CANCER

§ CANCER : is a disease of
cellular mutation,
proliferation and abberant
cell growth

§ NEOPLASIA : new growth or

autonomous growth of tissue

§ NEOPLASM : the lesion

resulting from the neoplasia
 MALIGNANT BENIGN
• invasive growth, § expansive growth,
• capable of metastases to § frequently exhibiting slow
other tissues and organs rates of proliferation
§ do not invade surrounding
tissues
§METASTASES : secondary growths of cells
from the primary malignant neoplasm

§TUMOR : Lesion characterized by swelling or

increase in size, may or may not be neoplastic
 GENOTOXIC
Carcinogens that interact
with DNA resulting in
mutation
CARCINOGENS
NON -
GENOTOXIC
Carcinogen that modify
gene expression but do
not damage DNA
 INITIATION
§stable, heritable change

§ Rapid, irreversible process that results in a

carcinogen-induced mutational event
 INITIATION
§INITIATORS/INITIATING AGENTS
§Chemical or physical agents that interact with
cellular components

§Chemical carcinogens that covalently bind to DNA

and form adducts that resulting in mutations
 INITIATION
§Outcomes:
1. The initiated cell can remain in a static non-
dividing state

2. The initiated cell may possess mutations

incompatible with viability or normal function and
be deleted through apoptopic mechanisms

3. The cell may undergo cell division resulting in the

proliferation of the initiated cell
 PROMOTION
§Selective clonal expansion of initiated cells to
produce a preneoplastic lesion

§TUMOR PROMOTERS
§ Both exogenous and endogenous agents that operate at
this stage
§ Not mutagenic and not able to induce tumors by
themselves
 PROMOTION
§ Tumor promoters generally show organ –
specific effects

§ Reversible upon removal of the promoting

agent

§ Focal cells may return to single initiated cell

thresholds
 PROGRESSION
§PROGRESSION
§ involves the conversion of benign preneoplastic
lesions into neoplastic cancer

§ DNA damage including chromosomal aberrations

and translocations may occur due to an increase in
DNA synthesis and cell proliferation in the
preneoplastic lesions
 PROGRESSION
§Irreversible in that neoplasm formation,
malignant or benign

§Accumulation of nonrandom chromosomal

abberations and karyotypic instability are
hallmarks of progression
§ IMPORTANT:

Tumors are not just a collection of clonal

neoplastic cells but a complex tissue with
multiple cell populations that interact with
one another and function as a unique tissue
§ GENOTOXIC/DNA REACTIVE
CARCINOGENS
§ Subdivided:
1. Direct – acting carcinogens : agents that can
bind directly to DNA without being metabolized

2. Indirect – acting carcinogens : compounds that

require metabolism in order to react with DNA
§ MUTAGENESIS
§ Effects of mutations depend on when in the
cell cycle adducts are formed, where the
adducts are formed, and the type of repair
process used in response to the damage

§May result from misread DNA (through

transitions or transversions) frame-shifting,
or broken DNA strands
§ DAMAGE BY ALKYLATING
ELECTROPHILES
§ The ultimate carcinogenic forms of these
chemicals are frequently strong electrophiles that
can readily form covalent adducts with
nucleophilic targets
§DNA REPAIR
§ Formation of a carcinogen – DNA adduct, the
persistence of the adduct is a major determinant
of outcome.
§ Mismatch repair of single-base mispairs
§ Excision repair
§ End-joining repair of non-homologous DNA
 CLASSES OF GENOTOXIC
CARCINOGENS
1. POLYAROMATIC HC
§ benzo(a)pyrene are found at high levels in charcoal
broiled foods, cigarette smoke and in diesel exhaust
2. ALKYLATING AGENTS
§ Alkylating agents readily react with DNA at more than 12
sites. The N7 position of guanine and N3 position of
adenine are the most reactive sites in DNA for alkylating
chemicals
 CLASSES OF GENOTOXIC
CARCINOGENS
3. AROMATIC AMINES AND AMIDES
§ Exposure through dye industry, cigarette smoke
§ Aromatic amines undergo phase I (hydrolysis,
reduction and oxidation) and phase II
(conjugation) metabolism
§ NONGENOTOXIC CARCINOGENS
MODE OF
DESCRIPTION EXAMPLE
ACTION
Cytotoxicity Sustained cell death that is Chloroform
accompanied by persistent Melamine
regenerative growth
Receptor – Induction of CYP2B by phenobarbital is Phenobarbital
mediated CAR mediated by activation of constitutive
androstane receptor (CAR)
PPARα - Involves agonist binding to nuclear Trichloroethylene,
(Peroxisome hormone receptor PPARα perchloroethylene,
Proliferator- - Highly expressed in cells that have fibrates,
activated active fatty acid oxidation capacity plasticizers
Receptor - α
§ NONGENOTOXIC CARCINOGENS
MODE OF
DESCRIPTION EXAMPLE
ACTION
Hormonal Mode of Cause tissue – specific changes Biogenic amines,
Action through interaction with a steroids, peptide
receptor hormones
DNA Methylation Altered methylation Phenobarbital
Diethanolamine
Oxidative Stress Reactive oxygen species left Ethanol, Acrylonitrile
unbalanced by antioxidants,
can result to damage to cellular
macromolecules
§ GAP JUNCTIONAL INTERCELLULAR
COMMUNICATION AND CARCINOGENESIS

§Play an important role in the regulation of cell

growth and cell death through the ability to
exchange small molecules between cells
§ Cell communication is BLOCKED! àexchange of growth
inhibitory signals from normal cells to initiated cells is
prevented à allowing the potential of unregulated growth
and clonal expansion of initiated cell populations
§ PROTO-ONCOGENES AND TUMOR-
SUPPRESSOR GENES
§ Encode a wide array of proteins that function to control
cell growth and proliferation
§ Proto – oncogenes
§ encodes a protein that is capable of transforming cells
in culture or inducing cancer in animals
§ Tumor – suppresor genes
§ Proteins encoded act as inhibitors of cell proliferation
or cell survival
§TUMOR-SUPPRESSOR GENES
Tumor Disorder Neoplasm
suppressor
Rb1 Retinoblastoma Small-cell lung cancer
p53 Li-fraumeni syndrome Breast, colon, lung cancers
BRCA1 unknown Breast carcinoma
WT1 Wilm’s tumor Lung cancer
p16 unknown Melanoma
§CHEMOPREVENTION

§Study of chemicals that prevent, inhibit, or

slow down the process of cancer

§Chemopreventive agents may function as

inhibitors of carcinogen formation, blocking
agents, and/or suppressing agent
Carcinogenic factors associated with lifestyle
CHEMICAL (S) NEOPLASM(S)
Alcoholic beverage Esophagus, liver, oropharynx, and
larynx
Aflatoxins (corn, peanuts) liver
Betel chewing mouth
Dietary intake (fat, protein, Breast, colon, endometrium, gall
calories) bladder
Tobacco smoking Mouth, pharynx, larynx, lung,
esophagus, bladder
 GROUP EVIDENCE
1. Agent is carcinogenic in humans Human data strong
Animal data strong
2A. Agent is probably carcinogenic to Human epidemiology data suggestive
humans Animal data positive
2B. Agent is possibly carcinogenic to Human epidemiology data weak
humans Animal data positive
3. Agent is not classifiable as to Human and animal inadequate
carcinogenecity to humans
4. Agent is probably not carcinogenic Human and animal data negative
to humans

International Agency for Research on Cancer (IACR) Classification