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Silvio De Flora

E’ POSSIBILE PREVENIRE I TUMORI?

Dipartimento di Scienze della Salute

Università degli Studi di Genova

GE

NUEN

SE

ATHE

NAE

UM

Coordinatore GdL SItI Prevenzione Tumori / Screening

Genova, Seminario UNiTE, 01/03/2017

IL GIURAMENTO DI IPPOCRATE

Giuro su Apollo il medico e Asclepio e Igea e Panacea e tutti i dei e le dee, facendoli miei testimoni, che terrò fede a questo giuramento secondo la mia capacità e il mio giudizio….

Asclepio Panacea Igea

Ippocrate

0

100

200

300

400

500

1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000

ACCRESP

1407

DIG

INF

THE EPIDEMIOLOGICAL REVOLUTION OF THE 20th CENTURY

S. De Flora, A. Quaglia, C. Bennicelli & M. Vercelli, FASEB J. 19, 892–897, 2005

De

ath

s p

er

10

0,0

00

ITALY, 1901–2000 (RAW MORTALITY DATA)

0

100

200

300

400

500

1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000

ACCRESP

1407

DIG

INF

CER

CARD

CAN

De

ath

s p

er

10

0,0

00




0

100

200

300

400

500

1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000

CAN

DIG

ACCRESP

INF

1436

CER

CARD

De

ath

s p

er

10

0,0

00

ITALY, 1901–2000 (AGE-STANDARDIZED MORTALITY DATA)

–72.4%–74.4%

–51.9%–67.9%

M

M

F

F

CEREBROVASCULARDISEASES

CARDIOVASCULARDISEASES

–18.3%

–12.9%

MF

CANCER

1 2 3



0

100

200

300

400

500

1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000

ACCRESP

1407

DIG

INF

CER

CARD

CAN

De

ath

s p

er

10

0,0

00




METABOLIC DEACTIVATION OF MUTAGENSS. De Flora, Nature 271, 455-456, 1978

CHROMIUM(VI) REDUCING CAPACITY OF ORGANS, CELL

POPULATIONS AND FLUIDS IN THE HUMAN DIGESTIVE SYSTEM

De Flora et al., Carcinogenesis 18, 531–537, 1997

PORTAL SYSTEM BLOOD

[187 - 234 mg Cr(VI)]

INTESTINAL BACTERIA

[11 – 24 mg Cr(VI) eliminated

daily with bacteria in feces]

GASTRIC JUICE

[> 84 – 88 mg Cr(VI)/day]

SALIVA [0.7 – 2.1 mg Cr(VI)/day]

LIVER CELLS

[3,300 mg Cr(VI)]

BRONCHIAL

TREE CELLS

PERIPHERAL

LUNG PARENCHYMA

CELLS [260 mg Cr(VI)]

ELF [0.9 – 1.8 mg Cr(VI)]

PAM [136 mg Cr(VI)]

BLOOD

[187 – 234 mg Cr(VI)]

CHROMIUM(VI) REDUCING CAPACITY OF ORGANS, CELL

POPULATIONS AND FLUIDS IN THE HUMAN RESPIRATORY TRACTDe Flora et al., Carcinogenesis 18, 531–537, 1997

0

100

200

300

400

500

1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000

ACCRESP

1407

DIG

INF

CER

CARD

CAN

De

ath

s p

er

10

0,0

00




IL CANCRO IN ITALIA

Sede del cancro

Tutte le sedi

Colon-retto

Mammella

Polmone

Prostata

Vescica

Pancreas

Stomaco

N. di casi

(AIRTUM, 2016)

365.000

(190.000 M,

176.000 F)

52.000

50.000

41.000

35.000

27.000

13.500

13.000

N. di morti

(ISTAT, 2013)

176.000

(99.000 M,

77.000 F)

19.000

12.000

33.000

7.000

5.600

11.000

10.000

Prevalenza

(2015)

2.200.000 (2006)

3.000.000 (2015)

(4,7% M, 5,3% F)

427.000

693.000

88.000

399.000

254.000

Dal 2008 al 2016 diminuzione annuale del 2,5% nei maschi, piccolo aumento

nelle femmine (da 169.000 nuovi casi nel 2015 a 176.000 nel 2016)

Dal 2008 al 2013 diminuzione nei maschi (-1,5% annuo) e nelle femmine

(-0,7% annuo)

