Cancer I Flashcards
What is the sequence of genetic alterations?
- Initiation
- Promotion
- Progression
- Metastasis
What is Initiation?
Mutations in the genome that result in changes in the proliferation potential – does not lead to malignant transformation.
What is Promotion?
Promoters stimulate pre-neoplastic cells to proliferate, forming a benign tumour. But these tumour cells can still be corrected by repair mechanisms.
What is Progression?
Characterised by rapid cell proliferation, invasion of basal lamina, and acquisition of new mutations to cancer-promoting genes – malignant transformation has occurred.
What is Metastasis?
One or more dividing cells acquire mutations that allow them to detach from the tumour and be carried by the blood or lymph to invade other tissues.
Accumulated DNA mutations can induce cancer. What factors are linked to DNA mutations?
- Chemical substances
- Physical agents
- Ionising radiation
- Viruses
Generally, how do viruses cause DNA mutations? Give an example of an oncogenic virus.
Viruses induce transformation by integrating into the host cell’s genome and disrupting chromosomal DNA.
Human Papillomaviruses (HPVs) cause cervical cancer, which can be easily prevented by prophylactic vaccination.
Why was Harald zur Hausen awarded the 2008 Nobel Prize in Physiology or Medicine?
- Discovered that HPV causes cervical cancer.
- Realised that HPV-DNA can exist in a non-productive state in tumours
- Assumed that if tumour cells contained an oncogenic virus, the cells’ genome should have integrated viral DNA
Why was the search for HPV in cancer cells difficult?
- Only parts of the viral DNA integrated into the host cells’ genome
- HPV has many types, but only 2 of them cause cancer
What HPV types cause cervical cancer?
HPV Types 16 & 18
Describe how the papilloma virus replicates.
- Virion attaches to host’s cell surface
- When inside its host, it releases its capsid proteins to uncoat its viral DNA
- Portion of viral DNA is transcribed in nucleus, producing an mRNA encoding for early viral proteins
- Viral DNA is replicated and some viral proteins are made
- Late translation – capsid proteins are produced.
- Virions mature
- Virions are released
How does HPV cause cancer?
- HPV protein 6 causes ubiquitination of p53 = Promotes p53 degradation by proteasomes via interactions with E6AP (E6 Associated Protein; ubiquitin ligase)
- p53 degradation results in inhibition of apoptosis and accumulation of mutations
- HPV-infected cells can thereby evade cell death, proliferate, and cause cancer
HPV vaccines are based on virus-like particles (VLPs). Describe VLPs.
- Sometimes embedded in lipid bilayer
- Not infectious as they lack viral nucleic acid (DNA)
- Elicit both strong T cell and B cell responses
How are VLPs generated?
- L1 gene (encodes for capsid proteins) is cloned and inserted into plasmid
- The plasmid is used for the expression of suitable host cells (yeast or insect – both have similar glycolysation machinery as human cells)
- The capsid proteins spontaneously self-assemble into empty viral capsids (or VLPs)
- The empty VLPs are harvested and purified to remove contaminating cell debris and aggregates
- VLPs are put into vaccines and administered to humans so they can produce specific antibodies against the proteins in the VLPs
Give an example of a HPV vaccine.
Gardasil
- Developed by Merck & Co, Inc.
- Found highly effective against HPV Types 16 and 18 (cervical cancer) + HPV Types 6 & 11 (genital warts)
