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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
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.
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
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