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

TÁMOP-4.1.2-08/1/A-2009-0011

• 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

TÁMOP-4.1.2-08/1/A-2009-0011

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

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)

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

TÁMOP-4.1.2-08/1/A-2009-0011

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

??

? ? ?

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

TÁMOP-4.1.2-08/1/A-2009-0011

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

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

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

TÁMOP-4.1.2-08/1/A-2009-0011

Cancer epidemiology worldwide

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