Rossi et al., 2013

MASCHI FEMMINE

INCIDENZA E MORTALITA’ DEI TUMORI IN ITALIA (1970-2015, DATI STANDARDIZZATI PER ETA’)

IL CANCRO NEL MONDO

Ogni anno il cancro è diagnosticato in più di 14 milioni di individui

Nel 2015, 8,8 milioni di individui sono morti di cancro, 2/3

in paesi a basso-medio reddito

Il cancro rappresenta globalmente 1/6 delle cause di morte

Oltre ad un immenso carico di sofferenze umane, questo

comporta un costo enorme, valutato in 1.160 miliardi di $

all’anno

Le previsioni sono che in pochi anni (da ora al 2030) il numero

di nuovi casi di cancro nel mondo aumenterà del 50%, e cioè

da 14 a 21 milioni, e il numero di morti sarà di 13 milioni

MAINSTREAM

SMOKE

SIDESTREAM

SMOKE

ENVIRONMENTAL

CIGARETTE

SMOKE (ECS)

Year

MALES FEMALES

0

10

20

30

40

50

60

70

80

90

100

0

10

20

30

40

50

60

70

80

90

100

De

ath

sp

er

10

0,0

00CRUDE DATA

AGE-STANDARDIZED DATA

Lung and stomach cancers in Italy

DIETA, ALIMENTAZIONE E CANCRO

FATTORI DI RISCHIO FATTORI PROTETTIVI

Dieta ipercalorica

Dieta iperproteica ?

Dieta iperglucidica (carboidrati semplici)?

Dieta iperlipidica (< 30% Cal; < 10% a. grassi saturi)

Contaminanti naturali (micotossine)

Componenti naturali (idrazine, pesticidi naturali)

Contaminanti artificiali (pesticidi)

Conservanti/additivi/coloranti

Precursori di cancerogeni endogeni

Eccesso di NaCl

Salatura alimenti

Affumicatura alimenti

Abbrustolimento e frittura alimenti

Eccessiva temperatura

Esercizio fisico

Inibitori nitrosazione (Vit. C)

Conservazione alimenti

a bassa temperatura

Forni a microonde

Vitamine antiossidanti (A, ac. folico, C, E)

Elementi chimici (Se, Ca)

Clorofillina

Vari composti protettivi (crucifere)

Fibre indigeribili

Prodotti lattiero-caseari fermentati

Frutta e verdura, bevande (vino, thé)

HPV

HPV

HPV

HPV

HPV

HPV

HBV HCV

HBV HCVHBV HCV

HBV HCV

H.P.

H.P.

EBV

HHV-8HIV

Infectious agents cause 17% of allcancers worldwide,

26% in developing world, 8% in developed world

Labbra e

cavità orale

Melanoma

ESPOSURE OF HAIRLESS MICE TO

HALOGEN LAMPS

S. De Flora & F. D’Agostini, Nature, 1992

CARCINOGENICITY OF THE LIGHT EMITTED BY

HALOGEN LAMPS

WITH COVERWITHOUT COVER

DISEASES

EXPOSURE MARKERS

EFFECTIVE DOSE

EARLY BIOLOGICAL DAMAGE

BIOLOGICALLY

DECODING THE BLACK BOX

Mutagenicity of escreta

Protein adducts

DNA adducts

8-oxo-dG

Metabolic alterations

DNA damage and repair

Cytogenetic effects

Activation of oncogenes

Deletion/mutation of oncosuppressor genes

Proliferation, differentiation, apoptosis, etc.

Analysis of metabolites

RISK

FACTORS

RISK

FACTORS

EXPOSURE MARKERS

EFFECTIVE DOSE

EARLY BIOLOGICAL DAMAGE

BIOLOGICALLY

Mutagenicity of escreta

Protein adducts

DNA adducts

8-oxo-dG

Metabolic alterations


Cytogenetic effects

Activation of oncogenes

Deletion/mutation of oncosuppressor genes

Proliferation, differentiation, apoptosis, etc.

