cancer et mech
TRANSCRIPT
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CANCER: ETIOLOGIC
AGENTS AND GENERALMECHANISMS
Salvador J. [email protected]
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CANCER BIOLOGY
Causes of Cancer:General Etiology
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Cancer: General Etiology andPathogenesis
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Environmental vs .
Hereditary Cancer85
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Cancer Etiology
Environmental Hereditary
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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 Pottin 1775
– Chimney sweeps and scrotal cancer
– Relationship between occupationalexposure 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 alreadyelectrophilic
• Indirect-acting carcinogens aremetabolically activated intoelectrophilic species
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Electrophilic Theory of
Chemical Carcinogenesis• Electrophilic (electron-seeking)
molecules will bind to nucleophilic(electron-rich) macromolecules in thecell
– 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 combustionof organic materials
• Present in chimney soot, charcoal-
grilled meats, auto exhaust, cigarettesmoke
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Ames Test
• Many synthetic and naturalcompunds 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• Aflatoxins
• Asbestos
• Benzene
• Cadmium
•
Coal tar
• Creosote
• DDT
• Polycyclicaromatichydrocarbons
• Radon
• Solar radiation
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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 mostcommon human cancer andone of the most preventable
• ~106 cases of BCC and SCC are
diagnosed per year
• This is more than all other types ofcancer combined
• Most of these will be caused byexposure to ultraviolet (UV)irradiation
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Asbestos
• Widely used in construction,insulation, and manufacturing
• Family of related fibrous silicates
• Chrysotile
• Crocidolite
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Malignant Mesothelioma
• Mainly occurs in pleural andperitoneal cavities
• Rare in general population
• Latent period of ≥20 years
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Ionizing Radiation
• Death of pioneer radiationresearchers from neoplasms
• High incidence of leukemia amongradiologists recognized in 1940s
• Osteosarcoma incidence in radium
dial painters
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Viral Carcinogenesis• Viral infections account for an
estimated one in seven humancancers worldwide
• Majority of these are due to infectionwith 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 degreesof low risk and high risk
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Low and High Risk HPV
• HPV subtypes classified as low riskor high risk based on whether the
genital tract lesions with which theseHPVs are associated are atsignificant risk for malignant
progression
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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 whichblock 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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Basic Mechanisms:General Pathogenesis
CANCER BIOLOGY
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Cancer:
General
Pathways
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Basic Mechanisms in
Neoplasms• Genetic bases
• Basic aspects of tumorigenesis
– Correlation between genetics and
kinetics
C G l
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Cancer GeneralMechanisms
• Single “gross” genetic
abnormalities
– Translocations
• Multiple “punctual”
genetic alterations
– Mutations
– LOH
• Malignantlymphomas
• Sarcomas
• Carcinomas• Malignant
melanomas
Activating Mechanisms
Activating/Inactivating Mechanisms
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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 repairgenes)
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Genetic Mechanisms ofTumors
• Gene deletions / amplifications
• Mutations
• Insertional
• Point Mutations
•
Genetic Instability• Microsatellite Instability (MSI)
• Chromosomal Instability (CIN)
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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
• (-) Tumorsuppressor genes
• Telomereshortening
• Mismatch repair(MMR) genes
• ChromosomalInstability
• MicrosatelliteInstability
? Cause or tumor progression byproduct
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Telomeres
and CellSenescence
T l T l d C
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Hahn, W. C. et. al. N Engl J Med 2002;347:1593-1603
Telomeres, Telomerase, and Cancer
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Invasivecarcinoma
Telomeres andChromosomal Anomalies
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Mismatch
Repair andMicrosatellites
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Basic Mechanisms in
Neoplasms• Genetic bases
• Basic aspects of tumorigenesis
– Correlation between genetics and
kinetics
Alterations of Specific Cellular
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DNA Repair
Oncogenes
Activation
Tumor SuppressorGenes
Inactivation
Differentiation Apoptosis/Proliferation
CANCER
Alterations of Specific CellularFunctions in Cancer
Specific Cellular Functions in
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DNA Repair
Tumor
SuppressorGenes
Oncogenes
Interstitial DeletionInactivating Mutation
Hypermethylation
Gene AmplificationGene Overexpression
Activating Mutation
Genetic Instability: RER Phenotype
CANCER
Specific Cellular Functions inCancer: Genetic Alterations
P g i A i iti
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Progressive Acquisitionof Neoplastic Features
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Hallmarks of Cancer Cells
• Self-maintainedreplication
• Longer survival
• Genetic instability
• Capable ofinducing
neoangiogenesis• Capable of
invasion andmetastasis
– Apoptosis down-regulation
– Lack ofresponse toinhibitoryfactors
– Self-sustainedproliferation
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Hallmarks of Cancer Cells
• Self-maintainedreplication
• Longer survival
• Genetic instability
• Capable ofinducing
neoangiogenesis• Capable of
invasion andmetastasis
–Apoptosisdown-
regulation –Telomerase
reactivation
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Hallmarks of Cancer Cells
• Self-maintainedreplication
• Longer survival
• Genetic instability
• Capable ofinducing
neoangiogenesis• Capable of
invasion andmetastasis
–Cooperativegenetic
damage –Mutagenic
agents
–Defectiverepair systems
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Hallmarks of Cancer Cells
• Self-maintainedreplication
• Longer survival
• Genetic instability
• Capable ofinducing
neoangiogenesis • Capable of
invasion andmetastasis
B i Bi l i F t
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Basic Biologic Featuresof Neoplasms
Oncogenic Lesion(e.g. RAS, MYC, E2F Activation)
DifferentiationAbnormal
ProliferationAngiogenesis Invasion
SenescenceApoptosis
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Multistep
Tumorigenesis
Acquired Capabilities, Molecular Pathways, and the Transformation
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Hahn, W. C. et. al. N Engl J Med 2002;347:1593-1603
of Human Cells: Emerging Rules That Govern Cancer Formation
C M l l P th
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Cancer Molecular Pathways
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Molecular Progression
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Molecular ProgressionMutation Accumulation
Cancer: General Etiology
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Cancer: General Etiologyand 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