Describe the HPV (the virus)
Non-enveloped double stranded DNA virus 8,000bp genome Passed through skin-to-skin contact Responsible for 99% of cervical cancers and can be considered the etiologic agent necessary for cervical cancer to develop. Most common STD.
What are the high risk types of HPV?
Types 16 and 18, account for 70% of cervical cancers Cause cervical dysplasia and cancer Adenocarcinoma has a strong association with type 18 HPV and is a more aggressive cancer with a greater recurrence rates and a higher likelihood of rapid progression or metastasizing.
What are the low risk types of HPV?
Types 6 and 11 Cause condyloma accumunatum (genital warts which can often be treated and are not usually linked with cancer)
What does HPV’s E6 protein do?
Inhibits tumor suppressor p53 resulting in the loss of cell cycle control and inhibition of apoptosis
What does HPV’s E7 protein do?
-Binds to and destabilizes tumor suppressor pRB resulting in the acceleration of DNA synthesis and cell cycle progression as well as the disruption of cell cycle control. -Alters cell metabolism and possibly causes chromosomal changes and mitotic mutations
Why is the HPV vaccine so important?
Cervical cancer is the second most common cause of cancer related death in women, creating a vaccine against HPV prevents cancer. Screening tests reduce morbidity and mortality but cannot prevent infection or precursors to cervical cancer and have trouble detecting lesions that progress quickly or are in early stages.
Describe the HPV vaccine
-Non-infectious and contain no DNA -Made up of virus like particles (VLP) -Recombinant viral capsid protein L1 assembles to this VLP that resemble native HPV particles and elicit a type specific HPV neutralizing Ab response from the patient to protect against future infection. -VLP is created by inserting the L1 gene into a yeast genome where it is transcribed and translated to create a recombinant L1 capsid protein, which then combine with four other L1 particles to create a pentamer, and 72 of these pentamers self assemble to create a non-infectious VLP.
What is the quadrivalent vaccine?
-Contains recombinant L1/VLPs for HPV types 6, 11, 16, & 18. -93-100% effective against preventing cervical precancers caused by types 16 and 18. -Also >99% effective against genital warts caused by types 6 and 11. -Vaccine is used for the prevention of cervical, vulvar, and vaginal cancers, precancers and dysplastic lesions and the prevention of genital warts
What is the bivalent vaccine?
-Contains recombinant L1/VLPs for types 16 & 18. -Vaccine is 93-100% effective against preventing cervical precancers caused by types 16 and 18. -Used for the prevention of cervical cancers, precancers and dysplastic lesions associated with types 16 and 18.
What is the vaccine schedule?
-Both quadrivalent and bivalent require 3 doses, recommended between ages 11 and 12 -2nd dose given 1-2 months after first dose -3rd dose must be separated from the second by at least 12 weeks and from the first by at least 24 weeks (6 months)
What nuclear features should you recognize in comparing tumors to their normal counterparts?
- Irregular nuclear membrane
- Irregular chromatin distribution
- Large nuclei –> increased N/C ratio
- Hyperchromasia
- Abnormal nucleoli
- Multiple nuclei
- Piling up of nuclei
- Increased mitosis
- Abnormal mitotic figures
What cytoplasmic features should you recognize in comparing tumors to their normal counterparts?
- Pleomorphism
- Anaplasia
- Hypercellularity
What 3 steps are required for a malignant transformation?
- Initiation - causes a mutation in the DNA, but does NOT cause proliferation (reversible)
- Promotion - induces cell proliferation, but is NOT mutagenic (reversible)
- Progression - irreversible genetic mutations
What is an initator? Does it cause cancer or proliferation? Is it reversible?
Initiators are compounds (chemicals, reactive electrophiles, UV radiation, etc.) that cause a non-lethal gene mutations. This may lead to hyperplasia or dysplasia, but most do not. They need to be triggered by a promoter to proliferate and become malignant. It is a reversible process.