Analysis of metabolites

STOP

PROTECTIVE FACTORS DISEASESMOLECULAR EPIDEMIOLOGY OF

ATHEROSCLEROSIS

S. De Flora et al., FASEB J. 11: 1021-1031, 1997

The levels of 32P postlabeled DNA adducts in the aorta from

85 atherosclerotic patients were significantly correlated with:

-Age of patients

-Number of cigarettes

-High blood pressure

-Blood triglycerides

-Blood cholesterol (total/HDL)

-SFS-positive DNA adducts

-8-Oxo-dGuo S. De Flora & A. Izzotti,

Mutat. Res. 667, 15–26, 2009

DNA DAMAGE, DNA REPAIR, AND TAU ALTERATIONS IN MOUSE BRAIN

S. La Maestra et al., Toxicol. Sci., 2011

Wildtype

FHIT +/–

Time (days)

Mic

e w

ith

alo

pe

cia

(%

)

INHIBITION OF ALOPECIA BY NAC AND BUDESONIDE

R. Balansky et al., Proc. Natl Acad. Sci. USA 103, 7823–8, 2006

8-oxo-dG LEVELS IN THE EYE TRABECULAR MESHWORK

(A. Izzotti et al., Am. J. Med. 114, 638-646, 2003)

25

20

15

10

5

0

GSTM1 - null GSTM1 +

Glaucoma patients (n = 39)

GSTM1 - null GSTM1 +

Controls (n = 47)

8–

ox

o–

dG

/10

5 n

ucle

oti

de

s

PROLIFERATION AND CHRONIC DEGENERATIVE DISEASES

Genetic predisposition


Oxidative stress

Chronic inflammation

Epigenetic mechanisms

CancerAtherosclerotic

plaque

Degenerative

diseases of

the myocardium

Neuro-

degenerative

diseases

CARDIOVASCULAR

DISEASES

CANCER

DIAGNOSIS

THERAPY

EPIDEMIOLOGY

PREVENTION

RISK FACTORS AND PROTECTIVE FACTORS

THE ICEBERG OF CHRONIC DEGENERATIVE DISEASES

COPD

THE 'OMICS TECHNOLOGIES

PROTEOME

Proteins

GENOME

DNA

Color ed by: SHAM vs CS, Default I nt er pret at ion ( sham. t xt )

Gene List : mm u ( 484)

MIRNOME

microRNAmRNA

TRANSCRIPTOME

Chronic

degenerative

diseases and

critical

periods of

life

PROTECTIVE FACTORS

S. De Flora & A. Izzotti, Mutat. Res., 667, 15–26, 2009

126 / 484 miRNAs

(26.0%)

downregulated by ECS

107 / 4858 genes

(2.9%)

upregulated by ECS

50 / 518 proteins

(9.7%)

upregulated by ECS

A. Izzotti et al., FASEB J. 23, 806–812, 2009

mRNA

SHAM

Proteins

SHAM

1000 10000

1000

10000

DNA

ENVIRONMENTAL CIGARETTE SMOKE IN RAT LUNG

MicroRNA

SHAM

0,01 0,1 1 10 100

0,01

0,1

1

10

100

CIG

AR

ETTE

SM

OK

E

BENIGN TUMOR

INITIATION(days - weeks)

PROMOTION(years - decades)

CANCER

PROGRESSION(~ 1 year)

INVASION

Exposure dose

Pharmacologic dose

Cellular dose

Target dose

Molecular dose

TOXICOKINETIKS

AND METABOLISM

DNA DAMAGE

AND REPAIR

CARCINOGENESIS

PROCESS

NEOPLASTIC MASS

S. De Flora et al., Mutat. Res. 480-481, 9-22, 2001

5

0

10

15

20

25

30

35

10

10

10

10

10

10

10

10

10

10

10

10

0

1

2

3

4

5

6

7

8

9

10

11

10

10

10

10

10

10

10

10

10

10

10

10

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

1

2

Cell

divisions

No. of

cells

Weight

(g)

GROWTH OF THE

NEOPLASTIC MASS

1240 10

310

METASTASIS

PRIMARYPREVENTION

SECONDARY

THERAPY -REHABILITATION

INTERVENTION

STRATEGIES

C

H

E

M

O

P

R

E

V

E

N

T

I

O

N

TERTIARYPREVENTION

PREVENTION

CRESCITA DI SARCOMA DI KAPOSI UMANO IN TOPI NUDI

A. Albini et al., Cancer Res. 61, 8171-8178, 2001

MASCHI

FEMMINE

3 ) +

Vo

lum

e d

el

tum

ore

(c

m

)

0

0.5

1.0

1.5

0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

CONTROLLI

Tempo (giorni)5 10 15 20 25 30

3

+

NAC

5 10 15 20 25 30

FEMMINE

MASCHI

1. Inhibition of mutation and cancer initiation in the extracellular environment or in nontarget cells1.1. Inhibition of uptake of mutagens/carcinogens

