Tumor viruses and oncogenes
References (1) The Biology of cancer 2006) by Weinberg R. , Chapter 3 & 4.
(2) Principle of Virology (2000) by Skalka A. et al., Chapter 16
(3) Viral carcinogenesis: revelation of molecular mechanisms and etiology of human disease (2000), Carcinogenesis, Vol.21, page 405-426
Tumor viruses (oncogenic viruses) 1. Tumor viruses: viruses that directly cause cancer in either experimental animals or humans RNA viruses DNA viruses 2. Viruses as etiological factors of human cancer (~15% of all human tumors worldwide are caused by viruses) 3. Tumor viruses contributes to: (1) the formation of current concepts of cancer biology molecular mechanisms of cancer formation (2) the recognition of the etiology of some human cancers
4. Viruses are usually not complete carcinogens in human cancers; tumor viruses establish long-term persistent infections in human, with cancer an accidental side of viral replication strategy 5. The best-characterized mechanisms of transformation by tumor viruses fall into two major classes (1) permanent activation of mitotic signal transduction cascades (2) disruption of the circuits that regulate cell cycle progression
Tumor viruses and human tumors
The main contributors are DNA tumor viruses. Evidence for their involvement comes partly from the detection of viruses In cancer patients and partly from epidemiology
Peyton Rous discovered a chicken sarcoma virus called Rous sarcoma virus (RSV)
Transformed cells forming foci (clusters) due to loss of cell-contact inhibition
Normal cells
Transformed cells
RSV-infected cells exhibit morphological changes
-cancer formation could be studied at the level of individual cells -cancer is a disease of malfunctioning cells rather than abnormally developing tissues Process of cellular transformation can be accomplished within the confines of a Petri dish
Soft agar assays -To detect loss of anchorage-independence Control Transformed
In vivo tumorigenesis assays
Immunocompromised host
Syngeneic host
The continued presence of a transforming gene is needed to maintain transformation
Whether virus remains in integrated form throughout the experiment?
(monkey kidney cells)
(Rat, mouse cells)
Viral genomes persist invirustransformed cells by becoming part of hostgenome (<0.1%) SV40 and polyoma virus serve as models to study DNA tumor virus-induced cellular transformation Viral
Oncogenicproteins in DNA tumors are viral proteins encoded by viral genome
Large T antigens bind and inactivate Rb and p53 Oncogenic proteins
Re-infection could not explain the stable transmission of RSV genome
virusRNA genome ~ 10 Kba RSV: Roussarcoma virus(by Peyton Rous, 1911)
KbaRNA genome ~ 8.5 Kb9 ALV: avian leukemia virus
How RSV acquire additional srcgene?
ALV
RSV
The structure of a retrovirus
The discovery of proto-oncogenes-
A version of the srcgene carried by RSV is also present in uninfected avian cells*
years
Capture of src by ALV leads to formation of RSV
RSV exploits a kidnapped cellular gene to transform cells
Most oncogenic transforming viruses are replication-defective
Oncogenes in avian or murine retroviruses are not viral genes; they derived from transduction of normal cellular genes (proto-oncogenes
RNA viruses contribute to the formation of current concepts of cancer biology
Slowly transforming retroviruses activate proto-oncogenes by inserting their genomes adjacent to these cellular genes
avian leukosis virus (ALV) or murine leukemia virus (MLV)
Some retroviruses naturally carry oncogenes
Essentially two classes of these viruses. Some, such as ALV and MLV, carry no oncogenes but can induce tumors that erupt only after a long latent period (i.e., many weeks) following the initial infection of a host animal. Other viruses, such as RSV, can induce cancer rapidly (i.e., in days or several weeks), having acquired an oncogene from a cellular proto-oncogene precursor. In reality, there is a third class of retroviruses
HTLV-1 (human T-cell leukemia virus 1)-The only currently accepted human tumor virus from the retrovirus family -Associated with adult T cell leukemia/lymphoma This virus carries oncogenetax-
tax gene product appears to activate transcription of two cellular genes that specify important growth-stimulating proteinsIL-2 (interleukin-2) and GM-CSF (granulocyte macro-phage colony-stimulating factor). virus-infected cells proceed to stimulate the proliferation of several types of hematopoietic cells.
Activation of proto-oncogenes
RNA virus-related
Retroviral transduction ex: RSV Promoter/enhancer insertion ex: ALV Trans-activation ex: HTLV-1
DNA virus-related
Altering activity/expression of host growth-related genes
Non-viral
Amplification
Point mutation
Chromosomal translocation
