Why are oncogenic viruses difficult to study?
- No characteristic shape, genome, or mechanism
- No characteristic target cell, patient, or pathway
- Animal models are not reliable predictors of human effects
How do malignant cells differ from normal cells?
- Tumorigenicity (i.e., will form tumors if transplanted to animals)
- Lack of differentiation
- Immortality (i.e., replicate without any limit)
- Lack of contact inhibition
- Resistance to apoptosis
- Chromosome abnormalities
All of these differences can be induced in cells experimentally by various viruses.
What are proto-oncogenes?
Genes that control the growth of human cells via numerous surface receptors and internal signaling pathways:
- myc: transcription factor
- sis: platelet-derived growth factor
- erb B: growth factor receptor
Oncogenes are over-expressed in many cancers.
What are tumor suppressor genes?
Genes that control the cell cycle, including the following proteins:
In the most general terms, how do cells manage DNA damage?
- Pause in the cell cycle
- Repair of DNA damage
- Resumption of the cycle, or death by apoptosis
How can retroviruses cause cancer?
Some retroviruses can cause cancer in animals through two mechanisms:
- Some contain oncogenes and express them in infected cells
- Some can insert their promoter into a chromosome and cause expression of regional oncogenes
How do DNA viruses cause cancer?
Oncogenic DNA viruses encode proteins that disturb the cell cycle and prevent apoptosis.
ex) Both the p53 and pRB proteins can be inactivated by viral proteins
To what degree are oncogenic viruses specific?
Oncogenic viruses are species-specific:
- SV40 virus: primate virus that causes cell transformation and cancer in rodents, transforms human cells to a malignant state. Expresses T antigen which inactivates p53 and pRB. Contaminant of early polio vaccines, yet the recipients did not develop cancer.
- Adenoviruses (various serotypes): Group of human viruses, some of which cause cell transformation and cancer in rodents, but only cause colds and sore throats in people.
- Some viruses cause cancer in animals, which may be preventable by vaccine.
- The only example of non-species specificity is the highly publicized incident in which modified mouse leukemia virus caused cancer in some English and French children in 2002.
What viruses cause cancer in humans?
- Human papillomaviruses
- Epstein-Barr virus
- Hepatitis viruses (HBV and HCV)
- Human T-cell lymphotropic virus (HTLV-1 and HTLV-2)
- Kaposi sarcoma herpes virus (KSHV, HHV8)
What are some types of human papillomavirus, and which ones cause cancer in humans?
Many, many types:
- ‘Low-risk’ types (HPV-2, HPV-4) cause warts
- ‘High-risk’ types (HPV-16, HPV-18) cause squamous cell carcinomas of the cervix, penis and oropharynx
- E2 normally suppresses E6 and E7; loss of E2 function, because of integration, therefore allows over-expression of E6 and E7
Progression to carcinoma is slow, requiring many years. Two HPV vaccines are available, consisting of empty virus capsids.
What is Epstein-Barr virus, and how can it cause cancer in humans?
A herpes virus that causes mononucleosis in the western world, but is associated with childhood lymphoma (Burkitt’s) in parts of Africa and in patients with AIDS.
- Tumors express a latent viral antigen of uncertain function
- Q8-14 translocation puts myc gene under control of an immunoglobulin promoter, leading to overexpression
- Virus is also assoc. with naso-pharyngeal cancer in Asia
- Co-factors are involved: malaria infection in Africa, food preservatives in Asia
What are hepatitis viruses, and how can they cause cancer in humans?
Hepatitis B virus (HBV) and hepatitis C virus (HCV) cause chronic hepatitis that predisposes to cirrhosis and liver cancer after many years.
- Prevalent in Africa and Asia
- Mechanism of tumors is uncertain; tumor cells contain integrated HBV but no consistent expression of any viral protein in cancer cells OR activation of cellular oncogene
- BUT childhood infection is important
- Preventable by the hepatitis B vaccine
What is human T-cell lymphotropic virus, and how can it cause cancer in humans?
- HTLV-1 and HTLV-2
- Mechanism unknown, but blood-borne
- RNA virus, but with no oncogene
tax gene causes overexpression of interleukin-2 and the receptor for interleukin-2
- Other proteins dysregulate RNA metabolism
- Prevalent in Caribbean countries
- Causes leukemia and lymphoma
What is Kaposi sarcoma herpes virus, and how can it cause cancer in humans?
- KSHV, HHV8
- Associated with Karposi sarcoma in patients with HIV
- Mechanism uncertain
Which human cancers have a virus-vaccine?
Cervical cancer (HPV vaccines w/ empty capsids)
Hepatocellular carcinoma (hepatitis B vaccine)