1. CARCINOGENESIS
H.A MWAKYOMA, MD

2. 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.

3. 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.

4. 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

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

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

7. 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

8. 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

9. 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

10. 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

11. CHEMICAL CARCINOGENESIS

12. 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)

13. 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

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

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

16. 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”

17. 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

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

19. 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.

20. 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

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

22. 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

23. 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

24. 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

25. 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

26. 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:

27. 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

28. 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

29. 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)

30. 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

31. 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