Cancer
-In young animal, cell multiplication exceeds cell death, so animal
increase in size
-In adults, the process of cell birth and death are balanced
-Sometimes, Control system for cell multiplication break down, and
a cell begins to grow and divide in an unregulated fashion
Descendant cells inherit this property proliferate without
responding to regulation, forming a mass called a tumor
A cancer is mainly caused by mutation in somatic cells, number
of mutation may vary from 3-20
   

ONCOGENES
◼ Normal cells contains highly related but not
identical copies of retroviral transforming
genes
◼ Proto oncogenes are found in all animals,
exert normal cellular function
◼ Components of regulatory pathways to control
cell proliferation, division and differentiation.
◼ Incorrect expression of any component might
result in uncontrolled growth of cells.

Oncology and Oncogenic Viruses
Terminologies
◼ Oncogenes: encode proteins that associated with oncgenesis
◼ Transformation: stable and heritble change in the genes for
growth control
◼ Contact inhibition: Stop growing upon contact with
neighboring cell
◼ Immortalization: Cell divides for indefinite period
◼ Benign tumor: Composed of cells with abnormal growth but
non-invasive
◼ Malignant tumor: Composed of cells with abnormal growth
that invade to other organs
◼ Metastasis: Invasion of cancer to other part of the body
◼ Neoplasm: formation of new cells
◼ Hyper plastic: abnormal cell growth

Cancers Originate in Proliferating
Cells
◼ Cancers must occur in dividing cells so that mutations
are passed on many progeny cells
◼ Mutations in non-dividing cells do not induce cancer
◼ Stem cell present in different organs and tissues
divide continuously and generate more stem cells
◼ Oncogenic mutations in theses stem cells DNA can
accumulate and eventually transforming them into
cancer cells
◼ Cells that have acquired mutations have abnormal
proliferation capacity but can not undergo normal
process of differentiation

Benign vs. Malignant Tumors
Benign Malignant
Grow slowly Grow rapidly
Well-defined capsule Not encapsulated
Not invasive Invasive
Well differentiated Poorly differentiated
Low mitotic index High mitotic index
Do not metastasize Can spread distantly
(metastasis)

Classification & Nomenclature
◼ Benign
◼ Named according to the tissue from which
they arise, and includes the suffix - “oma”
◼ Lipoma
◼ Glioma
◼ Leiomyoma
◼ Chondroma

Classification & Nomenclature
• Malignant tumors
Named according to the tissues from which they
arise
Epithelial tissue – carcinoma
Ductal or glandular epithelium – adenocarcinoma
Example: mammary adenocarcinoma
Connective tissue – sarcoma
Example: rhabdomyosarcoma
Lymphatic – lymphomas
Blood forming cells – leukemia

Classification & Nomenclature
◼ Carcinoma in situ (CIS)
◼ Preinvasive epithelial malignant tumors of glandular or
Squamous cell origin that have not broken through the
basement membrane or invaded the surround stroma
◼ Cervix, skin, oral cavity, esophagus and bronchus
(epithelium)
◼ Stomach, endometrium, breast, large bowel (glandular)

Cancer cells accumulate mutations
• Most cancer cells have increased
number of mutations then the
normal cells
• As the cancer progresses, the
number of mutation increases
• Inactivation of mutator genes
decreases the repair damage of
DNA, and increase the rate of
mutation
• The occurrence of different
mutations creates an opportunity
to select population of cells with
particular properties

Cancer arise from a
single clone
• The occurrence of different mutations
creates an opportunity to select the
cells with particular properties
• In the case of cancer, a mutation that
increases the growth potential of a cell
will give it a selective advantage
• A cell that divides more often, will
generate more descendants
• At each stage during the progression
of a cancer, the cell population is
selected for those cells that can grow
more aggressively

Tumor cells are immortalized
and transformed
Three types of changes that occur when a
cell becomes tumorigenic
-Immortalization
-Transformation
-Metastasis
When cells are placed in culture,
-grow for division
-enter a senescent stage
-go through the crisis
-survival of crisis are capable of
dividing indefinitely

Properties of a transformed cell
Most prominent changes are
◼ Alteration in growth pattern- increased
growth rate, anchorage independence
◼ Alteration in cell surface
◼ Alteration in intracellular component
and biochemical processes- increase
protease and protease activators
◼ Tumorigenecity- forms tumor upon
injection in animals

Tumor Cells have altered Morphology
Cells cultured from tumors show
changes in some or all of these
properties. They are said to be
transformed
• A transformed cell grows in a much
less restricted manner
• It has reduced serum-dependence,
• It does not need to attach to a solid
surface
• The cells pile up into a focus instead of
growing as a surface monolayer.
• The cells may form tumors when
injected into appropriate test animals.

