Oncogenic Viruses Flashcards
T or F. Viruses rarely cause cancer.
T/F. Well most viral infections do not cause cancer, collectively viruses account for 15-20% of all cancers
Viruses are the leading causes of what kinds of cancers?
Liver and genital cancers
What are the three main mechanisms for tumor growth via viruses?
- Activate signaling pathways to stimulate constitutive growth
- Release cell cycle control to allow uncontrolled growth
- Infected cell destruction/clearance leads to unplanned regeneration
What are some of epidemiological criteria needed to establish a causative relationship between viruses and cancer?
• Coincident geographic distribution of infection,
cancer
• Higher incidence of viral markers in cases vs control references
• Viral markers should precede cancer
• Reduction in infection rates should reduce cancer
What are some of virologic criteria needed to establish a causative relationship between viruses and cancer?
- Virus should transform cells in vitro
- Virus genome present in tumor but not normal cells
- Tumor induction in experimental animals
What is the difference between immortalization of cells and transformation of cells?
Immortalized cells retain original properties but grow indefinitely, while transformed cells are immortalized but lose many growth properties
• Reduced need for serum growth factors
• Loss of contact inhibition
• Anchorage independent (can grow in soft agar)
• Appear round as opposed to typical morphology
• May cause tumors when introduced into suitable animal
ALV and RSV are known to be transducing retroviruses. What does this mean?
These viruses contain v- oncogenes in their genome. Thus, whenever they infects, these viruses will cause tumors rapidly and 100% of the time
Do non-transducing retroviruses commonly produce tumors?
Yes, even though they don’t have v-oncogenes, they will still commonly produce tumors although a slower pace (weeks to months)
Ex. MMTV will insert itself in the genome near a proto-c-oncogene and via an LTR act as a promoter to induce uncontrolled expression
How do non-transducing, long latency retroviruses work?
This group contains HTLV-1, the only retrovirus that causes human cancer. These retroviruses have low rates of tumor formation and take to tumor formation
Can both RNA and DNA tumor viruses activate signaling pathways to cause tumor?
yes.
Often the net result is an increase/dysregulation in kinase (phosphorylation) cascades that increase gene expression related to cell division
Other times the gene expression is upregulated by the introduction of new transcription factors
HTLV-1 targets and infects which host cells?
CD4+ T cells
What cancers does HTLV-1 cause?
adult T cell leukemia and lymphoma (ATL)
The main oncogene used by HTLV-1 to induce cancer is Tax. How does it work? 2 mechanisms
1) Tax appears to activate the Ikk complex (2 NEMO and an alpha and beta subunit), freeing NFkB to enter the nucleus and up-regulate cell proliferation in T cells.
Normally, Ikk is regulated and only turned on via ligand binding but Tax bypasses that to constitutively activate it by phosphorylating Ik-beta subunit, releasing NFkB
2) It also encodes v-cyclin, which binds and activated CDK6 for cell proliferation. The v-cyclin/CDK6 complex cannot be inhibited by Cip or Ink4
What cancers are associated with EBV?
type of herpes virus
Burkitt’s lymphoma, nasopharyngeal carcinoma, Hodgkin’s lymphoma, and Posttransplantation lymphoma
What is the main viral effector of EBV to induce cancer?
LMP-1 (latency membrane protein-1), is a membrane receptor that will dimerize in the absence of ligand if mutated to immortalize the cell via constitutive expression of NFkB (same pathway as HTLV-1, just different mutation site)
What is KSHV?
a herpesvirus that is latent predominantly in B cell but also in monocytes, T cells and endothelial cells
What cancers are associated with KSHV?
Kaposi’s sarcoma (lymphatic endothelial cancer),
Pleural effusion lymphoma (non-Hodgkin’s body cavity lymphoma),
Cattleman’s disease (benign lymph node tumors- not strictly a cancer)
Although KSHV has many effector mechanisms for inducing cancer, the main mechanism appears to be what?
a vGPCR that is constitutively active even in the absence of ligand
Is SV40 a human pathogen?
No, not cancer causing
Describe SV40.
5 kbp circular, dsDNA polyoma virus that is part of the Papova family
How does SV40 promote cell proliferation?
two encoded gene-proteins, small t-ag and large t-ag bind and inhibit protein phosphatase 2A, a ser/thr phosphatase that is responsible for shutting down cell signaling cascades. Thus, cell proliferation is maintained.
HPV is associated with what cancers?
cervical carcinoma, head/neck cancer, penile, anal cancer
HPV is polyoma virus with a circular genome
How does HPV work?
it can integrate into chromosomes of non-promisive cells for genome replication of E proteins. If E2 (a repressor gene) is split during integration from E6 and E7, they will be over-expressed
How do HPVE7 and SV40 LT promote tumor formation?
can bind to Rb and release E2F
HPVE7- can also block p21
How do HPVE6 and SV40 LT promote tumor formation?
degrade p53
What is the main mechanism of how HBV and HCV cause cancer? What cancer?
Hepatitis B and C viruses are the leading cause of hepatocellular carcinoma
Decades-old chronic infection/inflammation result in chronic immune response that leads to clearance of infected hepatocytes, causing the need for regeneration. Mutations accumulate over time leading to “conventional” cancer mechanisms, independent of viral proteins or genome integration
Thus, one way viruses cause cancer is unplanned regeneration
How else can HBV and HCV cause cancer?
HBV encodes a viral HBV X antigen that has shown some causative link to cancer but this is not the main mechanism of cancer generation- inflammation and cellular regeneration causing mutation, as described in the previous card, is.
What is an example of unplanned longevity causing tumor growth?
• EBV can lead to Burkitt’s lymphoma (a B cell lymphoma) if co-factors are present
EBV immortalizes B cells via a translocation of c-MYC on chromosome 14 with immunoglobulin heavy chains on chromosome 18. Since B cells live to make immunoglobulins, this translocation puts c-MYC under the control of a powerful promoter on the new chromosome, leading to constitutive expression and proliferation
NOTE: Burkitt’s can cause in the absence of EBV
