Oncogenic Viruses Flashcards
What percentage of human cancers are caused by viruses?
15-20%
Viruses are the leading cause of what 2 types of cancer?
liver
cervical
How do viruses cause cancer?
Altering the control of cell proliferation:
- Activate signaling pathways to stimulate constitutive growth
- Release cell cycle control, which allows uncontrolled growth
- Infected cell destruction/clearance leads to unplanned regeneration
Who is most likely to be affected by a virus-caused cancer?
immunocompromised patients
T/F: In order for a virus to replicate in a host, cancer cells must be produced.
F: cancer is simply a side effect of the viral infection
What cancer-related process is an alternative to viral lytic replication?
cell transformation (cancer induction)
Malignant tumors are (more/less) likely to yield viruses.
less
Why is the presence of viral genome in a tumor cell not sufficient evidence that it was the causative agent?
- it may be coincidentally located in a typical site of replication
- assay could have been contaminated
Epidemiologic criteria to be considered a cancer-causing virus:
a. Coincident geographic distribution of infection and cancer
b. Higher incidence of viral markers in cancer cases vs control references
c. Viral markers should precede cancer
d. Reduction in infection rates should reduce cancer
Virologic criteria to be considered a cancer-causing virus:
a. Virus should transform cells in vitro
b. Virus genome present in tumor but not normal cells
c. Tumor induction in experimental animals
6 known human cancer viruses
- Human T-lymphotropic virus type 1
- Human Herpesvirus 8
- Epsterin-Barr
- HPV
- Hep B virus
- Hep C virus
3 Viruses known to transform cells or cause tumors in animals.
- adenovirus
- polyomavirus
- poxvirus
What are properties of immortalized cells in culture?
Retain original properties but grow indefinitely
What are properties of transformed cells in culture?
Immortalized but lose many growth properties, such as:
- Reduced need for serum growth factors
- Loss of contact inhibition
- Do not need to be anchored
- Round morphology
- May cause tumors when introduced to appropriate animal
What makes it possible for RNA tumor viruses to cause cancer without killing hosts?
V-oncogene
derived from cellular oncogenes or protooncogenes
From where are v-oncogenes derived?
likely, ancestor picked up from host during replication
3 classifications of retroviruses
transducing
nontransducing
nontransducing, long latency
What type of retrovirus?
Contain v-oncogene, related to c-oncogene
Transducing
What type of retrovirus?
Low (<5%) rate of tumor formation
Nontransducing, long latency
What type of retrovirus?
No v-oncogene, but can activate c-oncogene via integration
Nontransducing
What type of retrovirus?
100% rate of tumor formation
Transducing
What type of retrovirus?
High rate of tumor formation, but not 100%
Nontransducing
What type of retrovirus?
Rapid tumor formation (days)
Transducing
What type of retrovirus?
Months or years to tumor formation
Nontransducing, long latency
What type of retrovirus?
Intermediate time to tumor (weeks to months)
Nontransducing
What type of retrovirus?
Rous sarcoma virus
Transducing
What type of retrovirus?
Contains a v-oncogene unrelated to c-oncogenes
Nontransducing, long latency
What types of viruses can induce transformation by activation of signaling pathways?
both DNA and RNA tumor viruses
2 possible results of transformation by activation of signaling pathways
- increase/dysregulation in kinase
(phosphorylation) cascades which increase gene expression related to cell division - upregulation of gene expression by the introduction of new transcription factors
How do transducing retroviruses affect host cell processes?
Carry v-oncogenes that control signal
transduction related to cell growth/regulation
What host proteins are affected by transducing retroviruses?
tyrosine kinases tyrosine kinase growth factor receptors Ser/Thr kinases transcription factors hormone receptors G proteins
How do v-oncogenes differ from c-oncogenes, and what is the result of this?
v-oncogenes are always active (constitutive)
results in loss of signaling control and inappropriate growth
T/F: All transducing retroviruses cause cancer in humans.
F: no examples exist
How do nontransducing retroviruses operate?
insertional activation
- part/whole genome randomly inserts into host chromosome
- Strong promoters or transcriptional enhancers in virus genome lead to unregulated overexpression of nearby concogenes
Nontransducing tumors are _____-clonal
mono
Why is there an intermediate-to-long lag time for tumor induction in nontransducing tumors?
integration events next to c-oncogenes and the subsequent alterations resulting in increased expression are rare
T/F: HTLV-1 is the only human example of a long latency retrovirus leading to cancer.
