Transcript carcinogenesis

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 noncarcinogenic 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.
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.
2.
3.
4.
Promotors – Proto-oncogenes
Inhibitors – Tumor or Cancer-suppressor
genes – p53
Genes regulating Apoptosis.
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 Gene
p53 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 Oncogenesis
Viruses 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
Disrupt normal host genes required for control of cell growth
and division (Alterations in Oncogenes, cancer suppressor
genes and genes regulating DNA repair resulting in upregulation of cell division  Carcinogenesis).
Alternatively, viral infection may result in immune dysfunction,
leading to decreased immune surveillance for early tumors.
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.
Summary of Carcinogenesis
Initiation
 DNA damage eg.Benzpyrene
Promotion
 Histological change – eg.
Turpentine (co-carcinogens)
Malignant transformation:
 Visible tumor formation
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- Ni, Cr, Cd, As.
Epigenetic Carcinogen
Cytotoxic carcinogens.
– Nitrillotriacetate, BHA, BHT.
• Tumor promotors.
– DDT, Dioxin
• Hormones.
– Estradiol, DES
• Immunosuppressants.
– Cyclosporin A
• Particulates.
– Asbestos.
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 Exposures
Benzidine
Urinary Bladder
Vinyl Chloride
Liver Mesenchyme
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
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 oil
They 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…..!