Tumor Viruses

• Tumor viruses have no characteristic size, shape, or chemical composition.

• Some are large, and some are small; some are enveloped, and others are
naked (i.e., nonenveloped); some have DNA as their genetic material, and
others have RNA.
• The factor that unites all of them is their common ability to cause tumor.
• They are more rapid, reliable, and efficient tumor producers than either
chemicals or radiation.
They have a small number of genes compared with a human cell (only three, four,
or five for many retroviruses
MALIGNANT TRANSFORMATION OF CELLs
• The term malignant transformation refers to changes in the growth
properties, shape, and other features of the tumor cell
• Malignant transformation can be induced by tumor viruses not only in
animals but also in cultured cells
• In culture, the following changes occur when cells become malignantly
transformed
Altered Morphology
• Malignant cells lose their characteristic differentiated shape and appear
rounded and more refractile when seen in a microscope.
• The rounding is due to the disaggregation of actin filaments, and the reduced
adherence of the cell to the surface of the culture dish is the result of changes
in the surface charge of the cell.
Altered Growth Control
• Malignant cells grow in a disorganized, piled-up pattern in contrast to
normal cells, which have an organized, flat appearance.
• The term applied to this change in growth pattern in malignant cells is loss
of contact inhibition.
 • Malignant cells grow well in suspension, whereas normal cells grow well
only when they are attached to a surface (e.g., a culture dish).
Malignant cells are easily cloned (i.e., they can grow into a colony of cells starting
with a single cell), whereas normal cells cannot do this effectively
Altered biochemical Properties
• Levels of cyclic adenosine monophosphate (AMP) are reduced in malignant
cells. Addition of cyclic AMP will cause malignant cells to revert to the
appearance and growth properties of normal cells.
• Malignant cells secrete more plasminogen activator than do normal cells.
This activator is a protease that converts plasminogen to plasmin, the
enzyme that dissolves the fibrin clot.
PROVIRUSES & ONCOGENES
• The two major concepts of the way viral tumorigenesis occur are expressed
in the term’s provirus and oncogene.
• In the provirus model, the genes enter the cell at the time of infection carried
by the tumor virus
• Both proviruses and oncogenes may play a role in malignant transformation.
Evidence for the provirus mode consists of finding copies of viral DNA
integrated into cell DNA only in cells that have been infected with the tumor
virus. The corresponding uninfected cells have no copies of the viral DNA
Proto-oncogene and oncogenes
Protooncogenes are genes that encodes diverse of proteins like
• Growth factors
• Growth factor receptors
• Transcriptional factor
• Signal transduction proteins
These are normal genes within our body but when these genes run into mutation,
chromosomal rearrangement or gene amplification then these protooncogenes will
convert into oncogenes which are abnormal genes and have ability to cause cancer.
Proto-oncogene transformation phases