1.1.1. Inhibition of penetration

1.1.2. Removal from the organism

1.2. Inhibition of the endogenous formation of mutagens

and carcinogens

1.2.1. Inhibition of the nitrosation reaction

1.2.2. Modification of the intestinal microbial flora

1.3. Complexation, dilution and/or deactivation of

mutagens/carcinogens outside cells

1.3.1. By physical or mechanical means

1.3.2. By chemical reaction

1.3.3. By enzyme–catalyzed reaction

1.4. Favoring absorption of protective agents

1.5. Stimulation of trapping and detoxification in nontarget cells

2. Inhibition of mutation and cancer initiation in target cells2.1. Modification of transmembrane transport

2.1.1. Inhibition of cellular uptake

2.1.2. Stimulation of extrusion outside cells

2.2. Modulation of metabolism

2.2.1. Inhibition of activation of promutagens/ procarcinogens by

Phase I enzymes

2.2.2. Induction of Phase I detoxification and Phase II

conjugation pathways, or acceleration of decomposition

of reactive metabolites

2.2.3. Stimulation of activation, coordinated with

detoxification and blocking of reactive metabolites

2.3. Blocking or competition

2.3.1. Trapping of electrophiles by either chemical reaction or

enzyme–catalyzed conjugation

2.3.2. Antioxidant activity and scavenging of reactive species

2.3.3. Protection of DNA nucleophilic sites

2.4. Inhibition of cell replication

2.5. Maintenance of DNA structure and modulation of DNA metabolism and repair

2.5.1. Increase of fidelity of DNA replication and repair

2.5.2. Stimulation of repair and/or reversion of DNA damage

2.5.3. Inhibition of error-prone repair pathways

2.5.4. Correction of hypomethylation

2.5.5. Inhibition of histone deacetylation

2.5.6. Blocking of telomerases or inhibition of their activity

2.6. Control of gene expression

2.6.1. Targeted inactivation of oncogenes

2.6.2. Inhibitionofoncogene expression

2.6.3. Inhibition of oncogene sequences or activity

2.6.3.1. Inhibition of translation targeted to oncogene mRNA

2.6.3.2. Inhibition of transcription of specific DNA sequences

2.6.3.3. Blocking of target genes

2.6.2.4. Farnesyltransferase inhibition

2.6.4. Neutralization or post–translational modification of oncogene products

2.6.5. Replacement of deleted tumor suppressor genes

2.6.6. Mimicking the DNA binding of tumor suppressor genes by antiidiotypic antibodies

2.6.7. Killing of cells lacking tumor suppressor genes

3. Inhibition of tumor promotion3.1. Inhibition of genotoxic effects (see 1 and 2)

3.2. Antioxidant activity and scavenging of free radicals

3.3. Antiinflammatory activity

3.3.1. Cyclooxygenase inhibition

3.3.2. Lipooxygenase inhibition

3.3.3. Inhibition of inducible nitric oxide synthase

3.3.4. Leukotriene receptor antagonism

3.4. Inhibition of proteases

3.5. Inhibition of cell proliferation

3.5.1. Inhibition of ornithine decarboxylase

3.5.2. Promoting proteasomal degradation of cyclins

3.5.3. Interference with multiple signaling pathways

3.6. Induction of cell differentiation

3.7. Modulation of cell apoptosis

3.8. Signal transduction modulation

3.9. Protection of intercellular communications

