CARCINOGENESIS H.A MWAKYOMA, MD

Learning objectives To understand the multistep process of carcinogenesis. To name the different factors that act in carcinogenic process. To be able to differentiate between the different carcinogens and their actions.

Key words: Oncogenesis: Pathogenesis of neoplasm Carcinogenesis: Pathogenesis of cancer Carcinogen - agent causing cancer. Oncogenic - agent causing neoplasm. Mutagen - agent causing mutation. Oncogenes – genes causing cancer p-onc, v-onc, c-onc – Proto/viral/cell - naming of oncogenes.

What is a carcinogen? A carcinogen is any substance or agent that, because of the way it affects cell DNA, can cause cancer Carcinogens may be; chemical substances; physical agents, such as asbestos dust; or biological agents, such as certain viruses and bacteria In the workplace, carcinogenic substances may be inhaled, absorbed through the skin or even ingested in some cases

Classification of Carcinogenesis According to etiologic factors Chemical Familial Physical Viral According to environmental factors Occupational Dietary Lifestyle Environmental

(Viral, Chemical, Physical) Etiological factors Exogenous Endogenous Carcinogenic agents (Viral, Chemical, Physical) Genetic or hereditary predisposition

Known or potential carcinogens Target organ chemicals: Aflatoxin Arsenic Benzene Benzidine Benzo(a) pyrene Beryllium Cadmium Chromium Coal Tar Nickel compounds Vinyl chloride 2-Naphthylamine Nitrosamine Liver Skin ,lung Bone marrow Bladder Skin, Lung Lung Prostate, Lung Skin, Lung, bladder Lung, nasal cavity Liver, lung, brain

Known or potential carcinogens Target organ 2.Diet: High fat diet Tobacco smoke Alcohol Smoked salted food Colon, breast Lung, oral, cervix Oral, esophagus, pancreas, liver GIT

Known or potential carcinogens Target organ 3. Industry: Aluminium production Iron and steel Isopropyl alcohol Paint & glass industry Rubber industry Auramine production Leather manufacturing Magenta production Lung, bladder Lung Nasal sinuses LUNG Bone marrow Bladder Bone marrow and nasal

Known or potential carcinogens Target organ 4. Medications: Phenacetin Chloramphenicol Chloronaphazine Busulphan Nitrogen mustard Procarbazine Testosterone No steroid estrogen Estrogen Cyclosporin Kidney Bone marrow Bladder Skin Liver Endometrium Lymphatic

CHEMICAL CARCINOGENESIS

Factors affecting chemical carcinogenesis Exposure (high doses) Metabolic activation (differ in different individuals) Genetic differences DNA repair enzymes (ex. DNA-alkyltransferase removes adducts due to exposure to N-nitrosamine compounds)

Carcinogenesis Hypotheses of the Origin of Neoplasia Multiple Hits and Multiple Factors Knudson proposed that carcinogenesis requires 2 hits 1st event – initiation Carcinogen = initiator 2nd event – promotion Agent = promoter Multiple hits occur – 5 or more Each hit produces a change in the genome which is transmitted to its progeny (ie. clone) Lag period Time between exposure (first hit) and development of clinically apparent cancer Altered cell shows no abnormality during lag period

The initiation stage of carcinogenesis is based on DNA mutation Genotoxic: gene damage

Stages of Carcinogenesis Initiation Initiating Event Cell Proliferation (clonal expansion) Second Mutating Event Promotion Cell Proliferation Progression "N" Mutating Event Cell Proliferation Malignancy

Multi-step Process Tumor initiation and progression results from stepwise accumulation of DNA mutations. Several characters of malignant neoplasm are the result of multiple genetic defects. Initial steps reversible(e.g. dysplasia), but final Malignant transformation is irreversible. “Hit & Run”

InitiationPromotion Initiator = Carcinogen Cocarcinogen interacts with initiator, may be an initiator itself Promoter acts at same time or after initiator, is not (usually) initiator alone at dosage at which it promotes

Chemical carcinogens Categorized to initiators & Promoters Initiators  Natural and Synthetic Two Categories: Direct acting & Indirect acting

Chemical Carcinogenesis:Initiators Direct Acting Carcinogens:- Require no chemical transformation Alkylating Agents: Cyclophosphamide Procarcinogenes (indirect-acting) needs activation Polycyclinc hydrocarbons – Benzpyrene Aromatic amines, dyes - Benzidine Natural products: Aflatoxin Others: Vinyl chloride, turpentine etc.