T
Causes adult T cell leukemia and lymphoma (ATL), an aggressive/fatal non-Hodgkin’s lymphoma
How HTLV-1 induce cancer?
Once it infects, it transforms CD4+ T cells:
a. Expresses an oncogene, Tax
b. Tax stimulates Ikk complex to cause IkB
degradation
c. IkB degradation frees NF-kB to direct transcription in the nucleus of T cells
d. Dysregulation of NF-kB function leads to immortalization and subsequent transformation of the T cells
Where does latent Epstein-Barr virus reside?
in B cells
causes Burkitt’s lymphoma, Hodgkin’s, post-transplantion lymphoma, nasopharyngeal carcinoma
Epstein Barr virus is a (DNA/RNA) virus
DNA
How does Epstein Barr virus infection lead to cell immortilization?
Virally encoded Latency membrane protein-1 (LMP-1) activates a kinase cascade that localizes NF-kB to the nucleus in B-cells, leading to immortalization
What does Epstein Barr virus encode?
multispanning transmembrane protein
that is similar to normal plasma membrane proteins, except it functions independent of ligand
THUS is it ALWAYS active
What 3 conditions are caused by Human herpesvirus 8 (KSHV)?
- Kaposi’s sarcoma (lymphatic endothelial cancer)
- Pleural effusion lymphoma (non-Hodgkin’s body cavity lymphoma)
- Castleman’s disease (lymph node tumors, not strictly a cancer)
KSHV encodes several potential oncogenes involved in signaling, including:
- Cytokine and chemokine homologues (stimulate transformation)
- vGPCR (constitutively active due to amino acid substitutions; induces growth and transformation)
What type of virus is Simian virus 40 (SV40)?
[DNA] polyomavirus
SV40 encodes:
2 versions of a “T” (transforming) antigen:
- Large (LT) antigen
- Small (sT) antigen
How does sT cause uncontrolled cell division?
- Antigen binds/inactivates 2A phosphatase (a Ser/Thr phosphatase) that is abundant in cells
- This increases the halflife of phosphorylation events, which results in longer kinase cascades
(Longer kinase cascades = uncontrolled cell division)
How does SV40 ultimately cause uncontrolled cell division?
SV40 sustains kinase cascades longer
How does LT cause uncontrolled cell division?
LT inhibits the negative regulation of the cell cycle by:
1. Binds/inactivates Rb protein
–This induces E2f-dependent transcription
and cell division
2. Binds/inactivates p53
–Prevents apoptosis
DNA tumor viruses inactivate:
tumor suppressor genes
Note: this is a side effect–not something needed for viral replication
How does HPV affect permissive cells?
undergoes lytic replication in them
How does HPV affect non-permissive cells?
transforms them, no replication in them
Low risk forms of HPV cause:
warts (benign tumors)
High risk forms of HPV cause:
cervical cancer
penile cancer
oral cavity/throat cancers
HPV is closely related to:
SV40
Explain how HPV drives formation of metastatic tumors.
In metastatic tumors, HPV is integrated into the genome.
- Integration disrupts expression of E2 (viral regulatory gene, dampens E6/E7 expression)
- No E2 = high level expression of E6/E7
- E6 binds and degrades p53
- E7 binds and inactivates Rb
What is E2?
a vira; regulatory gene that functions in decreasing E6/E7 expression
What does E6 do?
bind/degrade p53
What does E7 do?
bind/inactivate Rb
What does KSHV alter?
Cell signaling
Cell cycle control
What is v-cyclin?
KSHV-produced cyclin homologue, that binds/activates cyclin-dependent kinase 6
- This complex is not inhibited by Cdk inhibitors
- Cell cycle progresses rather than being regulated
What causes hepatocellular carcinoma?
chronic infection of the liver by hep B or C
theory:
1. Constant elimination of infected hepatocytes
2. Replication of hepatocytes (replacement?)
3. mutations accumulate, leading to uncontrolled proliferation/cancer
What is protein X?
produced by Hep B virus
liver-specific transcription factors that may play a role on dysregulation of cell division
Although EBV encodes proteins that lead to immortalization, Burkitt’s lymphoma asrises from:
chromosomal translocations
(after infection and immortalization of B cells, errors are made during cell division which causes c-myc over-expression)