4. Inhibition of tumor progression4.1. Inhibition of genotoxic effects (see 1 and 2)

4.2. Antioxidant activity and scavenging of free radicals

4.3. Inhibition of proteases


4.5. Effects on the hormonal status

4.5.1. Selective estrogen receptor modulation

4.5.2. Aromatase inhibition

4.5.3. Selective blocking of prostaglandin E2 receptors

4.5.4. Decrease in ovarian hormones by dietary isoflavones

4.5.5. Inhibiting the pituitary secretion of luteinizing hormone

4.5.6. Preventing conversion of testosterone into

dehydrotestosterone by 5a–reductase

4.5.7. Selective androgen receptor antagonism

4.6. Effects on the immune system

4.7. Inhibition of angiogenesis

4.8. Antineoplastic activity by either mechanical, physical, chemical, or biological means

5. Inhibition of invasion and metastasis5.1. Antioxidant activity and scavenging of free radicals


5.3. Inhibition of cell proliferation (see 3.4)

5.4. Modulation of cell apoptosis

5.5. Induction of cell differentiation

5.6. Inhibition of angiogenesis

5.7. Effect on cell-adhesion molecules

5.8. Inhibition of proteases involved in basement membrane degradation and

modulation of the interaction with the extracellular matrix

5.9. Activation of antimetastasis genes

MECHANISMS OF CANCER CHEMOPREVENTIVE AGENTS

S. De Flora and L.R. Ferguson, Mutat. Res., 591, 8–15, 2005

PRIMARY PREVENTION

SECONDARY PREVENTION

TERTIARY PREVENTION

S. De Flora and C. Ramel, Mutat. Res., 202, 285–306, 1988

PREVENTION OF LUNG TUMORS IN MICE

NUMBER OF TUMORS/MOUSE

0.35

CONTROLS

(STANDARD DIET)

11.06

URETHANE

(STANDARD DIET)

1.95

URETHANE

(DIET WITH NAC 0.2%)

S. De Flora et al., Cancer Lett. 32, 235-241,1986

PASSIVE SMOKING IN MUTANT MICE

S. De Flora et al. Molecular alterations and lung tumors in P53mutant mice exposed to cigarette smoke. Cancer Res. 63, 793–800, 2003

A. Izzotti et al. Gene expression in the lung of P53 mutant mice exposed to cigarette smoke. Cancer Res. 64, 8566–72, 2004

P53

F. D’Agostini et al. Early loss of Fhit in the respiratory tract of rodents exposed to environmental smoke. Cancer Res. 66, 3936–41, 2006

S. De Flora et al. Molecular alterations induced by cigarette smoke in mice heterozygous for Fhit. Cancer Res. 67, 1001–6, 2007

R. Balansky et al. Influence of Fhit on benzo(a)pyrene induced tumors and alopecia in mice. PNAS 103, 7823–8, 2006

Fhit

Phenethyl

Isothiocyanate Blackberry Myo-inositol N-Acetylcysteine Strawberry Ascorbic acid

Natural

agents

DIETARY AND PHARMACOLOGICAL AGENTS THAT HAVE BEEN TESTED FOR

THE ABILITY TO INTERFERE IN CIGARETTE SMOKE CARCINOGENESIS(S. De Flora et al., Trends Pharmacol. Sci. 37, 120-142, 2016)

Budesonide Aspirin Naproxen Licofelone Celecoxib

Anti-

inflammatory

drugs

Antidiabetic

drugsMetformin Pioglitazone

Bexarotene

Anticancer

drugs

Vorinostat Lapatinib

Gender

LIGANDS OF THE NUCLEAR

HORMONE SUPERFAMILYReference

Pioglitazone

(PPAR-γ-ligand)M

F

M+F

8.7

0

0

0

0

0

0

0

0

Izzotti et al.,

Carcinogenesis, 2013

La Maestra et al.,

Carcinogenesis, 2013

IbidemBexarotene or Targretin ® (RXR-

specific retinoid)

