tumor genetics minna thullberg [email protected] 08-585 87985
TRANSCRIPT
Basic concepts of carcinogenesis
Phenotypes of cancer cells
What is an oncogene
What is a tumor suppressor gene
Inherited versus sporadic cancer
The molecular pathway concept
Cancer is a disease of the genes
Discussion and microarray
Summary of the most important stuff
Break
G0 (i)
G1G2
S
M
X R
nucleus
cell
chromosomes
G0 (t)
Cells in the cell cycle
Cells in arrestTerminally differentiated
Latent ability to regenerate
Do not form tumors
Form tumors occasionally
Dividing cellsForm tumors with highest frequency
Multistep carcinogenesis
normal cells
genetic changeclonal expansion
genetic change
clonal expansion
genetic change
invasive tumor
Cancer is a genetic disease which develops stepwise
Normalepithelium
Hyperprolifer-ating epithelium
Earlyadenoma
Intermediate
adenomaLate
adenomaCarcinoma Metastasis
Chromosome:Alteration:
Gene:
5q
mut. or lossAPC
DNAhypo
methylation
12p
mut.K-ras
18q
lossDCC
17p
lossp53
otheralterations
Vogelstein 1990
Abnormal shape
loss of anchorage dependence
loss of serum dependenceloss of contact inhibition
Divide when they shouldn't
TRANSFORMED CELLS
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
Sustained angiogenesis
Tissue invasion metastasis
Genetic instability due to e.g.Protection against apoptosis or defect DNA repair
In the invasive tumor
Proliferation
e.g. Extracellular matrixCell-cell contact
Gene transcription
Growth inhibition
Growth stimulation
Adhesion
Growth factorreceptors
kinasesGTPases
Signal transduction
Transcription factors
e.g. Growth factors e.g. Growth inhibitors
Growth inhibitorreceptors
Contact inhibition
kinases
GTPasesContact receptors
Cell-cell contact
Arrest or Apoptosis
Cellular response of STRESS
Extracellular stress
HEAT
Chemical
Cytokines
Intracellular stress
DNA damage
Ca2+ concentrationcaspase
caspase
Stress receptor
Stress sensor
Protease cascade apoptosis
p53 ATM
P53 and/or ATM trigger arrest or apoptosis upon DNA damage
Cell cycle arrestimbalance
Parslow M
Telomere tandem
Parslow M
Telomeres protect the end of chromosomes
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 TELOMERASEan enzyme which synthesize telomeres and induces unlimited life-span
What is an oncogene?
Induces proliferation
Induces resistance to apoptosisInduces transformation
Upregulated in human tumors
or
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
e.g. Extracellular matrixCell-cell contact
Gene transcription
Growth inhibition
Growth stimulation
Adhesion
Growth factorreceptors
kinasesGTPases
Signal transduction
Transcription factors
e.g. Growth factors e.g. Growth inhibitors
Growth inhibitorreceptors
Contact inhibition
kinases
GTPasesContact receptors
Cell-cell contact
Proto-oncogenes are transformed into oncogenes by:
Activating mutations
Translocations
Transactivation
Integration of virus
Gene amplification
Genetic changes can be triggered by
DNA replication
Metabolism creating reactive metabolites
Stress from outside:
UV light, smoking, chemicals
From living:
A Tumor suppressor is normally controlling cell growth or apoptosis
And is lost or inactivated in cancer
Tumor suppressor
Normal situation
father
mother
functional proteins
2 alleles
fathermother
functional proteins
mutation
defect proteins
Inherited or spontaneousgenetic change
2 genetic hitsonly defect proteins
gene deletion NO functional proteins
disease
Further genetic changein the second allele
Tumor suppressor
Mechanisms of tumor suppressor gene inactivation
Inactivating mutations
Gene deletions
Viral oncogenes
Promotor silencing
Viral oncogenes e g in HPV express proteinswhich bind and inactivate p53 and pRbtwo guards of apoptosis and cell proliferation
Changes in the structure of a gene’s promotorcan lead to silencing of that geneand no protein will be expressed
Inherited cancer
Inherited predisposition for tumor disease
occurs typically through a mutation in a tumor suppressor gene
The tumor developswhen the second allele is also deleted or inactivated.
In spontaneous developed tumors there need to betwo hits in the tumor suppressor genesWhich take longer time
Examples of inherited cancer ”syndromes”
Retinoblastom(retina) pRb cell cycle control
Polyposis Coli (colon) APC differentiation
Ataxia Telangiectasi (general) ATM DNA repair
Breast Cancer BRCA1, BRCA2 DNA repair
Melanoma p16 cell cycle
G1G2
S
M
G0
X R
nucleus
cell
chromosomes
The Cell Cycle
G1G2
S
M
G0
XRCyclin D-CDK4
Cyclin D-CDK6
Cyclin E-CDK2
Cyclin A-CDK2
Cyclin A-CDC2
Cyclin B-CDC2
p16
Rb RbP
P P
cyclin D
cdk 4/6
p16
-Gene amplification-Chromosomal rearrangement-Proviral integration-Protein stabilisation
-Gene deletion-Inactivating mutations-Promotor silencing by DNA methylation
-Gene deletion-Loss of function mutations-Functional inactivation byviral oncoproteins
-Gene amplification-Loss of p16 binding
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 likeall 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
Sustained angiogenesis
Tissue invasion metastasis
Genetic instability due to e.g.Protection against apoptosis or defect DNA repair
In the invasive tumor