CANCER: ETIOLOGIC AGENTS AND GENERAL MECHANISMS Salvador J. Diaz-Cano [email protected]

CANCER: ETIOLOGIC CANCER: ETIOLOGIC AGENTS AND GENERAL AGENTS AND GENERAL

MECHANISMSMECHANISMS

Salvador J. Diaz-CanoSalvador J. Diaz-Cano

[email protected]@qmul.ac.uk

CANCER BIOLOGYCANCER BIOLOGY

Causes of Cancer: Causes of Cancer: General EtiologyGeneral Etiology

Cancer: General Etiology Cancer: General Etiology and Pathogenesisand Pathogenesis

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

Physical CarcinogensPhysical Carcinogens

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

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

Cancer: Cancer:

General General

PathwaysPathways

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

Telomeres Telomeres and Cell and Cell

SenescencSenescencee

Hahn, W. C. et. al. N Engl J Med 2002;347:1593-1603

Telomeres, Telomerase, and Cancer

Invasivecarcinoma

Telomeres and Chromosomal Anomalies

Mismatch Mismatch Repair and Repair and

MicrosatellitMicrosatelliteses

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

Progressive Progressive Acquisition of Acquisition of

Neoplastic FeaturesNeoplastic Features

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






–Apoptosis down-regulation

–Telomerase reactivation






–Cooperative genetic damage

–Mutagenic agents

–Defective repair systems






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

Multistep Multistep TumorigenesiTumorigenesi

ss

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 Molecular PathwaysCancer Molecular Pathways

Molecular Molecular ProgressionProgression

Mutation Mutation AccumulationAccumulation

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

Documents

CANCER: ETIOLOGIC AGENTS AND GENERAL MECHANISMS Salvador J. Diaz-Cano [email protected]