Cancer Et Mech

8/3/2019 Cancer Et Mech

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CANCER: ETIOLOGIC

AGENTS AND GENERALMECHANISMS

Salvador J. [email protected]



CANCER BIOLOGY

Causes of Cancer:General Etiology



Cancer: General Etiology andPathogenesis



Environmental vs .

Hereditary Cancer85

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Cancer Etiology

Environmental Hereditary







Environmental

Carcinogens• A cancer-causing agent

• Three main types:

– Chemical

– Physical (radiation)

– Biological (especially virus)



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



Chemical Carcinogens

• Direct-acting

• Indirect-acting (must be metabolized

to activated metabolic forms)



Electrophiles

• Direct-acting carcinogens are alreadyelectrophilic

• Indirect-acting carcinogens aremetabolically activated intoelectrophilic species



Electrophilic Theory of

Chemical Carcinogenesis• Electrophilic (electron-seeking)

molecules will bind to nucleophilic(electron-rich) macromolecules in thecell

– DNA

– RNA

– Proteins



Direct-acting

Carcinogens• Nitrogen mustard

• Nitrosomethylurea

• Benzyl chloride



Indirect-acting

Carcinogens• Polycyclic aromatic hydrocarbons

(PAH)

• Produced by incomplete combustionof organic materials

• Present in chimney soot, charcoal-

grilled meats, auto exhaust, cigarettesmoke



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



Human carcinogens -

environmental• Aflatoxins

• Asbestos

• Benzene

• Cadmium

•

Coal tar

• Creosote

• DDT

• Polycyclicaromatichydrocarbons

• Radon

• Solar radiation



Human carcinogens -

drugs/therapeutic agents• Adriamycin

(doxorubicin)

• Androgenic steroids• Chlorambucil

• Cisplatin

• Cyclophosphamide

• Cyclosporin A

• Diethylstilbestrol

• Ethylene oxide

• Melphalan

• Tamoxifen



Physical Carcinogens

• Ultraviolet light

• Ionizing radiation (X-rays)

• Asbestos





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





Asbestos

• Widely used in construction,insulation, and manufacturing

• Family of related fibrous silicates

• Chrysotile

• Crocidolite





Malignant Mesothelioma

• Mainly occurs in pleural andperitoneal cavities

• Rare in general population

• Latent period of ≥20 years



Ionizing Radiation

• Death of pioneer radiationresearchers from neoplasms

• High incidence of leukemia amongradiologists recognized in 1940s

• Osteosarcoma incidence in radium

dial painters



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



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



Human papilloma virus

(HPV)• Over 70 subtypes

• DNA virus with small double-

stranded circular genome

• Subtypes possess varying degreesof low risk and high risk



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







EBV - Involvement in

Human Tumors• African Burkitt lymphoma

• B-cell lymphomas of

immunosuppressed patients

• Some cases of Hodgkin lymphoma

• Nasopharyngeal carcinomas



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



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



Basic Mechanisms:General Pathogenesis

CANCER BIOLOGY



Cancer:

General

Pathways



Basic Mechanisms in

Neoplasms• Genetic bases

• Basic aspects of tumorigenesis

– Correlation between genetics and

kinetics

C G l



Cancer GeneralMechanisms

• Single “gross” genetic

abnormalities

– Translocations

• Multiple “punctual”

genetic alterations

– Mutations

– LOH

• Malignantlymphomas

• Sarcomas

• Carcinomas• Malignant

melanomas

Activating Mechanisms

Activating/Inactivating Mechanisms



Genetic Lesions in

Tumors• Activating or inactivating

• Dominant / Recessive / Dominant negative

• Somatic or germline

• Genetic targets (oncogenes, tumor

suppressor genes, mismatch repairgenes)



Genetic Mechanisms ofTumors

• Gene deletions / amplifications

• Mutations

• Insertional

• Point Mutations

•

Genetic Instability• Microsatellite Instability (MSI)

• Chromosomal Instability (CIN)



Gene Inactivation

• Genetic Changes

– Inactivating mutation

– Interstitial DNA deletion

• Epigenetic Changes

– Promoter hypermethylation



Genetic Instability in

Tumors• (+) Oncogenes

• (-) Tumorsuppressor genes

• Telomereshortening

• Mismatch repair(MMR) genes

• ChromosomalInstability

• MicrosatelliteInstability

? Cause or tumor progression byproduct



Telomeres

and CellSenescence

T l T l d C



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

Telomeres, Telomerase, and Cancer



Invasivecarcinoma

Telomeres andChromosomal Anomalies



Mismatch

Repair andMicrosatellites



Basic Mechanisms in

Neoplasms• Genetic bases

• Basic aspects of tumorigenesis

– Correlation between genetics and

kinetics

Alterations of Specific Cellular



DNA Repair

Oncogenes

Activation

Tumor SuppressorGenes

Inactivation

Differentiation Apoptosis/Proliferation

CANCER

Alterations of Specific CellularFunctions in Cancer

Specific Cellular Functions in



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



Progressive Acquisitionof Neoplastic Features



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





• Longer survival





–Apoptosisdown-

regulation –Telomerase

reactivation





• Longer survival





–Cooperativegenetic

damage –Mutagenic

agents

–Defectiverepair systems





• Longer survival



neoangiogenesis • Capable of


B i Bi l i F t



Basic Biologic Featuresof Neoplasms

Oncogenic Lesion(e.g. RAS, MYC, E2F Activation)

DifferentiationAbnormal

ProliferationAngiogenesis Invasion

SenescenceApoptosis



Multistep

Tumorigenesis

Acquired Capabilities, Molecular Pathways, and the Transformation



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



Cancer Molecular Pathways



Molecular Progression



Molecular ProgressionMutation Accumulation

Cancer: General Etiology



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

Documents

Cancer Et Mech