Download Principles of carcinogenesis-1

Principles of carcinogenesis-1&2
Dr D Ponraj
Bioscience/SHS/NYP
Introduction
• Carcinogenesis:
• Its the process which results in the transformation of
normal cells to neoplastic cells by causing
permanent genetic alterations (it strictly applies to
malignant tumours).
• Oncogenesis: It includes the causation of all
tumours, benign and malignant
• Carcinogen: Its an agent known or suspected to
participate in the causation of tumours (and called
carcinogenic agents).
• Genetic alterations are absolutely fundamental in
carcinogenic process
Identification of carcinogens
• Epidemiological studies (colorectal cancers,
oesophagial Ca)
• Assessment of occupational risks (scrotal Ca in
chimney sweeps)
• Direct accidental exposure (throtrast in
angisarcoma of liver, Chernobyl nuclear reactor
accident)
• Carcinogenic effects on lab animals
• Transforming effects on cell cultures
• Mutagenicity testing in bacteria
Main classes of carcinogens
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1. Chemicals
2. Viruses [Genetic- oncogenes]
3. Ionising radiation & non-ionising radiation
4. Hormones, mycotoxins and parasites
5. Miscellaneous agents (asbestos & metal
like nickel)
• Genetic
Cellular & molecular events in
carcinogenesis
• Its a multistep process
• May require a initiating (polycyclic hydrocarbon)
and promoting (croton oil) agent. If an agent
possess both these agents its called “complete
carcinogen”, if it has only one action its called
incomplete carcinogen”
• Growth persists even in the absence of the causative
agent.
• Genetic alteration of oncogenes and tumour
suppressor genes (Ca colon).
Chemical carcinogensis
• Direct-acting compounds:
• which do not require chemical transformation for
carcinogenity.
• They are highly reactive electrophiles (have electrondeficient atoms) that can react with neuleophilic
(electron rich) sites in cell.
• Indirect-acting compounds or procarcinogens:
which require metabolic conversion in vivo to produce
the ultimate carcinogen capable of transforming cells.
Chemical carcinogens
• 1. Polycyclic hydrocarbons:
• the first carcinogen discovered in soot, a tary
residue of coal combustion.
• Responsible for scrotal ca in chimney sweeps
of London.
• The most active component is
benzo[alpha]pyrene and dibenzanthracene.
• Benzopyrene in tobacco smoke is the most
important carcinogenic agent.
• 2. Cigarette smoking:
• Including cigar and pipes-is associated
with Ca lung, oesophagus, bladder, oropharynx.
• Passive smokers also affected
• Inhaled polycyclic hydrocarbons (tars) are converted
in the liver to an epoxide by a microsomal enzyme,
aryl hydrocarbon hydroxylase.
• This epoxide (ultimate carcinogen) is an active
compound that combines with guanine in DNA,
leading to neoplastic transformation.
• 10 “pack years”: an increase in 10 times for cancer
for some one who smokes a pack of cigarette a day
3. Aromatic amines:
• Such as benzidine and naphthylamine is
associated with bladder cancers.
• They are mostly procarcinogens and enters
through skin, lung (leather and dye industries) or
intestine.
• Cause cancer in animals, but varies in different
species of animals tested. Controlled by FDA.
• Detected by measuring urine levels.
• 4. Cyclamates and
Saccharin:
These are artificial sweeteners
used in diabetes.
No carcinogenic effect in
humans but have carcinogenic
effect in animals.
• 5. Azo dyes:
• These are dyes used for
colouring of food (scarlet red
& butter yellow).
• They were shown to cause
liver cancer in animals.
6. Aflatoxins
• Its the most potent carcinogen known.
• Its a toxic metabolite produced by the fungus
Apergillus flavus, known to cause liver cancer in
man. In Africa, dietary intake of large amounts of
aflatoxins have shown to result in hepatocellular
carcinoma.
• Ingested aflatoxin is oxidised in the liver to an
ultimate carcinogen that binds with guanine in the
DNA of hepatic cells.
• First the liver goes for acute liver cell necrosis
followed by regenerative hyperplasia and possibly
cancer.
7. Nitrosamines:
• Their ability to react with both nucleic
acids and cytoplasmic macromolecules
provides a theoretical basis for carcinogenic
action.
• Nitrosamines are derived mainly by
conversion of nitrites in stomach.
• Nitrites are ubiquitous in food because of
their common use as preservatives, mainly
in processed meat, ham, bacon, sausage...
• Better refrigeration of food for past 20 years
has decreased use of preservatives and
hence cancer
• The high incidence of gastric cancer in
Japan is thought to be due to high intake of
smoked foods which contain more
polycyclic hydrocarbons than to high
nitrosamine levels.
8. Asbestos
• Crocidolite, the variety of asbestos having the
finest diameter fibres (<0.25 mm), presents the
greatest hazards
• Asbestosis also leads to fibrous proliferation in
the pleura, where it results in fibrous plaques that
are reliable radiological indicator.
