337: Describe the mechanisms by which viruses cause cancer

Intro

An oncovirus is a virus that can cause cancer Majority of viruses are not oncogenic and oncogenic viruses only rarely result in a tumor Cofactors often required e.g. diet, environmental carcinogens Cancer causing viruses might have been easlily prevented through vaccination or diagnoses with simple blood tests allowing treatment with less toxic antiviral compounds Tumorigenic association with hose offers no advantage to the virus- reduces viral yield, spread and threatens host life There are a number of viruses associated with causing cancer in humans :human papilloma virus Direct oncogenic mechanism; insertion of additional oncogenic genes into host or enhance already existing oncogenic genes in the genome Indirect viral oncogenecity involves chronic non specific inflammation occuring over decades of infection.

PDZ

E6 also mediates degradation of the cellular PDZ domain which assists in localisation of cellular elements --> its degradation contributes to cancer

P53

E6 binds and degrades cell protein P53. P53 acts as a tumour suppressor gene by causing cells to arrest if DNA damage has occurred. The degradation of P53 means tumours are not suppressed.

Telomerase

E6 induces the activation of telomerase. Many cancer cells can become "immortal" because telomerase replaces the DNA lost during replication, allowing cell line to divide without ever reaching the limit. Telomerase allows cells to live longer

Down regulation of MHC molecules

E7 downregulates the ability of MHC molecules --> Reduces the ability of body to detect something is wrong when there is decreased HPV presentation

Dysregulation of cell cycle

E7 dysregulates cell cycle through interaction with AP1 transcription complex and with CDK inhinitors PD1 and P27. Cell cycle dyssregulation is a hall mark of cancer cells

Rb

E7 inactivates a cell protein called Rb. Rb is a tumour supresser gene

Chromosome duplication errors

E7 induces chromosome duplication errors which leads to more mutations and genomic instability

E6 Oncoprotein

P53 PDZ Telomerase

Summary of viruses causing cancer

Persistent high risk HPV infection --> High viral load --> Integration of high risk HPV DNA genome into host chromosome --> Upregulation of E6 and E7 oncoproteins E6/7 effects TOGETHER, they induce a state of genomic instability This genomic instability coupled with other things including: Host immune factors, viral genetic factors, host and viral epigenetic factors, modulation of cellular and viral genes, environmental and dietary mutagens incl. tobacco, other sti's etc.. LEADS TO HPV ASSOCIATED SQUAMOUS CELL CARCINOMA

What are two main points?

Persistent infection, cell cycle degregulation AND Accumulation of secondary genetic changes

E7 Oncoprotein

Rb Chromosome duplication errors Dysregulates cell cycle through API transcription complex, CDK inhibitors Down regulation of MHC ability

Human papilloma viruses

Small non envelloped icosahedral virus which replicates in the nucleus of squamous epithelial cells Disease ranges from asymptomatic infections, benign warts, invasive tumors. Only high risk HPV types cause cancer 16,18 High risk have two oncoproteins E6 and E7 which can contribute to cancer Freq of progression to cancer is low Circular ds genomes