
mut or loss
Gene:
APC
12p
mut
K-ras
.
18q
loss
DCC
17p
loss
p53
DNA
hypo
methylation
Normal
epithelium
Hyperprolifer
ating epithelium
Early
adenoma
other
alterations
Intermediate
adenoma
Vogelstein 1990
Late
adenoma
Carcinoma
Metastasis
TRANSFORMED CELLS
Divide when they shouldn't
loss of serum dependence
loss of contact inhibition
loss of anchorage dependence
Abnormal shape
Chernoff J
Phenotypes of cells in a tumor
Loss of Differentiation
Increased Proliferation
Heterogeneity
All tumors seem to be different
Common characteristics of cancer cells
Increased cell proliferation due to
* Growth without growth factors
* Insensitivity to growth inhibitors
Resistance to apoptosis (committed cell death)
Indefinite lifespan= limitless replicative potential
Genetic instability due to e.g.
Protection against apoptosis or defect DNA repair
Sustained angiogenesis
Tissue invasion metastasis
In the invasive tumor
Proliferation
Growth
stimulation
Growth
inhibition
e.g. Growth factors
e.g. Growth inhibitors
Growth factor
receptors
Growth
inhibitor
receptors
GTPases
kinases
Adhesion
e.g. Extracellular matrix
GTPases
Cell-cell contact
Contact
receptors
Signal transduction
kinases
Gene transcription
Transcription factors
Contact inhibition
Cell-cell contact
Arrest or Apoptosis
Cellular response of STRESS
Intracellular stress
Extracellular stress
Protease cascade
apoptosis
caspase
HEAT
DNA damage
Chemical
imbalance
caspase
Cytokines
Cell cycle arrest
Ca2+ concentration
Stress receptor
Stress sensor
p53
ATM
P53 and/or ATM trigger arrest or apoptosis upon DNA damage
Parslow M
Telomeres protect the end of chromosomes
Telomere tandem
Parslow M
The telomeres get shorter for each round of replication
Until a certain limit when the cell stops to divide
Cell division with too short telomeres induces gene instability
Stem cells and most cancer cells express TELOMERASE
an enzyme which synthesize telomeres and
induces unlimited life-span
What is an oncogene?
Induces proliferation
or
Induces resistance to apoptosis
Induces transformation
Upregulated in human tumors
A Proto-oncogene can become an oncogene
by a genetic change
Viral oncogenes (HPV)
Proto-oncogenes are:
Growth factors
Growth factor receptors
Signal transduction proteins (kinases, G-proteins)
Transcription factors
Cell cycle proteins
Inhibitors of apoptosis
Telomerase?
Proliferation
Growth
stimulation
Growth
inhibition
e.g. Growth factors
e.g. Growth inhibitors
Growth factor
receptors
Growth
inhibitor
receptors
GTPases
kinases
Adhesion
e.g. Extracellular matrix
GTPases
Cell-cell contact
Contact
receptors
Signal transduction
kinases
Gene transcription
Transcription factors
Contact inhibition
Cell-cell contact
Proto-oncogenes are transformed into oncogenes by:
Activating mutations
Translocations
Transactivation
Gene amplification
Integration of virus
Genetic changes can be triggered by
From living:
DNA replication
Metabolism creating reactive metabolites
Stress from outside:
UV light, smoking, chemicals
A Tumor suppressor is normally
controlling cell growth or apoptosis
And is lost or inactivated in cancer
Tumor suppressor
Normal situation
mother
father
2 alleles
functional proteins
Tumor suppressor
Inherited or spontaneous
genetic change
mother
mutation
father
defect proteins
functional proteins
Further genetic change
in the second allele
gene deletion
2 genetic hits
only defect
proteins
NO functional proteins
disease
Mechanisms of tumor suppressor gene inactivation
Inactivating mutations
Gene deletions
Viral oncogenes
Promotor silencing
Viral oncogenes e g in HPV express proteins
which bind and inactivate p53 and pRb
two guards of apoptosis and cell proliferation
Changes in the structure of a gene’s promotor
can lead to silencing of that gene
and no protein will be expressed
Inherited cancer
Inherited predisposition for tumor disease
occurs typically through a mutation in a tumor suppressor gene
The tumor develops
when the second allele is also deleted or inactivated.
In spontaneous developed tumors there need to be
two hits in the tumor suppressor genes
Which take longer time
Examples of inherited cancer ”syndromes”
Retinoblastom(retina) pRb
Polyposis Coli (colon)
APC
Ataxia Telangiectasi (general)ATM
Breast Cancer
Melanoma
cell cycle control
differentiation
DNA repair
BRCA1, BRCA2
p16
DNA repair
cell cycle
The Cell Cycle
G0
nucleus
cell
M
chromosomes
G1
G2
X
S
R
Cyclin B-CDC2
Cyclin A-CDC2
G0
M
p16
G1
G2
R
Cyclin D-CDK4
X
Cyclin D-CDK6
S
Cyclin E-CDK2
Cyclin A-CDK2
-Gene amplification
-Chromosomal rearrangement
-Proviral integration
-Protein stabilisation
-Gene deletion
-Inactivating mutations
-Promotor silencing by
DNA methylation
p16
cyclin D
cdk 4/6
-Gene deletion
-Loss of function mutations
-Functional inactivation by
viral oncoproteins
-Gene amplification
-Loss of p16 binding
P
Rb
P
P
Rb
Hanahan and Weinberg, Cell, 2000
As for the genetic reprogramming of this integrated circuit in
cancer cells, some of the genes known to be functionally
altered are highlighted in red.
Summary
Cancer develops stepwise through genetic changes
Several genes are affected and it seems like
all tumors are different
An oncogene promote tumor growth
A tumor suppressor normally control cell growth,
or apoptosis but it is functionally lost in tumors
Common characteristics of cancer cells
Increased cell proliferation due to
* Growth without growth factors
* Insensitivity to growth inhibitors
Resistance to apoptosis (committed cell death)
Indefinite lifespan= limitless replicative potential
Genetic instability due to e.g.
Protection against apoptosis or defect DNA repair
Sustained angiogenesis
Tissue invasion metastasis
In the invasive tumor
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