Seven types of protein control
cell growth
◼ Cancers can result from expression of
mutant from proteins like:
 Growth factors (I)
 Growth factor receptors (II)
 Signal transduction Proteins (III)
 Transcription factors (IV)
 Pro- or anti- apoptotic proteins (V)
 Cell cycle control proteins (VI)
 DNA repair proteins (VII)

. Growth factor (I)
Growth factor
receptor (II)
Intracellular
transducer (III)
Intracellular effector
region (PTK)
Second messenger
(phosphorylated proteins)
Transcription factors (IV)
DNA
Transcription
DNA repair
Proteins (VII)
RNA
Cell cycle control
proteins (VI)
mRNA Proteins
Anti-apoptosis
proteins (V)
Intracellular
receptors (II)
Virus encoded
activators of
growth –factor
receptors (Ia)

Mechanisms of oncogenic
activation
◼ Mechanisms of activation of proto
oncogene and converting to a cancer
gene vary
- over expression
- constituently active
- express in wrong time
- express in wrong place
Interaction of proto-oncogene product
with other proteins altered

Mechanisms of activations
◼ Transduction by retroviruses
◼ Insertional mutagenesis
◼ Translocation
◼ Gene amplification
◼ mutation

Transduction
◼ Cellular proto oncogenes may
transduced into retroviral genome
◼ Transduced gene replicated and
transmitted like viral genes
◼ Upon infection the transduced gene
expressed abundantly under viral signal

Insertion
◼ Insertion of a retroviral promoter
adjacent to cellular oncogene
◼ First occurred in avian leucosis virus
Host
gene
5’LTR 3’ LTR
C- myc

Translocation
◼ Translocation of a proto-oncogene near a
strong regulatory sequence
◼ Translocation may affect the expression of
proto-oncogene or gene product
Translocation in Burkitt’s lymphoma
H pro.
H-gene
C-myc pro.
C-myc gene
H pro.
C-myc gene
C-myc pro.
H-gene
Chromosome 14 8 Chromosome 14 8

Gene Amplification
◼ Increase in copy number of a potential
gene resulting in excess production of
the encoded protein
◼ Amplification of oncogene HER-2/neu
occur in breast cancer
◼ Gene amplification mostly occur at the
late stage of tumor progression

Mutation
◼ Point mutation or deletion might change
the function of a protein,
◼ Substrate specificity,
◼ cell binding property,
◼ Binding specificity of a transcription
factors etc.
◼ Altered protein may lead to oncogenic
activation, eg. C-ras gene

Oncogenic Viruses
◼ DNA Viruses
- Human papilomaviruses (HPV)
- Epstein Barr Virus (EBV)
- Hepatitis B Virus (HBV)
◼ RNA Viruses
-Retroviruses
-Hepatitis C Virus
◼ RNA tumor viruses introduce a transforming gene into the cell
(??HCV)
◼ DNA tumor viruses induce or alter the expression of a pre existing
cellular gene/s (proto-oncogene)

Transformation by DNA and RNA Viruses
◼ DNA tumor Viruses do not carry any
transduced oncogene but, most of
the RNA tumor viruses do
◼ DNA tumor Viruses do not produce
tumor in their natural host cells, but
replicate there.
◼ RNA tumor viruses cause cancer in
their natural host
◼ Both kind of tumor viruses integrate
their genome into host DNA; at
least a few copies of gene

Transformation ……… Viruses (cont)
• Permissive cells are productively
infected. The virus proceeds
through a lytic cycle that is
divided into the usual early and
late stages. The cycle ends with
release of progeny viruses and
(ultimately) cell death.
• Nonpermissive cells cannot be
productively infected, and viral
replication is abortive. Some of the
infected cells are transformed; in
this case, the phenotype of the
individual cell changes and the
culture is perpetuated in an
unrestrained manner.

Transformation ……… Viruses (cont)
• The oncogenes of DNA transforming viruses
carry out early viral functions.
• The oncogene becomes integrated into the
host cell genome and is expressed
constitutively.
• The oncogenes of polyomaviruses are T
antigens, which are expressed by alternative
splicing from a single locus.
• Adenoviruses express several E1A and E1B
proteins from two genes.

Retroviruses activate or incorporate
cellular genes
◼ Retroviruses can transfer
genetic information both
horizontally and vertically.
◼ Horizontal transfer is
accomplished by the normal
process of viral infection, in
which increasing numbers of
cells become infected in the
same host.
◼ Vertical transfer results
whenever a virus becomes
integrated in the germ line of
an organism as an endogenous
provirus; like a lysogenic
Bacteriophage.

• Nondefective viruses follow the usual retroviral life cycle.
They provide infectious agents that have a long latent period,
and often are associated with the induction of leukemias.
Two classic models are FeLV (feline leukemia virus) and
MMTV (mouse mammary tumor virus).
• Tumorigenicity does not rely upon an individual viral
oncogene, but upon the ability of the virus to activate a
cellular proto-oncogene (s).
⚫ Acute transforming viruses have gained new genetic
information in the form of an oncogene. This gene is not
present in the ancestral (nontransforming virus); it originated
as a cellular gene that was captured by the virus by means of
a transduction event during an infective cycle. These viruses
usually induce tumor formation in vivo rather rapidly, and
they can transform cultured cells in vitro. Reflecting the fact
that each acute transforming virus has specificity toward a
particular type of target cell, these viruses are divided into
classes.
• Acute transforming retroviruses have oncogenes that are
derived from cellular genes.

◼ When a retrovirus captures a cellular gene by
exchanging part of its own sequence for a
cellular sequence, some of the original retro -
viral sequences are replaced by a cellular
sequence, creates a transducing virus that has
two important properties,
-Usually these viruses are replication-defective, cannot
replicate by itself, but they can propagate with a
wild-type "helper" virus
-During an infection, their expression may alter the
phenotype of the infected cell