Direct Acting Agents Weak carcinogens Require no chemical transformation Chemotherapeutic drugs Alkylating agents Cyclophosphamide, chlorambucil, nitrosoureas Second malignancy decades later Acylating agents 1-Acetyl-imidazole, Dimethylcarbamyl chloride

Electrophiles Chemical entities which react with centres having a “surplus” of electrons, or nucleo-philes. Protein, RNA and DNA contain nucleophilic sites

Many Carcinogens Are Electrophilic Molecules That React Directly with DNA-Direct acting carcinogens Common property Highly unstable compounds ( Electron-deficient atoms) Interacted with DNA→ DNA adduct→ mutations Activation of other chemical carcinogens: aflatoxin, vinyl chloride Some carcinogens are activated by reaction with other electrophilic groups Niternium ions Carbonium ions Free radicals

Indirect Agents Require metabolic conversion before they become active. Procarcinogen:- initial chemical Ultimate carcinogen: active end product Examples Polycyclic hydrocarbons: fossil fuels, active epoxides bind DNA Benz[a]anthracene: skin cancer Benzo[a]pyrene: cigarette smoke- lung cancer

Indirect Agents Continued Examples Aromatic amines and azo dyes Converted in liver by P-450 Beta-naphthylamine: Bladder ca. in rubber factories Azo dyes: developed for food color Nitrosamines and amides Formed endogenously in acid environment of stomach GI cancers? Aflatoxin B Aspergillus flavus in grains Hepatocellular carcinoma

Chemical carcinogens=Promoters Endogenous  hormones and Bile salts Exogenous Diethylstilbestrol (used for Threatened Abortion) Postmenopausal endometrial carcinoma offspring exposed in- utero vaginal cancer Fat = colon cancer Estrogen = liver tumours Tobacco and viral infection = tissue damage and reactive hyperplasia

Carcinogenesis is a probabilistic event that depends on carcinogen dose and potency Incomplete carcinogen Only one property Initiating or promoting agents Complete carcinogenes Many certain polycyclic hydrocarbons Lower doses: initiating agents Higher doses: complete carcinogens Tobacco smoke+coal tar: complete carcinogen POTENCY:

Promotion - 1 “Incomplete” carcinogen requires a promoter “Complete” carcinogen both initiates and promotes Stimulation of cell division for fixation Not genotoxic Dose-dependent, may have threshold

Promotion - 2 Promoters induce small foci of “preneoplastic” proliferation where transformed cells reside in tissues Selection pressure favours more rapidly proliferating foci At high concentrations, cytotoxic promoters may inhibit carcinogenesis by negative selection pressure on susceptible cells

Promoters - 3 Promoters are mitogens, may be endogenous as well as exogenous hormones (estrogen, prolactin, thyroxin) Exogenous promoters phorbol esters (experimental) phenobarbital foreign bodies aromatic hydrocarbons (also initiators) dioxin (most potent in animal studies)

Progression Proliferation of successful clone Adaptive growth Dormancy period in many cases, ends for many reasons (hormonal, nutritional, lymphokines, immunodeficiency etc.) Tumour vascularization, angiogenesis Develops into detectable tumour

Initiators & Promoters carcinogenic agent not sufficient for tumor formation by themselves permanent DNA damage (Mutations) rapid and irreversible Promoters  Changes are reversible non- tumorigenic by themselves not affect DNA directly induce tumors in initiated cells & reversible