cancer: etiologic agents and general mechanisms salvador j. diaz-cano s.j.diaz-cano@qmul.ac.uk
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CANCER: ETIOLOGIC CANCER: ETIOLOGIC AGENTS AND GENERAL AGENTS AND GENERAL
MECHANISMSMECHANISMS
Salvador J. Diaz-CanoSalvador J. Diaz-Cano
s.j.diaz-cano@qmul.ac.uks.j.diaz-cano@qmul.ac.uk
Environmental Environmental vsvs. . Hereditary CancerHereditary Cancer
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Cancer Etiology
Environmental Hereditary
Environmental Environmental CarcinogensCarcinogens
• A cancer-causing agent• Three main types:
– Chemical– Physical (radiation)– Biological (especially virus)
Chemical Chemical CarcinogenesisCarcinogenesis
• 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
Chemical CarcinogensChemical Carcinogens
• Direct-acting• Indirect-acting (must be
metabolized to activated metabolic forms)
ElectrophilesElectrophiles
• Direct-acting carcinogens are already electrophilic
• Indirect-acting carcinogens are metabolically activated into electrophilic species
Electrophilic Theory of Electrophilic Theory of Chemical Chemical
CarcinogenesisCarcinogenesis• Electrophilic (electron-seeking)
molecules will bind to nucleophilic (electron-rich) macromolecules in the cell– DNA– RNA– Proteins
Direct-acting Direct-acting CarcinogensCarcinogens
• Nitrogen mustard• Nitrosomethylurea• Benzyl chloride
Indirect-acting Indirect-acting CarcinogensCarcinogens
• Polycyclic aromatic hydrocarbons (PAH)
• Produced by incomplete combustion of organic materials
• Present in chimney soot, charcoal-grilled meats, auto exhaust, cigarette smoke
Ames TestAmes 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
Human carcinogens - Human carcinogens - environmental environmental
• Aflatoxins• Asbestos• Benzene• Cadmium• Coal tar
• Creosote• DDT• Polycyclic
aromatic hydrocarbons
• Radon• Solar radiation
Human carcinogens - Human carcinogens - drugs/therapeutic drugs/therapeutic
agentsagents• Adriamycin
(doxorubicin)• Androgenic
steroids• Chlorambucil• Cisplatin• Cyclophosphamide• Cyclosporin A
• Diethylstilbestrol
• Ethylene oxide• Melphalan• Tamoxifen
Skin cancer is one of the Skin cancer is one of the most common human most common human cancer and one of the cancer and one of the
most preventablemost 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
AsbestosAsbestos
• Widely used in construction, insulation, and manufacturing
• Family of related fibrous silicates
• Chrysotile• Crocidolite
Malignant Malignant MesotheliomaMesothelioma
• Mainly occurs in pleural and peritoneal cavities
• Rare in general population• Latent period of ≥20 years
Ionizing RadiationIonizing Radiation
• Death of pioneer radiation researchers from neoplasms
• High incidence of leukemia among radiologists recognized in 1940s
• Osteosarcoma incidence in radium dial painters
Viral CarcinogenesisViral 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
Oncogenic VirusesOncogenic Viruses
• Human papillomaviruses - HPV• Epstein-Barr Virus (EBV)• Human herpesvirus 8 (HHV8)• Hepatitis B virus - HBV• Hepatitis C virus - HCV• HTLV-I, HTLV-II
Human papilloma Human papilloma virus (HPV)virus (HPV)
• Over 70 subtypes• DNA virus with small double-
stranded circular genome• Subtypes possess varying
degrees of low risk and high risk
Low and High Risk Low and High Risk HPVHPV
• 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
EBV - Involvement in EBV - Involvement in Human TumorsHuman Tumors
• African Burkitt lymphoma• B-cell lymphomas of
immunosuppressed patients• Some cases of Hodgkin
lymphoma• Nasopharyngeal carcinomas
How Do Viruses like How Do Viruses like HPV and HBV Cause HPV and HBV Cause
Cancer?Cancer?• Very small viruses
• Can integrate their viral DNA into host genome
• They code for viral proteins which block tumor suppressor proteins in cells
Helicobacter pyloriHelicobacter 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
Basic Mechanisms: Basic Mechanisms: General PathogenesisGeneral Pathogenesis
CANCER BIOLOGYCANCER BIOLOGY
Basic Mechanisms in Basic Mechanisms in NeoplasmsNeoplasms
• Genetic basesGenetic bases
• Basic aspects of tumorigenesisBasic aspects of tumorigenesis
– Correlation between genetics and Correlation between genetics and
kineticskinetics
