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CANCER-CAUSING VIRUSES IN ANIMALS AND MAN
Virus-induced cell transformation:
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The discovery of virus-induced transformation in vitro was an enormous
boost to cancer research
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Because the virus contained relatively few genes, this offered the prospect
of uncovering the molecular basis of neoplasia
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Polyoma, SV40 and adenovirus are all very small viruses
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They rely on the host cell for replication machinery
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They contain genes whose products stimulate the host cell to enter DNA
synthesis, in order to provide the replication enzymes needed by the virus
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The viral gene products hijack the cellular products, thereby stimulating
the host cell to enter DNA synthesis
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The end result of infection is normally cell death (lysis)
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In non-permissive cells (non-susceptible species) viral replication is
blocked
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However, the cells are still triggered to enter the cell cycle
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In most cells, the non-replicating virus is soon lost
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Rarely, the viral DNA integrates randomly into the genome of the nonpermissive cell
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The stimulus for cell proliferation is then permanent, resulting in cell
transformation
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Transformation is accidental and not a feature of the normal virus life
cycle
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It depends on a rare integration event and infection of an inappropriate
host
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Are members of the retrovirus group
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Single-stranded viral RNA is converted to a double stranded, circular DNA
“pro-virus”, by reverse transcriptase
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In addition, the proviral DNA, once established in the genome, could serve
as a template for transcription by cellular RNA polymerase, thereby
yielding RNA molecules that could be incorporated into progeny virus
particles or, alternatively, could function as mRNA that is used for the
synthesis of viral proteins
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Proviral DNA, however, is longer than viral RNA due to the duplication of
specific sequences at the 5’ and 3’ ends
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This results in 2 long terminal repeats (LTRs), one at each end of the
DNA intermediate
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LTRs contain:
• Integration signals
• Promoter elements, including cap sites
• Enhancer elements
• Polyadenylation sites
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The rare SV40 genomes that do not succeed in becoming established in
chromosomal DNA are found integrated in a haphazard fashion that often
includes only fragments of the wild-type genome
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Slow transforming viruses (e
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mouse leukaemia virus) can induce
tumours only after a long latent period (months/years)
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They induce tumours within 2-3 weeks and in
addition, transform cells in the culture
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These viruses also contain additional genetic information (an
“oncogene”) that isn’t present in the slow progenitor virus, responsible
for transformation
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An oncogene is a gene that has the potential to cause cancer
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In RSV, the oncogene is tagged onto the end of the viral genome and does
not interrupt viral genes required for replication
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In all other acutely transforming retroviruses, the oncogene replaces viral
sequences, thereby disrupting genes required for replication - such
viruses are therefore replication defective
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Propagation depends on the presence of a helper virus (of the slowtransforming type) to provide the missing gene products
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Using a DNA probe that specifically recognized the transformationassociated (i
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src) sequences of the RSV genome, researchers made the
unexpected discovery that src-related sequences were present in the
DNA of chicken cells not infected by RSV
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Further research indicated that the src genome was a normal, highly
conserved gene of all vertebrate species
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The cellular homologues (c-src) are called proto-oncogene and are
now known to code to key elements of the pathways involved in
controlling cell growth
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Capture of a proto-oncogene by a virus, resulting in the formation of a
viral oncogene) is entirely gratuitous and plays no part in the viral life
cycle
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Oncogenic viruses transform despite being derived from cellular genes
because:
• Over-production – as a result of coming under the control of a
strong viral promoter/enhancer
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• Mutation – deletions or point mutations in regulatory domains
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The latter has rearrangements
and point mutations
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Tumours result from these types of viruses due to integration of the
virus next to a cellular proto-oncogene, which is then overexpressed as a
result of the adjacent strong viral promoter/enhancer
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This is called promoter insertion or enhancer insertion
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There are two favoured integration sites:
• Int-1 – also now known as Wnt1
• Int-2 – also now known as FGF3
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AGENT
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About 30 different strains infect genital region
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High risk viruses include: 16, 18, 31, 33 and 45 (most common)
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A vaccine against HPV 16 and 18 is present
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Persistent, chronic infection is strongly associated with liver cancer, with
60% if the cases due to HBV
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There is a 200 fold increased risk after a long latency period of about 2030 years
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Vaccination against HBV is available
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Hodgkin’s lymphoma
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Human Herpes virus 8 (HHV-8):
Causes Kaposi sarcomas in HIV patients
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This is associated with adult T cell leukaemia/lymphoma in a small
proportion of infected individuals
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Human Tumour Viruses:
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• Do not, in general, cause transformation by integration next a
proto-oncogene
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Most human tumour viruses are not retroviruses – human T cell
leukaemia virus 1 and 2 are the only examples
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This is because HTLV-1 contains an extra viral gene called Tax
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Tax encodes a protein that activates transcription of pro-viral DNA and, as
a side effect, also stimulates expression of cellular growth factors that
induce cell proliferation
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Combination of increased proliferation and reduced checkpoint
control my increase the chances of mutations, leading to neoplasia
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For all human cancers associated with viral infection, only a small
minority of infected individuals develop cancer and only after a long
latency period
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This implies that there must be co-factors present because a virus
infection is not sufficient for tumour development
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EBV causes glandular fever in developed countries
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In Burkitt’s lymphoma, the co-factor is malaria and as well as HIV
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• A low/absent response leads to a “healthy” carrier state
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This is because prolonged attempts at regeneration increase the risk
of mutations during cell replication
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