"I think of life itself now as a "I think of life itself now as a wonderful play that I've written wonderful play that I've written for myself... and so my purpose for myself... and so my purpose

is to have the utmost fun is to have the utmost fun playing my part…!"playing my part…!"

Shirley MacLaine,Actress and Author

Revision slides first …..Revision slides first …..

Etiology of CancerEtiology of Cancer

Dr Ejaz Waris

Non-lethal Genetic damage lies at Non-lethal Genetic damage lies at the center of carcinogenesis.the center of carcinogenesis.

Loss/damage to suppressor genes,Loss/damage to suppressor genes, Duplication of promotor genesDuplication of promotor genes Loss/damage to Apoptosis genesLoss/damage to Apoptosis genes Loss/damage of DNA repair genes.Loss/damage of DNA repair genes.

Carcinogenesis:Carcinogenesis:

We owe, Sir Percival Pott the knowledge We owe, Sir Percival Pott the knowledge of carcinogenesis. Pott, related the of carcinogenesis. Pott, related the increased incidence of scrotal cancer in increased incidence of scrotal cancer in chimney sweeps. On his findings, Danish chimney sweeps. On his findings, Danish Chimney Sweeps Guild ruled that it’s Chimney Sweeps Guild ruled that it’s members must members must bathe dailybathe daily..No public health measure since that No public health measure since that time, has so successfully controlled a time, has so successfully controlled a form of cancer……!!!form of cancer……!!!

Etiology of NeoplasiaEtiology of Neoplasia

Environmental causes: (Carcinogens)Environmental causes: (Carcinogens)Chemicals Chemicals Viruses Viruses Radiation Radiation

Hereditary causes- Genetic defects.Hereditary causes- Genetic defects.

Point to be noted !Point to be noted !

In males bronchogenic carcinoma and in In males bronchogenic carcinoma and in females breast carcinoma are at the top !females breast carcinoma are at the top !

Preneoplastic conditionsPreneoplastic conditions

Cirrhosis of liverCirrhosis of liverAtypical hyperplasia of endometriumAtypical hyperplasia of endometriumLeukoplakiaLeukoplakia Inflammatory bowel diseaseInflammatory bowel diseaseAdenomatous colonic polypsAdenomatous colonic polyps

CHEMICAL CARCINOGESISCHEMICAL CARCINOGESIS

IT’S A MULTISTEP IT’S A MULTISTEP PROCESSPROCESS

CHEMICAL CARCINOGENESIS CHEMICAL CARCINOGENESIS CONSISTS OF TWO PROCESSES:CONSISTS OF TWO PROCESSES:

INITIATIONINITIATION

PROMOTIONPROMOTION

Chemical Carcinogenesis:Chemical Carcinogenesis:

Initiators- Cause irreversible damage to Initiators- Cause irreversible damage to DNA,but at maximum they can cause severe DNA,but at maximum they can cause severe dysplasia. dysplasia.

eg.Benzopyreneeg.Benzopyrene Promoters – itself cannot induce cancer,they Promoters – itself cannot induce cancer,they

propagate or enhance the effects of initiatorspropagate or enhance the effects of initiatorsAlcohol,smoking (co-carcinogens)Alcohol,smoking (co-carcinogens)

Thus resulting in Malignant transformation:Thus resulting in Malignant transformation:Visible tumor formation – further DNA damage.Visible tumor formation – further DNA damage.

Chemical Carcinogenesis:Chemical Carcinogenesis:

Direct Acting Carcinogens:Direct Acting Carcinogens:Alkylating Agents: CyclophosphamideAlkylating Agents: Cyclophosphamide

Indirect acting / Procarcinogenes Indirect acting / Procarcinogenes (needs activation)(needs activation)Polycyclinc hydrocarbons – BenzopyrenePolycyclinc hydrocarbons – BenzopyreneAromatic amines, dyes - BenzidineAromatic amines, dyes - BenzidineNatural products: AflatoxinNatural products: AflatoxinOthers: Vinyl chloride, turpentine etc.Others: Vinyl chloride, turpentine etc.

Known Chemical carcinogensKnown Chemical carcinogens

A- Asbestos - Lung, mesothelioma. GI A- Asbestos - Lung, mesothelioma. GI tract (esophagus, stomach, large intestine) tract (esophagus, stomach, large intestine)

b- Arsenic - Lung, skin, hemangiosarcoma b- Arsenic - Lung, skin, hemangiosarcoma c- Beryllium - Lung c- Beryllium - Lung d- Cadmium - prostate d- Cadmium - prostate e. Benzene - Leukemia e. Benzene - Leukemia

f. Chromium- Lung f. Chromium- Lung g. Ethylene oxide g. Ethylene oxide Leukemia Leukemia h. Nickelh. Nickel.. Nose, Lung .. Nose, Lung i. Radoni. Radon.. Lungs .. Lungs j. Vinyl chloride j. Vinyl chloride Angiosarcoma Angiosarcoma k.Aflatoxins – HCCk.Aflatoxins – HCC l-Nitrates – Gastric carcinomal-Nitrates – Gastric carcinoma M.Aniline Dyes,B-naphthylamine – TCC of M.Aniline Dyes,B-naphthylamine – TCC of

bladderbladder

Lets see mode of action of any one Lets see mode of action of any one of the chemical carcinogens !of the chemical carcinogens !

