Carcinogenesis

Carcinogenesis refers to the process by which a

normal cell is transformed into a malignant cell and

repeatedly divides to become a cancer. A chemical

which can initiate this process is called a chemical

carcinogen. Some chemicals which are non-

carcinogenic or only weakly carcinogenic can greatly

enhance the effectiveness of carcinogenic chemicals.

Such "helpers" are called cocarcinogens. They may

act by altering uptake or metabolism of carcinogens

by cells.

Carcinogenesis may take as long as 15-25 years in

humans and in several animal models has been shown

to involve two stages, initiation and promotion.

-In general, carcinogens are mutagens indicating

that they have the potential to interact with

DNA.

-Patients with DNA repair defects, such as

xeroderma pigmentosum (defect in repair of

damage induced by UV and bulky aromatic

chemicals), have increased incidence of cancer.

Key words:

Carcinogenesis: Pathogenesis of cancer

Carcinogen - agent causing cancer.

Oncogen - agent causing neoplasm.

Mutagen - agent causing mutation.

Oncogenes – genes causing cancer

p-onc, v-onc – Proto/viral/ - naming of oncogenes.

Factors affecting carcinogenesis

These factors can be divided into three main groups:

Environmental Toxins

chemical

physical (e.g. radiation)

Dietary

natural products found in spices, etc.

additives (rarely)

Lifestyle

hormonally-mediated

other

Chemicals Generally Recognized as

Carcinogenic in Humans

Chemicals Generally Recognized as Carcinogenic in Humans

Industrial ExposuresBenzidine Urinary Bladder

Vinyl Chloride Liver

Certain tars Skin and

Asbestos Peritoneum (lungs when combined with cigarette

smoking)

Benzene Lymphoid Tissue

Other Exposures

Diethylstilbestrol VaginaI

Arsenic Compounds Skin cancer

Cigarette Smoke Lungs, urinary tract

Betal Nut Buccal Mucosa

Diets play important roles in the development of tumors.The following factors should be considered.

Natural Foods May Contain Carcinogens:

Mushrooms»»Hydrazine

Betal Nut»»Hydrocarbons

Food contaminants:

Aflatoxin B1»»Peanuts

Nitrosamines»»Beer, Wine, Pickled Vegetables

Food Processing:

Barbecued Meat»»Polycyclic Hydrocarbons

Heat Processing of Protein-Rich Foods»»Heterocyclic Aromatic

compounds

Dietary Fat:

Saturated Fatty Acids

Polyunsaturated Fatty Acids: Corn oil, Safflower oil

Natural Foods May Contain Anticarcinogens»»Vitamins, Antioxidants

Carcinogens

Chemicals

Viruses

Radiation

Hereditary causes- Genetic defects.

Combination – common.

Molecular Basis of Carcinogenesis

Genes control cell division by cytokines.

Four important classes of regulatory genes

(for cell division):

1. Promotors – Proto-oncogenes

2. Inhibitors – Tumor or Cancer-suppressor genes – p53

3. Genes regulating Apoptosis.

4. DNA repair genes.

Carcinogenesis

Genetic mutations are largely responsible for the

generation of malignant cells. Two major categories of

mutated genes are oncogenes and tumor suppressor genes.

1-Oncogenes are abnormal forms of normal genes called

proto-oncogenes that regulate cell growth. Mutation of

these genes may result in direct and continuous stimulation

of the molecular biologic pathways that control cellular

growth and division.

For example, the ras gene encodes the Ras protein, which

regulates cell division. Mutations may result in the

inappropriate activation of the Ras protein, leading to

uncontrolled cell growth and division.

2-Tumor suppressor genes ,p53, are inherent genes

that play a role in cell division and DNA repair and

are critical for detecting inappropriate growth

signals in cells. If these genes, as a result of inherited

or acquired mutations, become unable to function,

genetic mutations in other genes can proceed

unchecked, leading to neoplastic transformation.

Another important regulatory protein, prevents

replication of damaged DNA in normal cells and

promotes cell death (apoptosis) in cells with

abnormal DNA. Inactive or altered apoptotic genes

allows cells with abnormal DNA to survive and

divide.

p53 Genep53 senses DNA damage, and induces G1 arrest

and induces DNA repair process.

Cell with un-repairable DNA is directed to

apoptosis by p53 gene.

“P53 is a guardian of the genome.

Its loss leads to accumulation of damaged DNA

may result in malignancy”

Loss of p53 is seen in virtually every type of

cancer.

Over half of human malignant cells show loss of

p53 gene by special tests.

Non-lethal Genetic damage lies at

the center of carcinogenesis.

Loss/damage to suppressor genes,

Duplication of promotor genes

Loss/damage to Apoptosis genes

Loss/damage of DNA repair genes.

Molecular Basis of Neoplasia:

Proto-oncogene

Oncogene

Viral OncogenesisViruses contribute to the pathogenesis of human malignancies

through the integration of viral genetic elements into the host

DNA. These new genes are expressed by the host; they may affect

cell growth or division, or disrupt normal host genes required for

control of cell growth and division. Alternatively, viral infection

may result in immune dysfunction, leading to decreased immune

surveillance for early tumors.

Insertion of viral nucleic acids mutation

Alterations in Oncogenes, cancer suppressor genes and genes

regulating DNA repair resulting in up-regulation of cell division

Carcinogenesis.

Human Papilloma Virus

Cervical neoplasia – warts, papilloma, ca cx

Epstein-Barr virus –

Burkitts Lymphoma, Nasopharyngeal ca.

Hepatitis B & C virus

Hepatocellular carcinoma.

