Viruses and cancer

Question 1

oncogenesis

Answer 1

The series of events that transforms a normal cell into tumor cells is known as oncogenesis.

Question 2

Changes in normal body cells due to viruses

Answer 2

Changes in normal body cells due to viruses may be induced by; mutation, activation of oncogenes (tumor genes) and inactivation of tumor suppressors.

Question 3

Evidence of viruses in tumors

Answer 3

based on its regular
presence of virus DNA in the tumor cells,
which may form all or part of the virus
genome.

• The virus DNA may be integrated into a cell
chromosome in some tumors, while in other
tumors, it is present as multiple copies of
covalently closed circular DNA (cccDNA).

Question 4

Virus-induced cancers

Answer 4

• Papillomavirus-linked cancers
• Polyomavirus-linked cancers
• Epstein-Barr virus-linked cancers
• Kaposi’s sarcoma
• Adult T cell leukemia
• Hepatocellular carcinoma

Question 5

1. Papillomavirus-linked cancers

Answer 5

• Papillomaviruses are tiny DNA viruses infecting mammals and birds, for which those infecting humans are known as HPV.
• HPV infect humans via tiny skin cuts or bruises and mucous membranes, where they infect basal cells in the epithelium.
• Sequencing of HPV genome have identified over 200 types, with preference for infecting various sites of the body such as, genitals, hands, resulting in a carcinoma or a benign wart (papilloma).

Question 6

1. Cervical carcinoma

Answer 6

1. Cervical carcinoma: Is induced by HPV infection, and is the third most common cancer in females, accounting for about 16% of all cancers.
   • Annually, about 500,000 new cases of cervical carcinoma is reported, resulting in about 275000 deaths.
   • HPV infecting the genitals are transmitted between humans through sexual contact.
   • Majority of HPV infections are not persistent, but persistent infection has a high probability of forming cancers, which is dependent on HPV type categorized as: 1. High-risk HPV: e.g., HPV-16 and 18 2. Low-risk HPV: e.g., HPV-6 and 11 (linked with benign genital warts).

Question 7

Detection and prevention of HPV-
induced cancers

Microscopic observation

Answer 7

Sequence of morphological
changes due to cancer formation can be observed from
cells extracted from the cervix.

Question 8

Detection and prevention of HPV-
induced cancers

DNA analysis

Answer 8

molecular analysis of cervical cells could
detect the HPV gene in the cell chromosome.
• Staging: important to determine the stage of the
cancer through MRI, X-ray, etc., to determine best form
of treatment.
• Detected pre-cancer cells can be destroyed or killed to
prevent tumor development.

Question 9

HPV-induced skin cancer:

Answer 9

Is a rare form of cancer, with a genetic basis (epidermodysplasia verruciformis).
• found in persons susceptible to some uncommon HPV types; type 5 (mainly) and type-8.
• HPV-induced skin cancer results in warts, which cover the skins of the patient at childhood, and between 25-33% of patient develop squamous cell carcinoma in areas of the skin exposed to UV-light.
• HPV DNA have been found in over 80% of cases of the skin cancer, but the DNA isn’t incorporated in cell chromosome in most cases, which is in contrast to cervical carcinoma.

• HPV type-16 have been found to be associated with cancers in other tissues of the vagina, vulva, anus, penis, mouth, neck, anus, etc.

Question 10

Polyomavirus-Linked Cancers

Answer 10

• Polyomaviruses are DNA viruses that infect mammals and birds resulting in mainly subclinical conditions.
• They share similar characteristics with the papillomaviruses, except that they are smaller.
• Some members are important agent of cancer:

Merkel cell polyomavirus

simian virus 40

Question 11

Merkel cell polyomavirus

Answer 11

causes a uncommon skin cancer which mainly infect the aged and immunocompromised individuals. The genome of tumor cells due to the virus have been observed to express the T (tumor) antigen of the virus

Question 12

Simian virus 40 (SV40):

Answer 12

: Is a monkey polyomavirus extracted from primary cell culture of kidney cells. Divergent views exist whether the SV40 virus is linked with human cancers or not.

Question 13

Epstein-Barr Virus-linked cancers

Answer 13

Burkitt’s lymphoma (BL):

Nasopharnygeal carcinoma (NPC):

Question 14

Burkitt’s lymphoma (BL):

Answer 14

Is caused by EBV belonging to the family Herpesviridae.
EBV induces B cell tumor, which shows high prevalence in children from central Africa and the new Papua Guinea. BL tumor cells arise from chromosomal rearrangement in B cell gene, when a c-myc gene is transferred next to the enhancer of an immunoglobulin gene, resulting in its over expression.

Question 15

Nasopharnygeal carcinoma (NPC):

Answer 15

The tumor is induced by EBV and infect humans worldwide. EBV genome is present in tumor cells of NPC as covalently closed circular DNA (cccDNA), similarly as Burkitt’s lymphoma. Other cancers associated with EBV are:
• Hodgkin’s lymphoma
• Non-Hodgkin’s lymphoma in AIDS
• Post transplant lympho-proliferative disorder

Question 16

Kaposi’s Sarcoma

Answer 16

• Is one of the aggressive and versatile cancers associated with AIDS.
• The cancer was discovered in 1994 and named as the Kaposi’s sarcoma-associated herpesvirus (KSHV).
• The cancer is more prevalent in central Africa, especially homosexual men.
• KSHV establishes a latent infection in B cells and in the endothelial cells lining blood vessels.
• Immunosuppression can induce cancer in host arising from uncontrolled growth and division of cells.
• In B cells, uncontrolled cell growth and division results in a primary effusion lymphoma or multicentic Castleman’s disease.
• In endothelial cells uncontrolled cell growth and division results in Kaposi’s sarcoma.

