Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011
CANCER AND TUMOR DEVELOPMENT – SENESCENCE AND CANCER, EPIDEMIOLOGY AND STATISTICS
Krisztián KvellMolecular and Clinical Basics of Gerontology – Lecture 27
Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011
TÁMOP-4.1.2-08/1/A-2009-0011
Cell cycle-stop
Apoptosis
Differentation Angiogenesis
DNA Repair
Oxidative Stress
DNA Damage Endogenous EffectsExogenous Effects
p53
DNA damage-triggered cell fate responses
Transcription of Candidate Genes
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• CaretakersFirst line of defense, prevent genomic oncogenic mutations to occur
• GatekeepersSecond line of defense, eliminate (by apoptosis) or senesce cells with oncogenic mutations
Tumor suppressor genes
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HumanMouseCommon
p16
p21 RB
Senescence
Culture stress
Telomereshortening
p38
RAS
p53
Molecular level senescence pathways
ROS
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Nuclear translocation
Anti-inflammation
Cell cycle arrest
Cell DNAcleavage
PS exposure
Inflammatorycell activity
Cytoplasmic localization
Ubiquitination anddegradation of FoxO
Apoptosis blockade
JNK
Mito
NF-kBp27 c-Myc
Akt
Cytc
Caspase-1Caspase-3
p300 CBP
AC FoxO PFoxO
14-3-3
Fas LBim
NoxaTRAIL
p53
Cancer inhibition
14-3-3P
Active FoxOProteins P
SIRT1
Molecular level cell fate decisions
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• 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
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• 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
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TSGs Apoptosis
Senescence
Differentation: restricted growth
Benign cancer cells with limited proliferative potential
Differentation:acquisition ofself-renewal
potential Malignant cancerstem cell Heterogeneous malignant
stem cell tumour
Cancer stem cells escape routine elimination
Polycomb group proteinsOncogenic hits
Polycomb group proteins
Oncogenic hits
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Senescence
Senescencedefect
Apoptosis
Apoptosisdefect
Failsafedefect
TP53mutationARF
INK4A
INK4A
Apoptosis
Tumour
Tumour
Tumour
TP53mutation
TP53mutation
Normal cells
Normal cells
Normal cells
Drug-resistanttumour
Drug-resistanttumour
Drug-resistanttumour
Apoptosisdefect
Senescencedefect
Apoptosis
Senescence
RAS
MYC Therapy
Therapy
Therapy
p53
p53
p53
Bcl-xL
Oncogene
Malignant tumorescape mechanisms I
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Apoptotic cell death
Senescence induction
Malignant populationTherapy (DNA damage)
Terminal arrest Immune attraction Growth promotion EscapeBeneficial Detrimental
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? ? ?
Malignant tumorescape mechanisms II
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• 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
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• 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
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MDS/AMLCancerGenomic instability
Telomerase complexTERT TERC
DKC1
Constant increased recruitmentof stem cells into cell cycle
Cell cycle arrest/cell deathof progenitor cells
Cancer development and telomeres
Short telomeres
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Spontaneous telomere
stabilization
CrisisDivisions
Express TERT
Divisions
Express TERT
Express TERT
Express TERT
Telomere shortening
RB and p53inactivation
Senescence Immortality
Telomeremaintenance
Acquiring immortality via telomerase
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• 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
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• 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
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Acetylated histone tails
Methylatedhystone tails
Methylated DNA(CpG dinucleotides)
Transcription
CO-ACT
HAT
Epigenetic silencing
K4 HMT
TAF
TBP RNA-PIITF
HDACHP1DNMT1
MBDCO-REP
CAF-1
MBDK9 HMT
Acetylation status andepigenetic silencing I
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Methylated histone tails
Acetylated histone tails
Deacetylated hystone tails
Stable repression of cyc E and other growth-promoting
genes
HeterochromatinDNMT1?
RBHDACE2F
SUV39H1HP1?
E2F site
Transcription of cyc E and other growth-promoting genes
Euchromatin
E2F site
p300Cyc ECdk2
E2FP
p300/CBP
Acetylation status andepigenetic silencing II
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Cancer epidemiology worldwide
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• 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
Cancer statistics
