1. Manifestation of Novel Social Challenges of the European Union in the Teaching Material of 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

2. CANCER AND TUMOR DEVELOPMENT – SENESCENCE AND CANCER, EPIDEMIOLOGY AND STATISTICS Krisztián Kvell Molecular and Clinical Basics of Gerontology – Lecture 27 Manifestation of Novel Social Challenges of the European Union in the Teaching Material of 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

3. 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

4. TÁMOP-4.1.2-08/1/A-2009-0011 CaretakersCaretakers First line of defense, prevent genomic oncogenic mutations to occur GatekeepersGatekeepers Second line of defense, eliminate (by apoptosis) or senesce cells with oncogenic mutations Tumor suppressor genes

5. TÁMOP-4.1.2-08/1/A-2009-0011Human Mouse Common p16 p21 RB Senescence Culture stress Telomere shortening Telomere shortening p38 RAS p53 Molecular level senescence pathways ROS

6. TÁMOP-4.1.2-08/1/A-2009-0011 Nuclear translocation Anti-inflammationAnti-inflammation Cell cycle arrest Cell DNA cleavage cleavage PS exposure Inflammatory cell activity Inflammatory Cytoplasmic localization Ubiquitination and degradation of FoxO Ubiquitination and degradation of FoxO Apoptosis blockade JNK Mito Akt Cytc Caspase-1 Caspase-3 14-3-3 Cancer inhibition 14-3-3 PP Active FoxO Proteins Active FoxO Proteins PP SIRT1 Molecular level cell fate decisions

7. TÁMOP-4.1.2-08/1/A-2009-0011 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) I p53 has ambivalent talents I

8. TÁMOP-4.1.2-08/1/A-2009-0011 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 II p53 has ambivalent talents II

9. TÁMOP-4.1.2-08/1/A-2009-0011 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

10. TÁMOP-4.1.2-08/1/A-2009-0011 Senescence defect Senescence defect Apoptosis defect Apoptosis defect Failsafe defect Failsafe defect TP53 mutation TP53 mutation ARF INK4A Apoptosis Tumour TP53 mutation TP53 mutation TP53 mutation TP53 mutation Normal cells Drug-resistant tumour Drug-resistant tumour Drug-resistant tumour Apoptosis defect Apoptosis defect Senescence defect Senescence defect Apoptosis Senescence RAS MYC Therapy p53  Bcl-xL Oncogene I Malignant tumor escape mechanisms I

11. TÁMOP-4.1.2-08/1/A-2009-0011 Apoptotic cell death Senescence induction Malignant population Therapy (DNA damage) Terminal arrestImmune attractionGrowth promotionEscape BeneficialDetrimental ? ? ? ? ? II Malignant tumor escape mechanisms II

12. TÁMOP-4.1.2-08/1/A-2009-0011 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

13. TÁMOP-4.1.2-08/1/A-2009-0011 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

14. TÁMOP-4.1.2-08/1/A-2009-0011 MDS/AML Cancer MDS/AML Cancer Genomic instability Telomerase complex TERT  TERC  DKC1  Constant increased recruitment of stem cells into cell cycle Constant increased recruitment of stem cells into cell cycle Cell cycle arrest/cell death of progenitor cells Cell cycle arrest/cell death of progenitor cells Cancer development and telomeres Short telomeres

15. TÁMOP-4.1.2-08/1/A-2009-0011 Spontaneous telomere stabilization Spontaneous telomere stabilization Crisis Divisions Express TERT Express TERT Divisions Express TERT Express TERT Express TERT Express TERT Express TERT Express TERT Telomere shortening RB and p53 inactivation RB and p53 inactivation Senescence Immortality Telomere maintenance Telomere maintenance Acquiring immortality via telomerase

16. TÁMOP-4.1.2-08/1/A-2009-0011 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 I Antagonistic pleiotropy: telomere length I

17. TÁMOP-4.1.2-08/1/A-2009-0011 Rodent strategy:Rodent strategy: high annual mortality, low chances of cancer development = long telomeres, active telomerase to fight ROS Primate strategy:Primate strategy: low annual mortality, elevated chances of tumors = short telomeres, lack of telomerase to fight cancer II Antagonistic pleiotropy: telomere length II

18. TÁMOP-4.1.2-08/1/A-2009-0011 Acetylated histone tails Methylated hystone tails Methylated DNA (CpG dinucleotides) Transcription CO-ACT HAT Epigenetic silencing K4 HMT TAF TBP RNA-PII TF I Acetylation status and epigenetic silencing I

19. TÁMOP-4.1.2-08/1/A-2009-0011 Methylated histone tails Acetylated histone tails Deacetylated hystone tails Stable repression of cyc E and other growth- promoting genes Heterochromatin DNMT1? RB HDAC E2F SUV39H1 HP1? SUV39H1 HP1? E2F site Transcription of cyc E and other growth-promoting genes Euchromatin E2F site p300 Cyc E Cdk2 E2F P p300/CBP II Acetylation status and epigenetic silencing II

20. TÁMOP-4.1.2-08/1/A-2009-0011 Cancer epidemiology worldwide

21. TÁMOP-4.1.2-08/1/A-2009-0011 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