Cancer and tumor development – Senescence and cancer , epidemiology and statistics

1. 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 Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

2. 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 Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Krisztián Kvell Molecular and Clinical Basics of Gerontology – Lecture 27 Cancer and tumor development – Senescence and cancer, epidemiologyandstatistics

3. DNA damage-triggered cell fate responses Exogenous Effects DNA Damage Endogenous Effects p53 Transcription of Candidate Genes Cell cycle-stop Oxidative Stress Apoptosis DNA Repair Differentation Angiogenesis

4. Tumor suppressor genes • CaretakersFirst line of defense, prevent genomic oncogenic mutations to occur • GatekeepersSecond line of defense, eliminate (by apoptosis) or senesce cells with oncogenic mutations

5. Molecular level senescence pathways Human Culture stress Mouse Common Telomere shortening RAS p16 p38 p53 ROS p21 RB Senescence

6. Molecular level cell fate decisions CBP p300 FoxO Active FoxO Proteins P SIRT1 P Akt Fas L Noxa p27 c-Myc Bim TRAIL NF-kB p53 JNK AC 14-3-3 Nuclear translocation FoxO Cytoplasmic localization P Mito 14-3-3 Anti-inflammation Ubiquitination and degradation of FoxO Cytc Cell cycle arrest Caspase-3 Caspase-1 Apoptosis blockade Cancer inhibition PS exposure Cell DNA cleavage Inflammatory cell activity

7. p53 has ambivalent talents I • 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)

8. p53 has ambivalent talents II • 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

9. Cancer stem cells escape routine elimination Polycomb group proteins Oncogenic hits Apoptosis TSGs Senescence Oncogenic hits Benign cancer cells with limited proliferative potential Differentation: restricted growth Differentation: acquisition ofself-renewal potential Malignant cancer stem cell Heterogeneous malignant stem cell tumour Polycomb group proteins

10. Malignant tumorescape mechanisms I Apoptosis Senescence MYC Therapy TP53 mutation p53 ARF Bcl-xL Apoptosis defect Senescence defect INK4A Drug-resistant tumour Normal cells Tumour Apoptosis Senescence RAS Therapy TP53 mutation p53 INK4A Senescence defect Apoptosis defect Normal cells Tumour Drug-resistant tumour Apoptosis Oncogene Therapy TP53 mutation p53 Failsafe defect Normal cells Tumour Drug-resistant tumour

11. Malignant tumorescape mechanisms II Malignant population Therapy (DNA damage) ? ? Senescence induction Apoptotic cell death ? ? ? Terminal arrest Immune attraction Growth promotion Escape Beneficial Detrimental

12. p53 polymorphisms in cancer and longevity • Codon 72, proline → arginine, (evolutionarily late SNP), higher apoptotic efficiency • Mdm2 gene, G allele means more supressionand 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

13. Antagonistic pleitropy: p53 and p16 • 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

14. Cancer development and telomeres Constant increased recruitment of stem cells into cell cycle TERT TERC Telomerase complex DKC1 MDS/AML Cancer Short telomeres Genomic instability Cell cycle arrest/cell death of progenitor cells

15. Acquiring immortality via telomerase Express TERT Express TERT Express TERT Express TERT Spontaneous telomere stabilization RB and p53 inactivation Divisions Divisions Senescence Crisis Immortality Telomere shortening Telomere maintenance

16. Antagonistic pleiotropy:telomere length I • 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

17. Antagonistic pleiotropy:telomere length II • 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

18. Acetylation status andepigenetic silencing I Transcription K4 HMT HAT CO-ACT TAF TF TBP RNA-PII CAF-1 HDAC HP1 DNMT1 MBD CO-REP K9 HMT MBD Epigeneticsilencing Acetylatedhistonetails Methylated hystonetails MethylatedDNA (CpGdinucleotides)

19. Acetylation status andepigenetic silencing II Euchromatin Transcription of cyc E and othergrowth-promotinggenes p300 Cdk2 Cyc E P E2F E2F site p300/CBP Heterochromatin DNMT1? Stablerepression of cyc E and othergrowth-promotinggenes RB HDAC E2F Acetylatedhistonetails E2F site Deacetylatedhystonetails SUV39H1 HP1? Methylatedhistonetails

20. Cancer epidemiology worldwide

21. Cancer statistics • 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