Lecture 28 - Oncogenic Viruses Flashcards
Three classes of cancer-causing agents
1) Chemical carcinogens
2) UV and ionising radiation
3) Viruses
Carcinoma
Tumour of epithelial origin
Sarcoma
Tumour of fibroblasts
Tumours of leukocyte origin
Lymphoma (when solid)
Leukaemia (when circulating)
Are most cancers mono- or polyclonal?
Monoclonal
Some characteristics of transformed cells
1)
2)
3)
1) Lack of contact inhibition of growth
2) Lack of dependence on exogenous growth factors
3) Lack of anchorage dependence on some cell types
What happens in G1?
Synthesis of proteins required for DNA synthesis
When is DNA replicated?
S phase
What happens in G2 phase?
Synthesis of proteins for daughter cells
When is the restriction point in the cell cycle?
G1
What determines whether a cell stops at, or progresses beyond the restriction point in the cell cycle?
Environmental cues
C-onc
Cellular oncogenes or proto-oncogenes
V-onc
Viral-oncogenes.
Can be a host oncogene, modified host oncogene, or a novel viral protein
Examples of tumour suppressor genes
Retinoblastoma, p53
Four main classes of oncogene
1) Growth factors
2) Growth factor receptors
3) Intracellular signal transducers
4) Transcription factors
20% of human cancers are associated with what?
Human T cell leukaemia virus type 1 Hepatitis C virus Human papilloma virus Epstein-Barr virus Hepatitis B virus
RNA viruses associated with human cancers
Human T cell leukaemia virus type 1 (retrovirus)
Hepatitis C virus (flavivirus)
DNA viruses associated with human cancers
Human papilloma virus (papovavirus)
Epstein-Barr virus (herpesvirus)
Hepatitis B virus (hepadnavirus)
Are retroviruses lytic?
No
If a retrovirus carries an oncogene, what type is it?
V-onc that has a C-onc counterpart
What does retroviral transformation often involve?
Stimulating activators of cell cycle
Are oncogenic DNA viruses lytic?
Yes, normally
Type of V-onc often carried by DNA viruses
A unique viral product. No C-onc
What does DNA viral transformation often involve?
Inactivation of cell-cycle inhibitors
Two types of oncogenic retroviruses
Endogenous and exogenous
Normal retroviral proviral genome
LTRs flanking gag, env, pol
Defective oncogenic retroviral genome
LTRs flanking gag, env, pol, but an oncogene is disrupting one of the gag, env or pol
Replication-competent oncogenic retroviral proviral genome
LTRs flanking gag, env, pol, with an oncogene that isn’t disrupting gag, env or pol
Example of a replication-competent oncogenic retrovirus
Rous sarcoma virus
Three mechanisms of tumour production by exogenous retroviruses
1) Transducing (acute transforming)
2) Cis-activating (non-acute transforming)
3) Trans-activating
Transducing retroviruses
Introduce a v-onc gene under LTR transcriptional control into host genome
Cis-activating retroviruses
Insertional mutagenesis.
Doesn’t carry a v-onc gene, but upon integration LTR drives expression of a C-onc gene
Trans-activating retroviruses
Contains a gene-regulation protein that drives tumour growth
Type of tumours produced by transducing retroviruses
Polyclonal
State of most transducing retroviruses
Replication defective.
Except for Rous sarcoma virus
Are transducing retroviruses found in humans?
No. Rous sarcoma virus is a virus of chickens
How can insertional mutagenesis drive tumour growth?
1)
2)
Either:
1) Proviral LTR can act as a promoter for c-onc in cis with provirus.
2) Provirus unwinds DNA upstream of c-onc, acts as a transcriptional enhancer
Best-studied cis-acting retrovirus
Murine leukaemia virus
Examples of cis-acting retroviruses
Murine leukaemia virus
Koala retrovirus
Example of a trans-acting retrovirus
Human T-cell lymphotropic virus type 1 (HTLV-1)
What is human T-cell lymphotropic virus type 1 associated with?
Adult T-cell leukaemia-lymphoma
How is human T-cell lymphotropic virus type 1 transmitted?
Placenta, breast feeding, sexual intercourse, contaminated needles
Effects of human T-cell lymphotropic virus
Virus persists for life, often causing no disease.
After 20-40 years, a small proportion of those infected develop adult T-cell leukaemia-lymphoma
What does HTLV infect?
CD4+ T cells
Regulatory proteins in HTLV
Tax, rex
Tax
1)
2)
3)
1) Regulatory protein in human T-cell lymphotropic virus.
2) Transcription factor that acts on the LTR region, but also can act on C-onc genes in the host genome.
3) Also acts to upregulate IL-2, IL-2R transcription, to promote T cell proliferation
HTLV protein involved in oncogenesis
Tax
Why do some DNA viruses lead to oncogenesis?
Need host cell to be in S phase so that genomes can be replicated. Most cells are in G0 or G1.
Early proteins are normally encoded to get host cell into S phase
Features of DNA stimulated tumours
1)
2)
3)
1) Limited viral protein expression.
2) Early gene expression
3) Can show integration of viral genome or episome
Function of retinoblastoma susceptibility gene
Controls transition from G1 to S.
In hypophosphorylated active form sequesters E2F family of transcription factors, preventing them from driving the cell cycle forward
Function of p53
Transcription factor that induces expression of proteins that arrest cell growth and initiate apoptosis in response to DNA damage
Proportion of human tumours that have a mutation in the p53 gene
50%
Examples of viral strategies for suppressing p53 function
1)
2)
1) Hep C binds a protein to p53, prevents nuclear localisation
2) Papilloma viruses mark p53 for degradation
HPV seotypes that lead to carcinoma
HPV-16 and -18
HPV E6 protein
Marks p53 for degradation
HPV E7 protein
Inhibits retinoblastoma susceptibility protein
What happens in papillomavirus oncogenesis?
HPV is randomly integrated into host genome. E2 protein is lost, which normally negatively represses E6 and E7 proteins
Type of cancer linked to hep B
Hepatocellular carcinoma
Proportion of those infected with hep B that develop hepatocellular carcinoma
2-10% of patients
How does hep B lead to hepatocellular carcinoma?
1)
2)
1) Random integration of episome into host genome.
Transactivating gene X can deregulate a nearby C-onc (src tyrosine kinase).
2) Repeated destruction and regeneration of hepatocytes can lead to accumulation of mutations
Increase in hepatocellular carcinoma risk when infected with hep C
100x increase in risk
Cancers associated with EBV 1) 2) 3) 4)
1) Burkitt’s lymphoma (Africa)
2) Nasopharangeal cancer (common in China, SE Asia)
3) B cell lymphomas in immunosuppressed patients (EG: AIDS patients)
4) Detected in ~40% of Hodgkin’s lymphoma patients
Burkitt’s lymphoma genesis
Translocation of C-myc (chromosome 8) to a part of chromosome 14 which is under transcriptional control of a promotor for Ig heavy chain production
Role of EBV in Burkitt’s lymphoma
EBV transforms B cells, leading to uncontrolled expansion.
Enhances effects of mutations such as C-myc translocation from Chr.8 to Chr.14