Medical Biotechnology Master’s Programmes
at the University of Pécs and at the University of Debrecen
Identification number: TÁMOP-4.1.2-08/1/A-2009-0011
CANCER AND TUMOR DEVELOPMENT –
SENESCENCE AND CANCER,
EPIDEMIOLOGY AND STATISTICS
Krisztián Kvell
Molecular and Clinical Basics of Gerontology – Lecture 27
Medical Biotechnology Master’s Programmes
at the University of Pécs and at the University of Debrecen
Identification number: TÁMOP-4.1.2-08/1/A-2009-0011
Cell cycle-stop
Apoptosis
Differentation Angiogenesis
DNA Repair
Oxidative Stress
DNA Damage Endogenous Effects Exogenous Effects
p53
DNA damage-triggered cell fate responses
Transcription of Candidate Genes
• Caretakers
First line of defense, prevent genomic oncogenic mutations to occur
• Gatekeepers
Second line of defense, eliminate (by apoptosis) or senesce cells with oncogenic mutations
Tumor suppressor genes
Human Mouse Common
p16
p21 RB
Senescence Culture stress
Telomere shortening
p38 RAS
p53
Molecular level senescence pathways
ROS
Nuclear translocation
Anti-inflammation
Cell cycle arrest
Cell DNA cleavage
PS exposure Inflammatory cell activity
Cytoplasmic localization
Ubiquitination and degradation of FoxO
Apoptosis blockade JNK
Mito NF-kB
p27 c-Myc
Akt
Cytc
Caspase-1 Caspase-3
p300 CBP
AC FoxO FoxO P
14-3-3 Fas L
Bim
Noxa TRAIL p53
Cancer inhibition
14-3-3 P
Active FoxO
Proteins P
SIRT1
Molecular level cell fate decisions
• p53 as major tumor suppressor gene
- Potent inducer of apoptosis, cell cycle arrest, senescence
- 50% of sporadic malignancies share loss or mutation of p53 gene
- 80% of all human cancers have dysfunctional p53 signaling
- Heterozygous human p53 KO (Li-Fraumeni
syndrome) have high cancer incidence (50% by 30y)
p53 has ambivalent talents I
• p53 as pro-aging factor
- Increased p53 activity leads to signs of accelerated, even premature aging
- Beyond age 60-80y cancer incidence drops and pro-aging characteristics dominate
- Signal transduction crossover with IGF-1 and mTOR signaling, explains effects on longevity - p53 dosage has profound effects on stem cell
proliferation and regenerative capacity in the aged
p53 has ambivalent talents II
TSGs Apoptosis
Senescence
Differentation:
restricted growth Benign cancer cells with limited proliferative potential
Differentation:
acquisition of self-renewal
potential Malignant cancer
stem cell Heterogeneous malignant
stem cell tumour
Cancer stem cells escape routine elimination
Polycomb group proteins Oncogenic hits
Polycomb group proteins Oncogenic hits
Senescence
Senescence defect Apoptosis
Apoptosis defect
Failsafe defect
TP53 mutation ARF
INK4A
INK4A Apoptosis
Tumour
Tumour
Tumour
TP53 mutation
TP53 mutation Normal cells
Normal cells
Normal cells
Drug-resistant tumour
Drug-resistant tumour
Drug-resistant tumour Apoptosis
defect Senescence
defect Apoptosis
Senescence
RAS
MYC Therapy
Therapy
Therapy p53 p53
p53
Bcl-xL
Oncogene
Malignant tumor
escape mechanisms I
Apoptotic cell death
Senescence induction Malignant population
Therapy (DNA damage)
Terminal arrest Immune attraction Growth promotion Escape
Beneficial Detrimental
?
?
? ? ?
Malignant tumor
escape mechanisms II
• Codon 72, proline → arginine, (evolutionarily late SNP), higher apoptotic efficiency
• Mdm2 gene, G allele means more supression and more cancer compared to T allele
• Combination of G/G, Pro/Pro, smoker means >10×
odds for cancer (gene + environment)
• >85y Pro/Pro means 40% in survival despite 2.5×
odds for cancer
p53 polymorphisms in cancer and
longevity
• Senescence responses suppress tumors
• Senescence-inducers are also oncogenic
• Cancers share mutations in p53 or p16
• Loss of senescence response = tumor
• Classical trade-off relation
Antagonistic pleitropy: p53 and p16
MDS/AML Cancer Genomic instability
Telomerase complex TERT TERC
DKC1
Constant increased recruitment of stem cells into cell cycle
Cell cycle arrest/cell death of progenitor cells
Cancer development and telomeres
Short telomeres
Spontaneous telomere stabilization
Crisis Divisions
Express TERT
Divisions Express
TERT
Express TERT
Express TERT
Telomere shortening
RB and p53 inactivation
Senescence Immortality
Telomere maintenance
Acquiring immortality via telomerase
• Mouse telomeres are extremely long
• Mouse tissues often express telomerase
• Mouse cultured cells ‘spontaneously immortalize’
• Human telomeres are much shorter
• Most human tissues lack telomerase
• Human cultured cell immortalization is zero
Antagonistic pleiotropy:
telomere length I
• Rodent strategy:
high annual mortality, low chances of cancer
development = long telomeres, active telomerase to fight ROS
• Primate strategy:
low annual mortality, elevated chances of tumors = short telomeres, lack of telomerase to fight cancer
Antagonistic pleiotropy:
telomere length II
Acetylated histone tails Methylated
hystone tails Methylated DNA (CpG dinucleotides)
Transcription
CO-ACT HAT
Epigenetic silencing
K4 HMT
TAF
TBP RNA-PII TF
HP1 HDAC DNMT1
MBD
CO-REP CAF-1
MBD K9 HMT
Acetylation status and
epigenetic silencing I
Methylated histone tails Acetylated histone tails Deacetylated hystone tails
Stable repression of cyc E and other growth-promoting genes Heterochromatin
DNMT1?
RB E2F HDAC
SUV39H1 HP1?
E2F site
Transcription of cyc E and other growth-promoting genes Euchromatin
E2F site
Cyc E p300 Cdk2
P E2F
p300/CBP
Acetylation status and
epigenetic silencing II
Cancer epidemiology worldwide
• 13 million cancers every year, 8 million deaths
• Most frequent cancer types:
- Lung cancer
- Stomach cancer - Colorectal cancer - Liver cancer
- Breast cancer
• Most patients are aged 65+ years
- 1/3 person has thyroid cancer at autopsy
- 4/5 men have prostate cancer by 80 years of age