Transcript Autoimmunitás, immuntolerancia immundeficiencia

Oncopathophysiology
Tornóci László
Semmelweis University
Institute of Pathophysiology
A few risk factors of malignant
tumors
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smoking
diet
viruses
hormones
irradiation
environmental pollution
Malignant tumors are monoclonal
Virtually all malignant tumors
are of monoclonal origin.
All descendants of a single cell are called a clone in
cellular biology. Members of a clone are genetically
identical in theory.
First proof: CML G6PD, Fialkow
Consequences of clonality #1
Exponential cell growth
time [cell cycles]: 0
1
number of cells: 1
2
20
21
2
3
n
8
22
23
2n
Consequences of clonality #2
Exponential cell growth
tumor number
mass of cells
1 kg
1012
1g
109
(log scale)
106
103
0
malignant
transformation
10
20
30
40
diagnosis
patient
dies
time
Heterogeneity
The mutation rate of malignant tumors is higher than
that of the healthy tissues. The original clone will
give rise to subclones because of this (heterogeneity).
Why do some cancers appear to ‘accelerate’?
Why are the therapeutical results better:
• with cases that have been diagnosed early?
• after the first use of a chemotherapeutical drug, than after
subsequent uses?
The malignant transformation
The malignant transformation is not a single step, but it is
believed to be a result of 5-10 subsequent somatic mutations
(accumulating in the same cell). This is the so called multistep theory.
This is why:
• tumors are seen more frequently with age
• there are inherited malignant tumor
syndromes
(e.g. Li-Fraumeni sy: p53 mutation)
Development of colon cc.
CGAP: Cancer Genome Anatomy Project
Genes affected by the malignant
transformation
proto-oncogenes
tumor suppressor genes
genes correcting DNA
genes controlling apoptosis
Mechanisms of the genetical
changes
• point mutation
(eg. ras proto-oncogene)
• gene amplification
(eg. ERBB2 in breast cancer, resistance to
drugs)
• chromosomal aberrations
(eg. reciprocal translocation, Ph chromosome)
• epigenetic mechanisms
The Philadelphia chromosome
The Philadelphia chromosome
Genes affected by the reciprocal translocation:
ABL (9q34.1)
BCR (22q11)
Abelson leukemia proto-oncogene
breakpoint cluster region
The result is a new, abnormal, fusion gene on chromosome
9, which is translated into a protein that has tyrosine kinase
enzyme activity. This is specifically inhibited by the drug
called Gleevec. Very good results have been achieved in
CML and some other malignancies using this novel drug.
Epigenetic mechanisms
A gene control mechanism which is not coded in
the DNA sequence. Such is eg. parental imprinting
(gene expression depending on the parent’s sex).
The mechanism of imprinting is selective methylation of
genes. (Methylated genes are not expressed.) Most
malignant tumors seem to have less methylated genes, than
healthy cells.
A few important tumor
suppressor genes
• p53, p21, Rb
• HNPCC
• BRCA1, BRCA2
Function of p53 gene
UV irradiation
-irradiation
chemicals
DNA
damage
p53 gene
expression
p53 protein
oligomerization
p53 oligomers bind to specific
sites of DNA, acting as
transcriptional activators
arrest in G1
DNA repair
or
apoptosis
Function of p53
p53
WAF1/Cip1/sdi1
genes
WAF1: wild type p53-activated
fragment 1
Cip1: cdk-interacting protein 1
p53
oligomer
p21
proteins
sdi1: senescent cell derived inhibitor 1
p21
cdk
cyc
arrest in G1
cdk: cyclin dependent kinase
cyc: cyclin
Function of the Rb gene
free (active)
transcription factors
e.g. UBF, E2F
RNA polymerases
CDK4/6
pRb
CyclinD
UBF
pol I
rRNA
E2F
pol II
mRNA
phosphorylated pRb
phosphorylation
transcription, translation
of RNA polymerase genes
synthesis
Cell cycle continues in the presence of
phosphorylated (inactive) pRb; however, if pRb
is not phosphorylated, then the cell cycle stops
because of binding the transcription factors
HNPCC
HNPCC: Hereditary nonpolyposis colon cancer
• Incidence cca. 1:200
• It is present in 15% of colon cancers
• Risk of developing colon, ovarian, uterine and kidney
tumors
• It is analogous with MutS/MutL gene of yeast
BRCA1
• Incidence cca. 1:200
• In a family with breast cancer cases a
BRCA1 positive woman has an 85%
lifetime chance to develop breast or ovarian
cancer
• Prophylactic bilateral mastectomy is
advised
Problems with genetic tests
• What to do if the test is positive?
• A negative result cannot ensure that the
person tested will not get cancer.
• The most important privacy issue of the
future: how our tissues will be handled?
(Our genetic code is our own secret: the
employer, the insurance company must not
learn it!)
Therapeutical approaches
Classic methods
• surgery
• chemotherapy
• irradiation
New methods
• gene therapy
• inhibition of angiogenesis
• immunotherapy
Examples of using gene therapy
to treat malignant tumors
• reintroduce the normal copy of an inactivated tumor
suppressor gene (would need 100% efficacy)
• introduce genes coding for antigenes, cytokines to
enhance the immune response
• Introduce a gene causing toxicity (thymidine kinase
gene + gancyclovir treatment)
• artificial viruses (cytopathogenic adenovirus, that can
infect only cells deficient of p53)
Angiogenesis #1
• Tumors can grow to a maximum size of 1 mm
without their own blood supply (in situ carcinoma)
• Tumors spend a significant amount of time in the
„in situ” stage, before they become angiogenetic,
this is when they start growing
• Metastasis is angiogenesis dependent (it is both
needed for leaving the primary tumor and for the
growth of the metastasis)
Angiogenesis #2
Several tumors produce materials stimulating or inhibiting
angiogenesis. The primary tumor can inhibit the growth of
metastases or the growth of other tumors.
Endogenous promoters
Endogenous inhibitors
• VEGF (vascular
• thrombospondin-1
endothelial growth factor)
• FGFs (fibroblast growth
factors)
• angiopoietins
(induced by p53)
• angiostatin
• endostatin
Inhibition of angiogenesis
Methods/drugs:
• endogenous inhibitors
• gene therapy
• drugs (eg. thalidomid=Contergan)
Even leukemias were proved to be angiogenesis dependent!
(Increased microvascularization is seen in the bone marrow.)
Vascular endothelial cells are said genetically stable, so
resistance is not likely to develop against the inhibitors of
angiogenesis.
Targeted inhibition of
angiogenesis using nanoparticles
nanoparticles
tumor endothelium
ag-inhibiting gene
target-recognizing
molecules
integrins