2-20 Viral Oncogenesis

Question 1

Why are oncogenic viruses difficult to study?

Answer 1

• No characteristic shape, genome, or mechanism
• No characteristic target cell, patient, or pathway
• Animal models are not reliable predictors of human effects

Question 2

How do malignant cells differ from normal cells?

Answer 2

• 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.

Question 3

What are proto-oncogenes?

Answer 3

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.

Question 4

What are tumor suppressor genes?

Answer 4

Genes that control the cell cycle, including the following proteins:

• p53
• pRB

Question 5

In the most general terms, how do cells manage DNA damage?

Answer 5

• Pause in the cell cycle
• Repair of DNA damage
• Resumption of the cycle, or death by apoptosis

Question 6

How can retroviruses cause cancer?

Answer 6

Some retroviruses can cause cancer in animals through two mechanisms:

1. Some contain oncogenes and express them in infected cells
2. Some can insert their promoter into a chromosome and cause expression of regional oncogenes

Question 7

How do DNA viruses cause cancer?

Answer 7

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

Question 8

To what degree are oncogenic viruses specific?

Answer 8

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.

Question 9

What viruses cause cancer in humans?

Answer 9

1. Human papillomaviruses
2. Epstein-Barr virus
3. Hepatitis viruses (HBV and HCV)
4. Human T-cell lymphotropic virus (HTLV-1 and HTLV-2)
5. Kaposi sarcoma herpes virus (KSHV, HHV8)

Question 10

What are some types of human papillomavirus, and which ones cause cancer in humans?

Answer 10

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.

Question 11

What is Epstein-Barr virus, and how can it cause cancer in humans?

Answer 11

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
• Immortalization
• 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

Question 12

What are hepatitis viruses, and how can they cause cancer in humans?

Answer 12

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

Question 13

What is human T-cell lymphotropic virus, and how can it cause cancer in humans?

Answer 13

• 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

Question 14

What is Kaposi sarcoma herpes virus, and how can it cause cancer in humans?

Answer 14

• KSHV, HHV8
• Associated with Karposi sarcoma in patients with HIV
• Mechanism uncertain

Question 15

Which human cancers have a virus-vaccine?

Answer 15

Cervical cancer (HPV vaccines w/ empty capsids)

Hepatocellular carcinoma (hepatitis B vaccine)