Question 17

Adult T cell leukemia

Answer 17

• This tumor is linked with human T-
lymphotropic virus 1 (HTLV-1).
• HTLV-1 belongs to the retroviruses and each
of its associated tumor cells have been
observed to contain the provirus DNA in the
chromosome.
• The cancer is prevalent in parts of the world
(e.g. southwest Japan), where the virus is
prevalent.

Question 18

Hepatocellular carcinoma

Answer 18

• The cancer is associated with 2 viruses:
1. Hepatitis B virus (HBV): most important cancer agent.
2. Hepatitis C virus (HCV)
• Hepatocellular carcinoma causes liver cancer which constitute 4-5% of all cancer cases globally.
• Also, liver cancer is most prevalent virus-linked cancer in men.
• Persistent infection with HBV or HCV result in liver cirrhosis which in turn induces rapid cell division to replace the damaged liver cells.
• Mutation in any one of the resultant cell could lead to cancer.

Question 19

Derived cell lines from virus-induced

cancers

Answer 19

1. HeLa cell line: Is the most common cell line
   worldwide, extracted from cervical cancer.
   Each cell of the HeLa cell line contains a copy
   of its gene in the HBV-18 genome.
2. HBV-derived cell lines: derived from
   hepatocyte
3. Epstein-Barr virus (EBV)-derived cell lines

Question 20

Mechanism of virus-induced cancers

Answer 20

• Generally, virus-induced cancers may arise from long and
persistent infection with some carcinogenic viruses.

• E.g., in adult T cell leukemia, development of cancer due to a
virus may last about 60 years.

virus proteins
produced during persistent infection could trigger a
normal cell into a cancerous cells in several ways.

1. Virus deliberate interference with controllers of
   cell activities. 2. Accidental activation of cell genes
2. Retroviral oncogenes
3. Damage to immune defenses

Question 21

• The probability of a virus becoming carcinogenic in a host cell
involves a complex interaction which depend on:

Answer 21

1. condition of the host,
2. environmental factors around the host and
3. infection induced cellular changes.

Question 22

Virus deliberate interference with controllers

of cell activities

Answer 22

• Viruses must manipulate the internal environment of its host cell to successfully replicate its genes.
• E.g., DNA viruses such as adenoviruses, papillomaviruses and polyomaviruses require that the host cell is in the S-phase of the cell cycle for the derivation of DNA replication molecules.
• In humans, p53 and retinoblastoma protein (pRb) are two amongst the many proteins involved in cell cycle regulation.
• Mutation in the 2 gene copies of pRb protein could result in cancer of the retina (retinoblastoma).
• Also, research have shown that many proteins synthesized by viruses can interact with cell cycle regulatory proteins (p53 and pRb), increasing the possibility of the cell undergoing continuous cell division leading to cancers.

Question 23

Viruses and their proteins can form inhibitory interactions with cell cycle regulatory proteins (p53 and pRb) such as:

Answer 23

• HPV early proteins E6 and E7, situated in the nucleus can bind to p53 and pRb proteins respectively, causing their dissociation, resulting in cell transition to the S phase of the cycle.
• SV40 large T antigen binds (p53 and pRb).
• KSHV latency-associated nuclear antigen binds (p53 and pRb).
• Adenovirus E1A protein binds pRb
• HBV X protein binds p53

Question 24

Accidental activation of cell genes but viruses

Answer 24

• Some virus proteins may bind to a wrong
targeted cell proteins, resulting in outcomes
that are not beneficial to the virus, but could
be harmful to the host.
• E.g., some retroviruses can trigger tumor
formation as a result of incorporating their
provirus into a host chromosome at a site that
places a cell gene under the control of a virus
promoter.

Question 25

Retroviral oncogenes

Answer 25

• Some viruses are able to trigger cancerous cells in host due to the presence of an oncogene in viral genome.
• E.g., the Rous sarcoma virus contains the v-src gene in its genome; derived from the host cell proto-oncogenes both of which are related.

Question 26

Oncogenic Damage to immune defenses

Answer 26

• Oncogenic virus proteins can interact with host
cell proteins which could result in collapse of the
host immune barriers leading to the formation of
cancers.
• Specifically, oncogenic viruses may interfere with
apoptosis (programmed cell death), preventing
the destruction of a virus-infected cell.
• E.g. EBV and KSHV, released proteins can
interfere with acquired immune responses in
latently infected cells

Question 27

Prevention of virus-induced cancers

Answer 27

Prevention of transmission

2. Vaccination: various vaccines (from native capsid proteins or recombinant virus proteins) have been developed against some oncogenic viruses such as, HBV (administered to babies 2 days post-birth), HPV. 3. Elimination of viruses with persistent infections in host cells.
   So far, persistent HBV infection in host cells have been controlled, but not eliminated, by administering α-interferon and/or lamivudine.
   While HCV infection in some patients have been eliminated using α-interferon.