Cancer General Cancer General MechanismsMechanisms
• Single “gross” genetic abnormalities– Translocations
• Multiple “punctual” genetic alterations– Mutations– LOH
• Malignant lymphomas
• Sarcomas
• Carcinomas• Malignant
melanomas
Activating Mechanisms
Activating/Inactivating Mechanisms
Genetic Lesions in Genetic Lesions in TumorsTumors
• Activating or inactivating
• Dominant / Recessive / Dominant
negative
• Somatic or germline
• Genetic targets (oncogenes, tumor
suppressor genes, mismatch repair
genes)
Genetic Mechanisms Genetic Mechanisms of Tumorsof Tumors
• Gene deletions / amplifications
• Mutations
• Insertional
• Point Mutations
• Genetic Instability
• Microsatellite Instability (MSI)
• Chromosomal Instability (CIN)
Gene InactivationGene Inactivation
• Genetic Changes
– Inactivating mutation
– Interstitial DNA deletion
• Epigenetic Changes
– Promoter hypermethylation
Genetic Instability in Genetic Instability in TumorsTumors
• (+) Oncogenes• (-) Tumor
suppressor genes
• Telomere shortening
• Mismatch repair (MMR) genes
• Chromosomal Instability
• Microsatellite Instability
? Cause or tumor progression byproduct
Basic Mechanisms in Basic Mechanisms in NeoplasmsNeoplasms
• Genetic basesGenetic bases
• Basic aspects of tumorigenesisBasic aspects of tumorigenesis
– Correlation between genetics and Correlation between genetics and
kineticskinetics
DNA Repair
Oncogenes
Activation
Tumor Suppressor Genes
Inactivation
Differentiation Apoptosis/Proliferation
CANCER
Alterations of Specific Cellular Alterations of Specific Cellular Functions in CancerFunctions in Cancer
DNA RepairDNA Repair
Tumor Tumor Suppressor Suppressor
GenesGenes
OncogenesOncogenes
Interstitial DeletionInterstitial DeletionInactivating MutationInactivating MutationHypermethylationHypermethylation
Gene AmplificationGene AmplificationGene OverexpressionGene Overexpression
Activating MutationActivating Mutation
Genetic Instability: RER PhenotypeGenetic Instability: RER Phenotype
CANCERCANCER
Specific Cellular Functions in Specific Cellular Functions in Cancer: Genetic AlterationsCancer: Genetic Alterations
Hallmarks of Cancer Hallmarks of Cancer CellsCells
• 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
Hallmarks of Cancer Hallmarks of Cancer CellsCells
• Self-maintained replication
• Longer survival• Genetic instability• Capable of
inducing neoangiogenesis
• Capable of invasion and metastasis
–Apoptosis down-regulation
–Telomerase reactivation
Hallmarks of Cancer Hallmarks of Cancer CellsCells
• Self-maintained replication
• Longer survival• Genetic instability• Capable of
inducing neoangiogenesis
• Capable of invasion and metastasis
–Cooperative genetic damage
–Mutagenic agents
–Defective repair systems
Hallmarks of Cancer Hallmarks of Cancer CellsCells
• Self-maintained replication
• Longer survival• Genetic instability• Capable of
inducing neoangiogenesis
• Capable of invasion and metastasis
Basic Biologic Basic Biologic Features of Features of NeoplasmsNeoplasms
Oncogenic LesionOncogenic Lesion(e.g. RAS, MYC, E2F Activation)(e.g. RAS, MYC, E2F Activation)
Oncogenic LesionOncogenic Lesion(e.g. RAS, MYC, E2F Activation)(e.g. RAS, MYC, E2F Activation)
DifferentiationAbnormal
ProliferationAngiogenesis Invasion
SenescenceApoptosis
Hahn, W. C. et. al. N Engl J Med 2002;347:1593-1603
Acquired Capabilities, Molecular Pathways, and the Transformation of Human Cells: Emerging Rules That Govern Cancer Formation
Cancer: General Cancer: General Etiology and Etiology and PathogenesisPathogenesis
• Etiologic agents: Etiologic agents: – Environmental (chemical, physical, and Environmental (chemical, physical, and
biological) biological) – Hereditary (familial cancer syndromes)Hereditary (familial cancer syndromes)
• General mechanisms:General mechanisms:– Acquired capabilities (Self-maintained Acquired capabilities (Self-maintained
replication, longer survival, genetic replication, longer survival, genetic instability, neoangiogenesis, invasion instability, neoangiogenesis, invasion and metastasis)and metastasis)
– Activation of oncogenes, inactivation Activation of oncogenes, inactivation of TSG, non-effective DNA repairof TSG, non-effective DNA repair
– Caretaker and gatekeeper pathwaysCaretaker and gatekeeper pathways
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