What is a promoter? Does it cause mutations? Is it reversible?
A promoter is a compund (growth factor, hormones, bile salts, smoke, cytokines, etc.) that induces cell proliferation. It does not cause mutations. It triggers an initiated cell to proliferate. It is a reversible process.
How does Carcinogenesis start in terms of initiators and promoters? Why is the order of events important? Why is timing of events important?
First, an initiator (chemical, UV radiation, ROS from inflammation, etc.) will alter the cells DNA. Second, a promotor will cause that mutated cell to proliferate. Proliferating, mutated cells leads to cancer.
- Order of events is important - initiator then promoter; not promoter, then initiator
- Timing of events is also an important factor - the initiator and promoter need to occur within a reasonable time frame. Triggering an initiated cell 20 years later, will probably not lead to cancer.
How do chemical carcinogens cause DNA mutations? What metabolic enzyme is typically involved?
In general, the P450 enzyme reacts with many chemicals that leads to reactive, electrophilic speices (epoxides, carbonium ions). These react with DNA and RNA to cauase mutations. Some chemicals react directly with DNA.
- Direct Alkylating Agents (chemo drugs) - transfer alkyl groups to guanine residues on DNA
- Polycyclic Hydrocarbons (smoke, burned meat, etc.) - P450 Enzymes metabolize these compounds and form electrophilic epoxides that react with DNA/RNA.
- N-Nitrosamines , Aromatic Amines , Azo Dyes (smoke, cured meats, beers, etc.) - P450 Enzymes metabolize these compounds into highly reactive cabonium ions which can react with DNA.
- Alfatoxins - produced by Aspergillus Flavus. P450 Enzyme activates resulting in an expoxide that binds to guanine residues in TP53 gene.
What are the initators and promotors of cancer with regards to chronic inflammation? What is a potential treatment that would reduce the inflammation the potential cancer?
- Initiators - Reactive Oxygen Species (ROS) damages
- Promoters - Growth Factors (cytokines, PGE2, etc.)
- Treatment - COX-2 inhibitors and anti-oxidants
How do UV & ionizing radiation damage DNA? Describe the process in terms of direct and indirect damage.
What is more mutagenic, UV-A or UV-B?
- Direct - UV radiation causes pyrimadine dimers (thyamine-thyamine - aka cyclobutane dimers) that lead to a distortion of the DNA. This interferes with DNA replication which can lead to singel base substitutions of C–>T or CC–>TT. These are usally fixed by repair genes, but chronic exposure can lead to perminant mutations.
- Indirect - ROS species from inflammation (OH radicals) induce oxidative DNA adducts (8-oxo-deoxyguanosine). Chronic exposure and therefore inflammation can lead to promotion and proliferation of the mutated skin cells.
- UV-B is more mutagenic (higher energy)
What is Xeroderma Pigmentosum?
An autosomal recessive disorder that involves mutations to DNA repair genes - NER (nucelotide excision repair gene). These genes are required to protect the body against DNA damage from UV-B radiation. Causes lots of skin cancer. Chance of cancer is 2000 times more likely.
How do oncoviruses lead to cancer?
Oncoviruses integrate viral DNA into the host genome. The viral DNA is eventually transcribed to form viral proteins. Many of these viral proteins inhibit, induce, or tranlocate various proto-oncogenes or tumor suppressor genes.
For example: HPV viral proteins E7 and E6 inactivate tumor suppresor proteins p53 and rB.
How does the Human Papilloma Virus (HPV) cause cancer? What type of cancer(s) does it cause?
- HPV
- Inactivate p53 and rB proteins
- Cause _squamous cell carcinomas _
How does the Epstein Barr Virus (EBV) cause cancer? What type of cancer(s) does it cause?
- Epstein Barr Virus
- Causes a translocation of immunoglobulin genes t(8;14)
- Leads to Burkitt Lymophoma
