Lecture 6: Infectious Agents and Cancer Flashcards
Around what percentage of cancers are estimated to be caused by infections?
15% (particularly in regions in Africa and Asia related to income/economy - higher lower income counties)
What are four infectious agents commonly associated with cancer formation?
Helicobacter pylori (bacteria) - stomach cancer
HPV (Human papilloma virus) - predominantly causes cervical cancer
Hepatitis C virus - liver cancer
Hepatitis B virus - liver cancer
Give an example of a cancer enabled by HIV infection?
Kaposi’s sarcoma (due to destruction of immune system by HIV - immunosurveillance decreased)
What virus is associated with Burkitt’s Lymphoma?
Epstein-Barr Virus (EBV)
What was the Rous experiment?
- sarcoma removed from chickens and broken up into small pieces
- grind up the sarcoma
- collect filtrate that has passed through fine-pore filter to remove all the cellular particles
- inject the filtrate into young healthy chicken
- observed the development of sarcoma as the chicken developed
What is indirect pathogen driven carcinogenesis?
Chronic inflammation in response to pathogen that causes cellular damage by oxidative damage
Prevention of apoptosis
Induction of chromosomal instability and translocations
immunosuppression caused by virus that activates other tumourviruses (E.g. HIV causes immunosuppression that can result in infection with Kaposi’s sarcoma infectious agent)
What is direct pathogen driven cacinogenesis?
Integration of viral DNA to the cellular DNA - cells produce viral genes that cause DNA mutations
- introduction of viral oncogene into host cells
- modified viral oncogenes after introduction into host cell DNA
- modified host cell genes integrated into viral genomes act as oncogenes
What is Rous Sarcoma Virus (RSV)?
A retrovirus (RNA virus)
- env gene encodes surface glycoproteins - virus entry into cells by interacting with cell membrane
- gag gene encodes coat proteins
- pol gene encodes reverse transcriptase (generate DNA from the viral RNA)
- src gene (oncogene)
Describe the lifecycle of the retrovirus?
- virus enters cell, shedding viral envelope
- DNA generated from viral RNA template by reverse transcriptase
- dsDNA integrated into host cell genome as a provirus
- viral genome replicated by host machinery to produce many mRNAs that are transcribed and assembled into new viral particles
How was RSV shown to cause aberrant growth in cells?
- monolayer of cells
- infect one cell with RSV particle
- cell transformed - loss of contact inhibition
- formation of a focus due to continued proliferation of transformed cell
How was it shown that the cancerous phenotype required the presence of active viral proteins?
- normal morphology cells grown at 37 degrees
- infect cells with a temperature sensitive RSV mutant (proteins labile at higher temperatures)
- cancerous phenotype (transformed morphology) observed when cell continued to grow at 37 degrees
- then increased the temperature and showed that the cells reverted to normal morphology
- then shifted the temperature down and observed that the cells become transformed again
–> the viral proteins were inactive at the higher temperatures so cells do not become transformed.
What was causing the RSV virus to promote cancer formation?
Incorporation of the src gene from the host genome, which became an oncogene expressed by the virus
- when provirus integrated adjacent to the cellular src (encodes form important kinase protein in the host)
- c-src transcribed and packaged into viral capsid
How is c-Src activated and what does c-Src do?
intracellular kinase that activates downstream signalling pathways to promote proliferation
- inactive = closed conformation - phosphorylated C-terminal (at Y527) interacted with the SH2 domain
–> binding of growth factor to PDGF-R results in phosphorylation of receptor that binds to the SH2 domain of c-Src, displacing the C-terminus (which is dephosphorylated) and opening up the c-Src
- phosphorylation of the activation loop that exposes the catalytic cleft
- promotes activation of proliferation pathways downstream of Src
How does the v-src act as an oncogene?
the v-Src protein lacks the C-terminal tyrosine (Y527) that is normally phosphorylated in c-Src, resulting in constitutive activation of the Src and uncontrolled proliferation
What is ALV and how can it cause cancer?
Avian leukosis virus
- a slowly transforming retrovirus
–> provisus inserts randomly into host and occassionally inserts upstream of c-myc which results in uncontrolled proliferation by activating proto-oncogene (activation or overexpression)
–> provirus could also insert adjacent to c-src gene resulting in the formation of RSV (rare event)