The carcinogenicity of most aromatic The carcinogenicity of most aromatic amines and azo dyes is exerted mainly in amines and azo dyes is exerted mainly in the liver, where the "ultimate carcinogen" the liver, where the "ultimate carcinogen" is formed by the action of the cytochrome is formed by the action of the cytochrome P-450 oxygenase systems. P-450 oxygenase systems.

After absorption,azodyes like b naphthylamine After absorption,azodyes like b naphthylamine is hydroxylated into an active form, then is hydroxylated into an active form, then detoxified by conjugation with glucuronic acid. detoxified by conjugation with glucuronic acid. When excreted in the urine, the nontoxic When excreted in the urine, the nontoxic conjugate is split by the urinary enzyme conjugate is split by the urinary enzyme glucuronidase to release the electrophilic glucuronidase to release the electrophilic reactant again, thus inducing bladder cancer. reactant again, thus inducing bladder cancer.

Regrettably, humans are one of the few species Regrettably, humans are one of the few species to possess urinary glucuronidase.to possess urinary glucuronidase.

Viral Oncogenesis:Viral Oncogenesis:

Insertion of viral nucleic acids Insertion of viral nucleic acids mutation mutationAlterations in Oncogenes, cancer Alterations in Oncogenes, cancer

suppressor genes and genes regulating suppressor genes and genes regulating DNA repair resulting in up-regulation of cell DNA repair resulting in up-regulation of cell division division Carcinogenesis. Carcinogenesis.

Oncogenic DNA VirusesOncogenic DNA Viruses

Human Papilloma VirusHuman Papilloma Virus Cervical neoplasia – warts, papilloma, ca Cervical neoplasia – warts, papilloma, ca

cervixcervixEpstein-Barr virusEpstein-Barr virus – –

Burkitts Lymphoma, Nasopharyngeal Burkitts Lymphoma, Nasopharyngeal ca,Hodgkin’s disease,B cell lymphomaca,Hodgkin’s disease,B cell lymphoma

Hepatitis B & C virusHepatitis B & C virusHepatocellular carcinoma.Hepatocellular carcinoma.

Oncogenic DNA VirusesOncogenic DNA Viruses

Kaposi Sarcoma Hepes VirusKaposi Sarcoma Hepes VirusCauses Kaposi SarcomaCauses Kaposi Sarcoma

Oncogenic RNA virusesOncogenic RNA viruses

Human T-Cell Leukemia VirusHuman T-Cell Leukemia Virus

Radiation Carcinogenesis:Radiation Carcinogenesis:

Ionizing radiation Ionizing radiation dysjunction dysjunction random random fusion fusion mutation. mutation.

X Ray workers – LeukemiaX Ray workers – Leukemia Radio-isotopes – Thyroid carcinomaRadio-isotopes – Thyroid carcinoma Atomic explosion – Skin cancer, LeukemiaAtomic explosion – Skin cancer, Leukemia

Mutations

Neoplasia

Molecular Basis of Neoplasia:Molecular Basis of Neoplasia:

Proto-oncogeneProto-oncogene

OncogeneOncogene

V-OncV-Onc

OtherOther

Heredity

Heredity

Radiation

Radiation

Chemica

l

Chemica

l

Remember - Multi-step Remember - Multi-step ProcessProcess

Tumor initiation and progression results Tumor initiation and progression results from stepwise accumulation of DNA from stepwise accumulation of DNA mutations. mutations.

Several characters of malignant neoplasm Several characters of malignant neoplasm are the result of multiple genetic defects.are the result of multiple genetic defects.

Initial steps reversible(e.g. dysplasia), but Initial steps reversible(e.g. dysplasia), but final Malignant transformation is final Malignant transformation is irreversible. irreversible. “Hit & Run”“Hit & Run”

Tumor ProgressionTumor Progression

Multi-step TheoryMulti-step Theory

Stage of Stage of initiationinitiationLatentLatent stage stageStage of Stage of promotionpromotionStage of Stage of malignantmalignant transformation transformation

SummarySummary

DNA damage - loss of control over cell division.DNA damage - loss of control over cell division. Radiation, Chemicals & Viral infections are some Radiation, Chemicals & Viral infections are some

known causes of cancers.known causes of cancers. Cancer evolves in multiple steps by sequentially Cancer evolves in multiple steps by sequentially

acquiring different DNA damages.acquiring different DNA damages. Initiation, Latent stage, Promotion and Malignant Initiation, Latent stage, Promotion and Malignant

transformation are recognizable stages in transformation are recognizable stages in carcinogenesis.carcinogenesis.

Each character of malignancy depends on Each character of malignancy depends on unique DNA alteration.unique DNA alteration.

It is easy to kill cancer It is easy to kill cancer cells, but the challenge is cells, but the challenge is

keeping the patient alive at keeping the patient alive at the same time…..!the same time…..!

Do not fear mistakes…fear only the absence of constructive and

corrective responses to those mistakes…