Tumor

Question 0

RNA vs DNA tumor viruses

Answer 0

RNA - usually upregulation of oncogene
 - insertion, inc expression
 - ex retroviruses
DNA - usually inactivation of tumor suppressor genes
 - ex HPV, EBV
Other mechanisms...hepatitis B and C

Question 1

General tumor virus characteristics

Answer 1

RNA or DNA (see separate slide)
Associated with cancers
- cause cancer in animals (injection -> tumor)
- transformation of cell/tissue cultures (ex loss of contact inhibition, immortal, serum independence, morphology)

Question 2

Known tumor viruses

Answer 2

RNA
 - Hep C = flavivirus
 - HTLV, XMRV = retroviruses
DNA
 - Adeno
 - Hep B = hepadnavirus
 - EBV, Kaposi's = herpes
 - HPV - papovavirus
 - Polyomavirus
 - Poxvirus

Question 3

Papovaviruses

Answer 3

Includes papilloma (human), polyoma (rodents), SV40 (monkeys)

SV40 - small, icosahedral, circular dsDNA

• early genes -> T-antigen -> binds to ORC -> DNA replication
• late genes = capsid -> lysis
• T antigen also inactivates p53 and Rb -> tumors

Question 4

HPV

Answer 4

Papillomavirus = subtype of papovavirus = small circular dsDNA
Infection -> condylomas/warts - no integration
Strains 16 and 18 -> integration -> viral proteins (E6 blocks p53, E7 blocks Rb) -> 75% of cervical cancers

Topical imiquinod -> warts
Gardisil (warts and 16/18), cervarix (16/18 only) - virus-like particles, both effective

Question 5

Adenovirus

Answer 5

Not human tumor, only hamsters
E1A -> binds to Rb, p300, CBP (tumor suppressor genes)
- also transcription factor for S phase
E1B - increases levels of E1A

Question 6

EBV as tumor virus

Answer 6

Integration not required for transformation
- expression of EBNA (transcriptional activator), LMP1 (homologue of CD40)
Burkitt’s lymphoma -
- translocation of 8:14 or 8:22 -> c-myc gene is next to Ig promoter -> proliferation of B cells
- normally strong T cell response -> tumor if CTL inhibited (ie malaria)
- most common childhood cancer in equatorial Africa
Nasopharyngeal CA - epithelial cells, common in China, SE Asia
Also post-graft lymphoproliferative, Hodgkins, non-Hodgkins, gastric, etc

Question 7

Kaposi’s sarcoma

Answer 7

Only immune compromised - 15-20% of AIDS patients
Viral oncogenes:
- G-protein receptor analog -> VEGF overexpression -> angiogenesis
- cyclin homolog
- LANA - transcriptional activator
- IL-6

Question 8

Retrovirus life cycle

Answer 8

Extracellular virion = enveloped, 2x identical +RNA ->
Intracellular phase
-> reverse transcriptase -> ds DNA -> integrates ->
“provirus” -> RNA -> translation, new virions
- long terminal repeats (LTRs) important for integration, transcription

Question 9

Retrovirus classifications

Answer 9

All have similar life cycle
All have gag (capsid), pol (reverse transcriptase, integrase), env (envelope glycoproteins)

Oncoviruses - rare in humans (HTLV 1,2), more in rodent, bird
- may be acutely transforming (oncogene) or nonacute
Lentiviruses - not associated with tumors - HIV 1,2

Question 10

Transforming retroviruses

Answer 10

Rare in humans! Animals, therapies?

Transducing - inserts next to oncogene -> capture into virion -> bring to other cells
- rapid, efficient - mutations and high expression via viral promoter
- replaces essential virion RNA - “defective” - must have co-infection for proliferation
- ex Rous sarcoma in chickens via Src gene
Non-transducing - inserts so LTR upregulates oncogene (either close promoter or distant enhancer)
- nondefective but rare integration event
Human - HTLV -> T cell leukemia
- sexual transmission, blood, breast milk
- endemic in Japan, central Africa, Caribbean
- contains tax oncogene -> NFKB -> IL2 and receptor -> proliferation
- long latency (10-30 years), only 0.1% progress to leukemia

Question 11

Hepatitis tumors

Answer 11

Hep B
- relies on reverse transcriptase - inhibited by lamuvidine
- integration near proto-oncogene? viral oncogenes (->p53, myc)?
- destruction and regeneration of tissue
Hep C
- no oncogenes, only destruction/inflammation