CANCER: ETIOLOGIC AGENTS AND GENERAL MECHANISMS

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CANCER ETIOLOGIC AGENTS AND GENERAL MECHANISMS

• Salvador J. Diaz-Cano
• Roberto Mazzanti

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Basic Mechanisms in Neoplasms

• Genetic bases
• Basic aspects of tumorigenesis
• Correlation between genetics and kinetics

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I geni del cancro Il tumore è causato da
squilibrio fra divisione e morte cellulare
Numero di divisioni cellulari
Numero di morti cellulari
Omeostasi
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I geni del cancro Lo squilibrio fra divisione
e morte cellulare che causa il tumore è dovuto a
mutazioni nei geni che regolano i due
processi In virtù di ciò tali geni sono stati
chiamati geni del cancro oncogeni e geni
oncosoppressori
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I geni del cancro

• Condizione perché la mutazione di un gene del
  cancro induca il tumore
• Proto-oncogeni/oncogeni le mutazioni devono
  essere attivanti e si comportano come dominanti
  (basta che un solo allele sia mutato)
• Oncosoppressori e caretakers le mutazioni devono
  essere inattivanti e si comportano come recessive
  (è necessario che entrambi gli alleli siano
  mutati)

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Cancer General Pathways
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Cancer General Mechanisms

• Malignant lymphomas
• Sarcomas
• Carcinomas
• Malignant melanomas

• Single gross genetic abnormalities
• Translocations
• Multiple punctual genetic alterations
• Mutations
• LOH

Activating Mechanisms
Activating/Inactivating Mechanisms
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I geni del cancro
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I geni del cancro

• Gli eventi mutazionali che alterano i segnali
  mitotici e apoptotici e i geni coinvolti
• Attivazione permanente di geni inducenti la
  mitosi
• Attivazione permanente di geni inibenti
  lapoptosi
• Inattivazione permanente di geni inibenti la
  mitosi
• Inattivazione permanente di geni inducenti
  lapoptosi
• Inattivazione di geni che mantengono lintegrità
  del genoma (Geni caretakers)
• Gli oncogeni sinora identificati sono oltre un
  centinaio mentre gli oncosoppressori sono una
  ventina
• In genere si indicano con tre-quattro lettere in
  corsivo (es. myc, fos, bcl-2, ras)

Proto-oncogèni/Oncogèni
Geni oncosoppressori
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Genetic Lesions in Tumors

• Activating or inactivating
• Dominant / Recessive / Dominant negative
• Somatic or germline
• Genetic targets (oncogenes, tumor suppressor
  genes, mismatch repair genes)

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Genetic Mechanisms of Tumors

• Gene deletions / amplifications
• Mutations
• Insertional
• Point Mutations
• Genetic Instability
• Microsatellite Instability (MSI)
• Chromosomal Instability (CIN)

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Geni adibiti al riparo del DNA (caretakers)

• La loro mutazione è spesso alla base di sindromi
  neoplastiche familiari
• Prototipo sono i geni hMLH1, hPMS1e hPMS2,
  mutati nellHereditary Non Polyposis Colon Cancer
  (HNPCC) i geni BRCA-1 e BRCA-2, mutati nel
  carcinoma della mammella il gene ATM
  (atassia-teleangectasia)
• Tali geni sono implicati nel mismatch repair che
  corregge i difetti di appaiamento del DNA.
• La mutazione di questi geni non influenza
  direttamente la crescita cellulare né lapoptosi
  ma favorisce la trasformazione e accelera la
  progressione neoplastica.
• Gli individui affetti presentano instabilità di
  particolari regioni del DNA (coppie ripetute di
  1-6 nucleotidi) denominate microsatelliti

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Gene Inactivation

• Genetic Changes
• Inactivating mutation
• Interstitial DNA deletion
• Epigenetic Changes
• Promoter hypermethylation

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Genetic Instability in Tumors