M

F

M+F

0

0

0

12.2

0

0

0

0

0

PIOGLITAZONE

BEXAROTENE

Microadenomas Adenomas Malignant tumors

Pioglitazone +

BexaroteneM

F

M+ F

2.6

0

0

0

0

0

78.2

100

89.2

Ibidem

SHAM NAC OPZ OPZ+ NAC

5,6-BF PEITC I3C PEITC+ I3C

A. Izzotti et al., Mutat. Res. 591, 212–223, 2005

SMOKE-FREE RATS

ECS NACOPZ OPZ+ NAC

5,6-BF PEITCI3C PEITC+ I3C

SMOKE-EXPOSED RATS

EXPRESSION OF 4858 GENES IN RAT LUNG

SAFETY EFFICACY

-0.4 -0.3 0.20.10-0.1-0.2 0.80.70.60.50.40.3

0.2

0.1

0

-0.1

-0.2

0.6

0.5

0.4

0.3

ECS + BF

ECS + OPZECS + I3C

ECS + NAC

ECS + PEITC

ECS + OPZ + NAC

ECS + PEITC + I3C

SHAM

ECS

NAC

OPZ PEITC + I3C

PEITC

NAC + OPZBFP

CA

co

mp

on

en

t 2

PCA component 1

EFFECT OF ENVIRONMENTAL CIGARETTE SMOKE AND

CHEMOPREVENTIVES ON miRNA EXPRESSION IN RAT LUNG

A. Izzotti et al, Cancer Prev. Res. 3, 62–72, 2010

LUNG miRNAs

Emphysema-free lung

Em

physe

ma-

bea

ring

lung

Mic

road

enom

as-

bea

ring

lung

Microadenoma-free lung

Alveolar hyperplasia-free lung

EMPHYSEMA

ALVEOLAR

HYPERPLASIA

MICROADENOMAS

ADENOMA

Adenoma-free lung

Aden

om

a-bea

ring

lung

Alv

eola

rhyper

pla

sia-

bea

ring

lung

BLOOD miRNAs

Blood and lung microRNAs

as biomarkers of pulmonary

tumorigenesis in cigarette

smoke-exposed mice

Izzotti A., Balansky R., Ganchev G.,

Iltcheva M., Longobardi M., Pulliero A.,

Geretto M., Micale R.T., La Maestra S.,

Miller M.S., Steele V.E., De Flora S.

Oncotarget, 2016

TERTIARY PREVENTION(Treated cancer patients)

EARLY INTERVENTION(Cancer patients in preclinical or early stage)

PREVENTION OF PROGRESSION(Individuals affected by precancerous lesions)

TARGETED CHEMOPREVENTION(High risk individuals)

PUBLIC HEALTH INTERVENTION(Healthy subjects in the population)

EFFICACY

LOW COST

PRACTICALITY

TOLERABILITY

REQUIREMENTS INTERVENTION (Targets)

S. De Flora et al., IARC Sci. Publ. No. 139, 1996, pp. 291-301

THERAPY (Cancer patients)

ACE inhibitors

Beta–blockers

Statins

Dexrazoxane

L–Carnitine

Coenzyme Q10

N–Acetyl–L–Cysteine

Glutathione

Erdosteine

Selenium

Zinc

Melatonin

Flavonoids and polyphenols

Platelet antiaggregants

Anthracyclines and

anthraquinolones

Capecitabine, Cytarabine,

5–Fluorouracil

Paclitaxel, Vinca alkaloids

Cyclophosphamide

TK Inhibitors (Trastuzumab,

Imatinib, Bevacizumab,

Sorafenib, Sunitinib, etc)

COX–2 inhibitors

Estrogen receptor modulators

Irradiation to the thorax

Mitochondrial dysfunction

Apoptosis of cardiomyocytes

ROS generation

DNA damage

Endothelial cell damage

Antibody directed cellular cytotoxicity

ATP block

Cell signaling, survival block

Fibrosis

Hypertension

Sinus bradicardia

Atrium-ventricular block

Ventricular tachycardia

Arrhythmias

Thromboembolism

Anticancer drugs Mechanisms of cardiotoxicity Protective agents

A. Albini, G. Pennesi, R. Cammarota, F. Donatelli, S. De Flora, D.M. Noonan,

Cardiotoxicity of anticancer drugs: The need for cardio-oncology and

cardio-oncological prevention, J. Natl Cancer Inst., 102, 14-25, 2010

ITALY, GENERAL MORTALITY DATA, 1901–2000

Rate

s p

er

100.0

00

0

5

15

25

30

35

1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000

10

20

ITALY, 1901Population: 33 millionDeaths: 726,000Mortality rate: 22‰

ITALY, 2000Population: 58 millionDeaths: 560,000Mortality rate: 9.7‰

ITALY, 2000

Population: 58 million

Mortality rate:

Deaths:

22‰

1,276,000



Francesco

D’Agostini

Carlo

Bennicelli

Anna

Camoirano

Silvio

De Flora

Sebastiano

La Maestra

Maria

Bagnasco

Ilaria

RighiRoumen

BalanskyAlberto

Izzotti

Rosanna

T. Micale

Cristina

Cartiglia

Mariagrazia

Longobardi

Tanya M.

Pennisi

UNIVERSITY OF GENOA, ITALY

DEPARTMENT OF HEALTH SCIENCES

Laboratory of Environmental Genomics and Cancer Prevention

Patrizia

Larghero

Alessandra

BattistellaAlessandra

Pulliero

Vinesh Kumar

Thidil

PulyappadambaGiorgia

Travaini

E’ POSSIBILE PREVENIRE I TUMORI? - sitinazionale.org · Giuro su Apollo il medico e Asclepio e...

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