Radiation Carcinogenesis:

Ionizing radiation Carcinogenesis can result from ionizing

radiation and may develop from 2 different mechanisms;

1. Direct ionization – damages DNA and other molecules can

cause direct somatic mutations

2. Secondary effectors such as oxygen radicals can be formed

by ionizing radiation. Oxygen free radicals can damage and

kill cells and also induce mutations.

X Ray workers – Leukemia

Radio-isotopes – Thyroid carcinoma

Atomic explosion – Skin cancer, Leukemia

Summary

DNA damage - loss of control over cell division.

Radiation, Chemicals & Viral infections are some

known causes of cancers.

Cancer evolves in multiple steps by sequentially

acquiring different DNA damages.

Initiation, Latent stage, Promotion and Malignant

transformation are recognizable stages in

carcinogenesis.

Each character of malignancy depends on unique

DNA alteration.

Carcinogenesis

Initiation

DNA damage eg.Benzpyrene

Promotion

Histologic change – eg.

Turpentine (co-carcinogens)

Malignant transformation:

Visible tumor formation – further

DNA damage.

Initiation - point at which an irreversible alteration, usually

genetic, is introduced into a target cell.

(genotoxicity)=Interaction with DNA

May involve conversion of proto-oncogen to oncogen

Initiation:

(1) is essentially irreversible

(2) caused only by carcinogenic compounds

(3) occurs rapidly after carcinogen exposure

(4) alone does not result in tumor formation

Several exposures to an initiator may result in tumor without

presence of a promoter.

Promotion is the process whereby an initiated tissue or

organ develop focal proliferations and it requires the

presence of continuous stimulation.

A promotor: is a substance which doesn't damage DNA but

enhance growth of tumor induced by genotoxic

carcinogens e.g.: skin cancer in mice can be induced by

application of benzo [α ] pyrene ( initiator) followed by

phorbol ester from cotton oil ( promoter).

Promotion

(1) reversible

(2) acts only after exposure to an initiating agent

(3) requires repeated administration of a promoter

(4) is not carcinogenic in itself

Etiology and Pathogenesis of Neoplasia

Initiation and Promotion

Chemical Carcinogenesis

In general, chemical carcinogens are

electrophiles or can be metabolically

converted to electrophiles. (by metabolic

activation). These electrophiles can react

with nucleophilic centers (predominantly N

and O and to some extent S) in cellular

macromolecules such as DNA, RNA and

protein.

Classification of Carcinogens

Genotoxic– Act directly on DNA or expression of DNA during

translation.

• DNA replication errors.

• Point mutations.

• Chromosomal aberration.

Epigenetic– Non-DNA reactive.

– Potentiators.

– Ex.: hormone, immune function modifiers

Genotoxic Carcinogen

Chemical capable of producing cancer by directly altering the genetic material of target cells.

1- Direct carcinogens (no metabolic activation).

– Alkylating agents.

2-Indirect carcinogens (metabolic activation).

– Polycyclic aromatic hydrocarbons.

– Aromatic amines.

– Nitrosamines.

– Natural substances.

3– Inorganic carcinogens.

4- Heavy metals (Ni, Cr, Cd, As).

Epigenetic Carcinogen• Cytotoxic carcinogens.

– Nitrillotriacetate, BHA, BHT.

• Tumor promotors.

– DDT, Dioxin

• Hormones.

– Estradiol, DES

• Immunosuppressants.

– Cyclosporin A

• Particulates.

– Asbestos.

Chemicals Generally Recognized as

Carcinogenic in Humans

Chemicals Generally Recognized as Carcinogenic in Humans

Industrial ExposuresBenzidine Urinary Bladder

Vinyl Chloride Liver

Certain tars Skin and

Asbestos Peritoneum (lungs when combined with cigarette

smoking)

Benzene Lymphoid Tissue

Other Exposures

Diethylstilbestrol VaginaI

Arsenic Compounds Skin cancer

Cigarette Smoke Lungs, urinary tract

Betal Nut Buccal Mucosa

Diet & nutrients protecting from cancer :Fruits & vegetables

* High level of fibers

* Antioxidants which decrease damaging effects caused by free

radicals and reactive oxygen species on DNA

Examples:

a- Tocopherol & β- carotene ( carotenoids), vit C : decrease tumor

incidence.

b- Tomatos : contain lycopene protect against prostate cancer .

c- Green tea : contain polyphenols which act as antioxidants.

d- Red grapes : contain resveratrol which acts an antioxidant.

Garlic & onions ( allylsulphide + diallylsulphide) :

* They inhibit Cyt P450 ( Phase I) which converts percarcinogents

to carcinogens

* They activate glutathione-s- transferase ( GSTs ) which help

conjugation of carcinogens with cellular GSH ( Phase II)

Cruciferous vegetables :

* Eg: Cabbage - broccoli.

• They contain dithiol thiones & isothiocyanates

which activate phase II enzymes that help eliminating the

carcinogen.

Omega 3 fatty acids:

eg : fish oilThey crowd other fats replacing them inside the cells ,

thus preventing their promoter action.

Soy products:

* Contain weakly estrogenic isoflavonoids

* These isoflavonoids compete with estrogen for its

peripheral receptors on breast blocking them , ttt of

estrogen – dependant breast cancer ( as tamoxifen ).

Red grapes :

* Red grapes contain resveratrol & tumeric

contains curcumin.

* tumor cells secrete factor that promotes the

development of new blood vessels which are

necessary for tumor growth ; this process is

know as angiogenesis. Resveratrol & curcumin

suppress the release of growth factors by the

tumor inhibit angiogenesis.

Principle of Treatment

Surgical therapy – early stage/debulk

Chemotherapy

Radiotherapy

Immunotherapy

It is easy to kill cancer

cells, but the challenge is

keeping the patient alive

at the same time…..!