• () Oncogenes
• (-) Tumor suppressor genes
• Telomere shortening
• Mismatch repair (MMR) genes

• Chromosomal Instability
• Microsatellite Instability

? Cause or tumor progression byproduct
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Telomeres and Cell Senescence
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Telomeres, Telomerase, and Cancer
Hahn, W. C. et. al. N Engl J Med
20023471593-1603
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Mismatch Repair and Microsatellites
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Alterations of Specific Cellular Functions in
Cancer
DNA Repair
Tumor Suppressor Genes Inactivation
Oncogenes Activation
Differentiation Apoptosis/Proliferation
CANCER
RM, 2010
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Specific Cellular Functions in Cancer Genetic
Alterations
Genetic Instability RER Phenotype
DNA Repair
CANCER
Tumor Suppressor Genes
Oncogenes
Interstitial Deletion Inactivating
Mutation Hypermethylation
Gene Amplification Gene Overexpression Activating
Mutation
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Progressive Acquisition of Neoplastic Features
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Molecular ProgressionMutation Accumulation
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Hallmarks of Cancer Cells

• Self-maintained replication
• Longer survival
• Genetic instability
• Capable of inducing neoangiogenesis
• Capable of invasion and metastasis

• Apoptosis down-regulation
• Lack of response to inhibitory factors
• Self-sustained proliferation

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Hallmarks of Cancer Cells

• Self-maintained replication
• Longer survival
• Genetic instability
• Capable of inducing neoangiogenesis
• Capable of invasion and metastasis

• Apoptosis down-regulation
• Telomerase reactivation

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Hallmarks of Cancer Cells

• Self-maintained replication
• Longer survival
• Genetic instability
• Capable of inducing neoangiogenesis
• Capable of invasion and metastasis

• Cooperative genetic damage
• Mutagenic agents
• Defective repair systems

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Hallmarks of Cancer Cells

• Self-maintained replication
• Longer survival
• Genetic instability
• Capable of inducing neoangiogenesis
• Capable of invasion and metastasis

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Basic Biologic Features of Neoplasms
Abnormal Proliferation
Differentiation
Angiogenesis
Invasion
Oncogenic Lesion (e.g. RAS, MYC, E2F Activation)
Senescence
Apoptosis
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Multistep Tumorigenesis
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Cancer Molecular Pathways
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Acquired Capabilities, Molecular Pathways, and
the Transformation of Human Cells Emerging Rules
That Govern Cancer Formation
Hahn, W. C. et. al. N Engl J Med
20023471593-1603
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Interactions between stroma and cancer cells
From Pietras K Ostman A., 2010
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Cancer General Etiology and Pathogenesis

• Etiologic agents
• Environmental (chemical, physical, and
  biological)
• Hereditary (familial cancer syndromes)
• General mechanisms
• Acquired capabilities (Self-maintained
  replication, longer survival, genetic
  instability, neoangiogenesis, invasion and
  metastasis)
• Activation of oncogenes, inactivation of TSG,
  non-effective DNA repair
• Caretaker and gatekeeper pathways

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Cancer General Etiology and Pathogenesis
Chronic - Inflammation
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Environmental vs. Hereditary Cancer
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Environmental Carcinogens

• A cancer-causing agent
• Three main types
• Chemical
• Physical (radiation)
• Biological (especially virus)

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Chemical Carcinogenesis

• Firstly described by Sir Percival Pott in 1775
• Chimney sweeps and scrotal cancer
• Relationship between occupational exposure to
  chimney soot and scrotal carcinoma was established

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Chemical Carcinogens

• Direct-acting
• Indirect-acting (must be metabolized to activated
  metabolic forms)

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Electrophiles

• Direct-acting carcinogens are already
  electrophilic
• Indirect-acting carcinogens are metabolically
  activated into electrophilic species

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Electrophilic Theory of Chemical Carcinogenesis

