It may surprise people to hear that 10–15 per cent of all cancers across the globe can be attributed to 
viruses. This figure is likely to increase as research uncovers more viral genes within the tumour cells. 
One small benefit that has come about from the pandemic of AIDS has been the discovery that a new 
herpes virus, human herpes virus-8 (HHV-8) has been identified to play a role in the development of 
Kaposi’s sarcoma. The importance of understanding the role of viruses in the aetiology of cancer cannot 
be overemphasised. Studies of viruses have led to many of the critical discoveries in the workings of 

eukaryote cell biology: gene mutations in bacteriophages, cellular oncogenes, tumour suppressor genes, bacterial restriction enzymes and viral reverse transcriptase 
All of these have been uncovered through the study of viruses. The study of such fundamental 
mechanisms of cell biology provide new targets for the design of novel anticancer and antiviral drugs. 
Perhaps the most powerful implication from studying infectious links with cancer is the remarkable 
finding that vaccination can be used to prevent cancer. Vaccination against hepatitis B has reduced 
morbidity and mortality of liver cancer in Taiwan.
Cancer is the uncontrolled proliferation of cells resulting from the accumulation of mutations in genes 
that regulate the cell cycle. Normally, cell proliferation is tightly controlled such that cell division is 
matched by cell loss in order to maintain the size of an organ (e.g. the liver). The cells are able to 
respond in a balanced manner to the signals that promote or inhibit growth. In cancer the regulatory gene 
products malfunction and the cell divides continuously. Carcinogenesis is a multistep process: a series of 
events (up to nine in the case of colonic cancer) need to occur before the cancerous properties are fully 
developed. Cancer is also multifactorial in origin: several different triggers are required to cause the 

mutations, of which viral infection may be just one.
A number of viruses have been shown to directly cause cancer in animals. Rous in 1910 induced 
sarcoma in chickens by injecting filterable extracts from diseased animals. The filterable agent turned 
out to be a retrovirus and numerous retroviruses have been found subsequently to cause animal tumours. 
Such a direct causal relationship has not been so easy to establish in humans. Some of the viruses that 
have been linked with human cancer are as follows. 
•  Epstein Barr virus and Burkitt’s lymphoma.The first association of a virus with a human 
cancer was in 1964 with the direct observation of Epstein Barr virus particles by electron 
microscopy in cell cultures from humans with Burkitt’s lymphoma. This cancer is geographically 
limited to the malaria belt of Africa. Hybridisation with viral nucleic acid was also found in tumour 
•  Hepatitis B and hepatocellular carcinoma.Seroepidemiological studies in the 1970s linked the 
virus with hepatitis. Hepatoma is most prevalent in parts of the world where HBV is most common. 
Vaccination against childhood hepatoma has fallen significantly since introduction of hepatitis B 
vaccine. A precedent was found in animals when HBV-like viruses were found in cases of hepatitis 
and hepatoma in woodchucks! 
•  Human papillomavirus (HPV) and cervical carcinoma.There are over 80 antigenic types of 
HPV which infect skin or mucous membranes. HPV show strong tissue tropism, hence the different 
antigenic types are associated with particular lesions: mostly these are benign cellular proliferations 
such as warts, macules and papillomas of skin and mucous membranes. HPV are DNA viruses 
which cannot be cultured in vitrobut, instead, require nucleic acid hybridisation for identification 
in tissue. Cervical carcinoma is the most common in the developing world and because it is rare in 
nuns and very rare in virgins compared with people of multiple sexual partners, the sexually 
transmitted Herpes simplexvirus was originally suspected. However, HPV came under suspicion in 
1975 following weak hybridisation in cervical tissue using a probe from HPV of warts. In 1983, 
HPV-16 and HPV-18 genome were isolated from cervical cancer biopsies. HPV virus genes are 
expressed in most malignant tissues and in the HeLa cervical cell line. A series of trials are 

underway in the UK to examine the effect of vaccination against HPV-16 on cervical cancer.

A number of general observations can be made concerning the role of viruses in cancer. Cancer develops 
decades after primary infection, giving ample opportunity for chemical and physical (radiation) 
carcinogens to act. Many of the suspect viruses (EBV, HPV, hepatitis viruses) are ubiquitous across the 
globe yet only a small percentage of infected people develop the associated cancer. Most people will 

clear the viral genome or, failing that, coexist without symptoms or disease. 

There are two sets of genes and their products that are involved in the mechanisms by which viruses can 

trigger immortalisation of cells: 

•  tumour suppressor genes, 

•  oncogenes. 

