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March, 2013
Cancer Pathogenesis
1 fertilized egg
1016 cell divisions/lifetime
50x1012
Proliferation
Differentiation
Death
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Cellular equilibrium
Proliferation Differentiation Death
Transit
Renewing
Proliferating Exiting
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Proliferation
Differentiation
Death
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Angiogenesis
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Hanahan and Weinberg, Cell 100: 57, 2000
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Micro changes
- Microsatellite changes Mikrosatellite - 100.000 - Nucleotide changes
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Terminal Deletion
Insertion
Inversion
Robertsonian Translocation
Isochromosomes
http://www.tokyo-med.ac.jp/genet/cai-e.htm
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Nucleotide changes in the genome of cancer cells: unseen site of the iceberg
Nucleotide Deletions Nucleotide Insertions Nucleotide Substitutions
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http://www.tokyo-med.ac.jp/genet/cai-e.htm
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Chromosomal loss:
Mostly, it is a sign for the loss of a tumor suppressor gene
CDKN2 locus PTEN locus RB1 locus ??? locus p53 locus
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Plass - 2002
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Carcinogenic chemicals
Viruses
Cancer cell
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Hasar Etken Tr
Kanser Riski Deri Ka., Melanoma Tiroid Ka., Lsemi Akcier Ka. Karacier Ka. Yallk Kanserleri Karacier Ka.
areti P53 (CC-TT) Translokasyon p53 (G-T) p53 (249 G-T) P53 (C-T) Virus DNA ntegrasyonu
Fiziksel
Radyasyon Benzopren Kimyasal Aflatoksin Oksidatif Stres Biyolojik HBV
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Disease
F-A
Function
DNA Damage respose ?
Inheretance
OR OR OR OR OR OD OR OD
Cancer Risk
Lsemi Skin Ca. Various cancers Sarcoma Sarcoma Colon, Endometrium Ca. Lsemi, NF1 Breast, Ovary, Prostate, Pancreas Ca Lymphoma, Leukemia Breast Ca. ? Various cancers
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X-P
Bloom Werner RothmundThomson
BRCA1, BRCA2
DNA Repair OR
ATM
A-T
p53
Li-Fraumeni
OD
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++
Cancer
Mutated or activated oncogenes Loss or mutation of Tumor suppressor genes Malignant transformation
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ONCOGENES
Oncogenes are mutated forms of cellular proto-oncogenes. Proto-oncogenes code for cellular proteins which regulate normal cell growth and differentiation.
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Oncogenes
proto-oncogene = ras Oncogene = mutated ras Always activated Always stimulating proliferation
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N-ras
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bcr-abl2
bcr-abl2
1c-myc
2bcr-abl
GENE AMPLIFICATION
Oncogene c-myc N-myc Amplification ~20-fold 5-1,000-fold Source of tumor leukemia and lung carcinoma neuroblastoma retinoblastoma small-cell lung cancer chronic myoloid leukemia acute myeloid leukemia colon carcinoma epidermoid carcinoma
c-erbB
~30-fold
K-ras
4-20-fold 30-60-fold
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The result:
Overproduction of growth factors Flooding of the cell with replication signals Uncontrolled stimulation in the intermediary pathways Cell growth by elevated levels of transcription factors
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Familial RB (%30) RB
rb
Normal cells
RB LOH
rb RB
rb
Inactivation of a tumor suppressor gene requires two mutations, inherited mutation and somatic mutation.
Tumor cells
Normal cells
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Normal Cells
RB
RB
RB
RB
RB LOH
RB Mutation
Tumor cells
WT1 (11p)
Wilms tumor
Rb1 (13q)
transcription
retinoblastoma
p53 (17p)
transcription
Li-Fraumeni syndrome
BRCA1(17q)
BRCA2 (13q)
transcriptional
regulator/DNA repair
breast cancer
breast/ovarian tumors
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CELL CYCLE
Daugther cell
Mitosis
S
DNA replication
CELL CYCLE
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Rb gene
Rb protein controls cell cycle moving past G1 checkpoint Rb protein binds regulatory transcription factor E2F E2F required for synthesis of replication enzymes E2F - Rb bound = no transcription/replication Growth factor --> Ras pathway --> G1Cdk-cyclin synthesized Active G1 Cdk-cyclin kinase phosphorylates Rb Phosphorylated Rb cannot bind E2F --> S phase
Disruption/deletion of Rb gene Inactivation of Rb protein
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p53
Phosphyorylated p53 activates transcription of p21 gene p21 Cdk inhibitor (binds Cdk-cyclin complex --> inhibits kinase activity) Cell cycle arrested to allow DNA to be repaired If damage cannot be repaired --> cell death (apoptosis)
Disruption/deletion of p53 gene Inactivation of p53 protein --> uncorrected DNA damage --> uncontrolled cell proliferation --> cancer
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BRCA1/2
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Tumor Progression
Multiple mutations lead to colon cancer Genetic changes --> tumor changes
Cellular
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Hanahan & Weinberg 2000
HERCEPTIN
ERCEPTN
STI-571
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STI-571
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Thousands of Targets
?
?
? ?
?
HERCEPTIN
? ?
STI-571
?
? ?
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Biyoinformatik
~3.000.000.000 bp DNA
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