• Electrophilic (electron-seeking) molecules will
  bind to nucleophilic (electron-rich)
  macromolecules in the cell
• DNA
• RNA
• Proteins

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Direct-acting Carcinogens

• Nitrogen mustard
• Nitrosomethylurea
• Benzyl chloride

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Indirect-acting Carcinogens

• Polycyclic aromatic hydrocarbons (PAH)
• Produced by incomplete combustion of organic
  materials
• Present in chimney soot, charcoal-grilled meats,
  auto exhaust, cigarette smoke

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Ames Test

• Many synthetic and natural compunds in our
  environment have been screened by the Ames test
• Test is based upon correlation between
  carcinogenicity and mutagenicity

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Human carcinogens - environmental

• Creosote
• DDT
• Polycyclic aromatic hydrocarbons
• Radon
• Solar radiation

• Aflatoxins
• Asbestos
• Benzene
• Cadmium
• Coal tar

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Human carcinogens - drugs/therapeutic agents

• Adriamycin (doxorubicin)
• Androgenic steroids
• Chlorambucil
• Cisplatin
• Cyclophosphamide
• Cyclosporin A

• Diethylstilbestrol
• Ethylene oxide
• Melphalan
• Tamoxifen

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Physical Carcinogens

• Ultraviolet light
• Ionizing radiation (X-rays)
• Asbestos

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Skin cancer is one of the most common human
cancer and one of the most preventable

• 106 cases of BCC and SCC are diagnosed per year
• This is more than all other types of cancer
  combined
• Most of these will be caused by exposure to
  ultraviolet (UV) irradiation

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Lesione melanomatosa
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Asbestos

• Widely used in construction, insulation, and
  manufacturing
• Family of related fibrous silicates
• Chrysotile
• Crocidolite

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Fibre di asbesto
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Malignant Mesothelioma

• Mainly occurs in pleural and peritoneal cavities
• Rare in general population
• Latent period of 20 years

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Ionizing Radiation

• Death of pioneer radiation researchers from
  neoplasms
• High incidence of leukemia among radiologists
  recognized in 1940s
• Osteosarcoma incidence in radium dial painters

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Viral Carcinogenesis

• Viral infections account for an estimated one in
  seven human cancers worldwide
• Majority of these are due to infection with two
  DNA viruses
• HBV - linked to hepatocellular carcinoma
• HPV - linked to cervical carcinoma

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Oncogenic Viruses

• Human papillomaviruses - HPV
• Epstein-Barr Virus (EBV)
• Human herpesvirus 8 (HHV8)
• Hepatitis B virus - HBV
• Hepatitis C virus - HCV
• HTLV-I, HTLV-II

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Human papilloma virus (HPV)

• Over 70 subtypes
• DNA virus with small double-stranded circular
  genome
• Subtypes possess varying degrees of low risk and
  high risk

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Low and High Risk HPV

• HPV subtypes classified as low risk or high risk
  based on whether the genital tract lesions with
  which these HPVs are associated are at
  significant risk for malignant progression

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Epatoma
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Cirrothic liver and HCC
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EBV - Involvement in Human Tumors

• African Burkitt lymphoma
• B-cell lymphomas of immunosuppressed patients
• Some cases of Hodgkin lymphoma
• Nasopharyngeal carcinomas

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How Do Viruses like HPV and HBV Cause Cancer?

• Very small viruses
• Can integrate their viral DNA into host genome
• They code for viral proteins which block tumor
  suppressor proteins in cells

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Helicobacter pylori

• Gastric infection linked to gastric lymphomas and
  adenocarcinomas
• Detection of H pylori in majority of cases of
  gastric lymphomas
• Antibiotic treatment results in gastric lymphoma
  regression in most cases

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Environment-mediated drug resistance a major
contributor to minimal residual disease.
Meads Mb et Al, Nature reviewscancer, 2009
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Environment mediated drug resistance contributes
to MDR and acquired DR.
Meads MB et al. Nature reviewsCancer 2009