Tumour suppressor genes:
Most of the cells in the human body are not dividing but quiescent (metabolically active but not 
dividing). They are growth-arrested and, in terms of the cell cycle, in G0/G1 phase. Throughout the cell 
cycle there are checkpoints during which the damaged or mutated DNA is either repaired or the cell 
undergoes apoptosis. Of the proteins involved in surveillance, the two most important are p53 and pRb 
and, because they regulate the removal or repair of potentially malignant cells, they are termed tumour 
suppressor genes. Viruses need to prevent cells from recognising the foreign viral DNA and 
suppressing any proliferation (viral transformation). Likewise, apoptosis must be prevented or delayed 
until viral replication has finished. DNA viruses will force the cell to undergo DNA synthesis by 
producing early viral proteins that trigger DNA replication by sending the cell from G0/G1 into S phase. 
This can be achieved by either inhibiting the proteins (p53 and pRb) that prevent progression into S 

phase or stimulating the expression of growth-promoting genes. 

Genes that cause transformation of cells are called oncogenes. Strictly, oncogenes are mutated forms of 
proto-oncogenes. Proto-oncogenes are normal cell genes that are involved in cell signalling events that 
regulate growth and division. Proto-oncogenes are also referred to as c-oncs to distinguish them from 
viral oncogenes (v-oncs). Viral oncogenes are modified from cellular oncogenes and present only in 
RNA viruses. DNA viruses do not posses oncogenes. For RNA viruses to exert an oncogenic effect they 
must have a stage in their replication cycle when they produce DNA and insert this as a provirus in the 
host genome. Retroviruses are such viruses (although hepatitis B virus can also do this). Oncogenic 
viruses that transform cells act by inserting a v-onc into the genome or by insertional activation (the viral 

promotor promotes the transcription of a c-onc).


Before one leaves with the impression that all viruses cause cancer, we should remind ourselves that the 
multistep nature of carcinogenesis means that a virus that has one or two of the properties described is 
still unlikely to induce malignant growth. For example, EBV is known to immortalise B-lymphocytes (in 
vitro) from all people, not just people in the malaria belt, thus indicating that additional events are 
required to lead to lymphoma. Indeed the multiple trigger hypothesis might explain geographic 
restriction of certain tumours where malaria, burnt salt fish, herbal snuffs and other phenomena peculiar 
to specific cultures act as cofactors. Some viruses can immortalise cell lines in vitro but have no known 
associated human cancer (polyoma viruses). Conversely, some viruses (e.g. HBV linked with hepatoma) 
do not immortalise cell lines. 
Whilst immunosuppression by viruses (e.g. HIV) results in increased rates of cancer incidence (Kaposi’s 
sarcoma), HIV does not cause cancer directly. This suggests that immune systems hold these infections 

in check but profound immunosuppression cannot. Finally, viruses may act indirectly by increasing replication of cells. Faster-replicating cells are more prone to mutagenic events induced by cofactors, hence HBV may promote replication of liver cells 
such that other mutagenic agents (e.g. ingested fungal aflatoxins) have a greater effect. Incidentally, a 
similar sequence of events is postulated to occur in the development of gastric lymphoma following 
Helicobacter pylori  infections. 

Cited By Kamal Singh Khadka
Msc Microbiology, TU.
Assistant Professor in PU, PBPC, PNC, LA, NA.
Pokhara, Nepal.

Alcami, A. and Koszinowski, U.H. (2000) Viral mechanisms of immune evasion. Mol. Med. Today6, 
Collier, J. and Oxford, J. (2000) Human Virology, 2nd edition, Oxford University Press, Oxford, UK. 
Domingo, E. and Holland, J.J. (1997) RNA virus mutations and fitness for survival. Ann. Rev. 
Microbiol.51, 151–78. 
Everett, H. and McFadden, G. (1999) Apoptosis: an innate immune response to virus infection. 
Trends Microbiol.7, 160–5. 
Kalvakolanu, D.V. (1999) Virus interception of cytokine-regulated pathways. Trends Microbiol.7, 
Porterfield, J.S. (1992) Pathogenesis of viral infections; in McGee, J.O.D., Isaacson, P.G. and 
Wright, N.A. (eds) Oxford Textbook of Pathology, Oxford University Press, Oxford, UK. 
Villarreal, L.P., Defilippis, V.R. and Gottlieb, K.R. (2000) Acute and persistent viral life strategies 

and their relationship to emerging diseases. Virology 272, 1–6.


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