• It results in 2 types of cancer
• a.Malignant mesothelioma, which involves the
pleura, peritonium and pericardium
• b. Bronchogenic Carcinoma: this risk is greatly
magnified by smoking
9. Betel leaf:
• Associated with oral cancers, common in India,
srilanka.
• The carcinogenic agent is either Areca nut or the
crushed limestone or tobacco that is commonly chewed
along with betel leaf
10. Anticancer drugs:
• Leukaemia is the most common neoplastic disorder
associated with alkylating agents, such as
cyclophosphamide, busulfan, chlorambucil.
• These interfere with nucleic acid synthesis in normal
cells and may cause oncogenic mutation
11. Other industrial carcinogens
Heavy metals:
• nickel, chromium, and cadmium show an
increased incidence of lung cancer
Arsenic exposure,
• in agricultural workers exposed to arsenic containing pesticide, is associated with skin
cancer and to lesser extent, lung cancer
Vinyl chloride,
• a gas used to manufacture PVC, has been
shown to induce malignant vascular neoplasm
in liver (angiosarcoma)
Viral & Genetic Oncogenesis
Dr D Ponraj
Bioscience/SHS/NYP
Introduction
• Cluster of cancer cases in space and time
suggest a viral aetiology
• Tumours associated with viruses tend to be
more common in youth
• Immunosuppression favours viral
oncogenesis
• Viruses implicated in human carcinogenesis
include EB virus (Burkitt’s lymphoma) and
HPV (cancer cervix)
Types of oncogenic virus
• Both DNA and RNA viruses can cause
neoplasia.
• DNA viruses insert their nucleic acid directly
into the genome of the host cell.
– The replication is sporadic or absent;
– However, DNA may persist and produce
an oncogene like effect
• RNA viruses require RNA-directed DNA
polymerase (reverse transcriptase), an enzyme
that causes production of a DNA copy of the
RNA viral genome.
– Some RNA viruses contain built-in oncogene
that directly activates cell.
– Others insert adjacent to an endogenous
cellular oncogene that directly activates the
cell.
RNA viruses
• Only few are implicated in human neoplasms
• HTLV-I: Japanese T cell leukaemia was first
described in Japan.
• HIV: associated with B cell lymphoma. (In
patients with AIDS Kaposi sarcoma is the
commonest malignancy)
• All others mostly cause cancer in experimental
animals (eg mouse mammary tumour virus
MMTV)
DNA viruses
• HPV: subtypes 16 & 18 are the common
cause of malignancy in 85% of in invasive
squamous cell ca.
• They suppress tumour suppressor gene Rb
and P53.
• Cotransfection with ras gene results in full
malignant transformation.
• Normally HPV cause anogenital warts.
Epstein-Barr virus
• Discovered first in cell cultures from
Burkitt’s lymphoma, a B-cell lymphoma
endemic in Africa. It also cause infectious
mononucleosis.
• It also results in nasopharyngeal Ca.
• EB virus is not the sole cause of Burkitt’s
lymphoma, its one of the multistep factor in
development of Burkitt’s lymphoma.
• It involves mutation affecting N-ras oncogene
and t(8:14) translocation.
Others
• Hepatitis B virus
– liver cancer
• Herpes simple virus
– Ca cervix
Genetic mechanism
• Cancer now is increasingly regarded as a
genetic disease.
• Some times they are consistently associated
with chromosomal defect (eg, Philadelphia
chromosome in CML)
• There are two mechanisms leading to tumour
growth:
• 1.Loss or inactivation of recessive inhibitory
genes- Tumour suppressor genes.
– E.g. P53 (guardian of genome), Rb1,APC...
• 2. Enhanced or abnormal expression of dominant
stimulatory genes-Oncogenes.
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They govern the neoplastic behaviour of cells.
More than 600 such genes have been identified
Based on their function they are classified into 4 types
eg (ras, myc, sis, erb…)
• Both mechanisms operate in most tumours (e.g. Ca
colon), but inactivation of tumour suppressor genes
explain inherited predisposition of development of
tumour (e.g. retinoblastoma).
• Note: A 3rd category of genes that control apoptosis are
also involved in tumour growth.
Mechanisms of genetic mutation
Virus
# Mutations that "turn on" the oncogenes stimulate growth.
# Mutations that result in loss of tumor suppressor genes
and their products inhibit growth.
Apoptosis (programmed cell death)
• It is an energy-dependent process for deletion of
unwanted individual cells. It has a role in
morphogenesis, organ size.
• Individual cell deletion in physiological growth &
disease
• Reduced apoptosis contributes to cell
accumulation in neoplasia
• Increased apoptosis results in excessive cell loss
(atrophy)
• Activated or prevented by several stimuli
Modes of inheritance
• IN MAN: 23 (22+1) PAIRS OF
CHROMOSOMES
• Autosomal dominant (only one copy of genes need
to be inherited, thus both hetero & homozygous are
affected)
• Autosoaml recessive (both copies of genes must be
abnormal, thus homozygous individuals are
affected)
• Sex chromosome (X)- linked (defective gene is in
the X chromosome, males are sufferers, females
are carriers)