If we see the point mutation through animation, we see it all happen at the DNA
level Let's say we have the DNA molecule having one base mismatch base pair.
• Here in this pair guanine is replaced with adenine this base mismatch
happens during DNA replication and it continue within the strand when
DNA repair is compromised.
• So now instead of guanine we have adenine here this makes ACT codon.
• It will make UGAcodon of mRNA which is a stop codon from here protein
synthesis will stop thereby giving us altered form of protein that also led to
formation of oncogene. like we have point mutation in r e s gene that cause
cancer.
Then we have regulatory mutation which mostly happens when enhancer
sequences on DNA are mutated and regulation of gene is compromised there by
normal genes are over Express in that case
2) gene amplification It is when normal gene expression is amplified and from
that normal protein is over express which ultimately leads to
formation of oncogene.
3) chromosomal rearrangement
 • They are of two types
1)Chromosomal rearrangement in regulatory sequence
2) Rearrangement in protein coding sequences that cause fusion of genes.
• In first the normal protein is over expressed.
• In second there is formation of hyperactive fusion protein like bcr-
abl rearrangement.
RNA Tumor Viruses
1. Human T- cell Lymphotropic Virus:
• There are two human T- cell Lymphotropic viruses, that are HTLV-1 and
HTLV-2, both are associated with leukaemia and lymphoma.
HTLV- 1:
• HTLV-1 is the cause of tropical spastic paraparesis.
• It has no viral oncogene. Rather it has two important genes called Tax and
Rex.
• The Tax protein has 2 activities:
☆ It acts on the viral Long Terminal Repeat (LTR) sequence to stimulate viral
mRNA synthesis.
☆ It induces nuclear factor KB (NF-KB) which stimulates the production of IL-2
and IL-2 receptor.
• The Rex protein determines which viral mRNAs can exit the nucleus and
enter the cytoplasm to be translated.
It is an exogenously acquired virus because it’s proviral DNA is only found in
DNA of malignant lymphoma cells
• It infects CD4- positive T cells preferentially and will induce malignant
transformation in these cells in vitro.
• Transmission occurs primarily by breastfeeding and by exchange of
contaminated blood.
HTLV- 2:
 • HTLV-2 has 60% genetic homology with HTLV-1.
• Like HTLV-1, it is transmitted by blood and semen and infects CD4 positive
cells.
• Routine serologic tests don’t distinguish between HTLV-1 and
HTLV-2.
Hepatitis C Virus:
Chronic infection with hepatitis C virus, like hepatitis B virus also predisposes to
hepatocellular carcinoma
DNA Tumor Viruses
1)Human papillomavirus
• Family: Papillomavirus
• Non-enveloped, Capsid Symmetry: Icosahedral
• DNA structure: ds circular, supercoiled
• Replicate in nucleus.
• Transmission: Sexually transmitted disease
• Papillomata are benign but can progress to form carcinomas, especially in an
immunocompromised person.
• HPV primarily infects mucosal squamous epithelium.
• Carcinogenesis by HPV involves two proteins encoded by HPV genes E6
and E7 that interfere with the activity of the proteins encoded by two tumor
suppressor genes, p53.
• In cancer cells the viral DNA is integrated into the cellular DNA, E6 and E7
proteins are produced.
• There are at least 100 different types of HPV. Certain types of HPV,
especially types 16 and 18, are implicated as the cause of carcinoma of the
cervix, penis, and anus.
• For example, HPV-1 through HPV-4 cause plantar warts on the soles of the
feet, whereas HPV-6 and HPV-11 cause anogenital warts and laryngeal
papilloma’s
 Epstein–Barr Virus
• Family: Herpes virus
• Enveloped, Capsid Symmetry: Icosahedral
• DNA structure: ds linear
• Replicate in nucleus.
• Transmission: Sexually transmitted disease
• Epstein–Barr virus (EBV) is a herpes virus that was isolated from the cells
of an East African individual with Burkitt's lymphoma.
• EBV, the cause of infectious mononucleosis, transforms B lymphocytes in
culture.
• Cells isolated from East African individuals with Burkitt's lymphoma
contain EBV DNA and EBV nuclear antigen. Only a small fraction of the
many copies of EBV DNA is integrated; viral DNA is in the form of closed
circles in the cytoplasm.
• Infection by the virus is widespread but the tumor is rare. The current
hypothesis is that EBV infection induces B cells to proliferate, thus
increasing the likelihood that a second event (e.g., activation of a cellular
oncogene) will occur.
• In Burkitt's lymphoma cells, a cellular oncogene, c-myc, which is normally
located on chromosome 8, is translocated to chromosome 14 at the site of
immunoglobulin heavy chain genes. This translocation brings the c-myc
gene in juxtaposition to an active promoter, and large amounts of c-myc
RNA are synthesized. It is known that the c-myc oncogene encodes a
transcription factor, but the role of this factor in oncogenesis is uncertain.
Human Herpes virus 8
• Family: Herpes virus
• Enveloped, Capsid Symmetry: Icosahedral
• DNA structure: ds linear
• Replicate in nucleus
• Transmission: Sexually transmitted disease
• Human herpes virus 8 (HHV-8), also known as Kaposi’s sarcoma–
associated herpes virus (KSHV), causes Kaposi’s sarcoma (KS).
• KS is a malignancy of vascular endothelial cells that contains many spindle-
shaped cells and erythrocytes.
• It is the most common cancer in patients with acquired immunodeficiency
syndrome (AIDS).
• KSHV is transmitted both sexually and by saliva.
A protein encoded by KSHV called latency-associated nuclear antigen (LANA)
inactivates RB and p53 tumor suppressor proteins, which causes malignant
transformation of the endothelial cells.
Hepatitis B Virus
• Family: Hepadna virus
• Enveloped, Capsid Symmetry: Icosahedral
• DNA structure: ds incomplete circular
• Replicate in nucleus
• Transmission: Transmitted through blood, from mother to newborn and
sexually transmitted disease.
• HBV infection is significantly more common in patients with primary
hepatocellular carcinoma.
• This relationship is striking in areas of Africa and Asia, where the incidence
of both HBV infection and hepatoma is high.
• Chronic HBV infection commonly causes cirrhosis of the liver; these two
events are the main predisposing factors to hepatoma. Part of the HBV
genome is integrated into cellular DNA in malignant cells.
• However, no HBV gene has been definitely implicated in oncogenesis. The
integration of HBV DNA may cause insertional mutagenesis, resulting in the
activation of a cellular oncogene. In addition, the HBx protein may play a
role because it inhibits the p53 tumor suppressor protein.