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Block 2 Microbiology > Oncogenic Viruses > Flashcards

Oncogenic Viruses Flashcards

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1
Q

What % of human cancers are caused by viruses?

A

15-20%

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2
Q

What are the leading causes of liver and cervical cancer?

A

Viruses (HCV/HBV and HPV)

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3
Q

Generally speaking, how do viruses cause cancer?

A
  • By altering control of cell proliferation:
    1. Activate signaling pathways to stimulate constitutive growth
    2. Release cell cycle control to allow uncontrolled growth
    3. Infected cell destruction/clearance leads to unplanned regeneration
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4
Q

Is cancer necessary for oncogenic viral replication?

A

No -> side effect of virus infection

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5
Q

Are viruses produced from malignant tumors?

A
  • Generally, NO
  • Cancer induction, more specifically cell transformation, is an alternative to lytic replication
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6
Q

In virally-induced cancers, does cancer arise immediately post-infection?

A
  • NO -> in humans, cancer occurs long after infection
  • Virus-caused cancer occurs more frequently in people who are immunocompromised (i.e., HIV/AIDS)
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7
Q

What are the epidemiologic and virologic criteria for something to be considered a cancer-causing virus?

A
  • Epidemiologic:

a. Similar geo distribution of infection & cancer
b. Higher incidence of viral markers in cases vs control references
c. Viral markers should precede cancer
d. Reduction in infection rates = reduced cancer

  • Virologic:

a. Virus should transform cells in vitro
b. Virus genome in tumor, but not normal cells
c. Tumor induction in experimental animals

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8
Q

What are the 6 known human cancer viruses?

A
  1. Human T-lymphotropic virus type 1 (HTLV-1)
  2. Human herpesvirus 8 (Kaposi’s Sarcoma-associated Herpesvirus)
  3. Epstein-Barr Virus
  4. Human papillomavirus
  5. Hepatitis B virus
  6. Hepatitis C virus
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9
Q

What are some viruses known to transform cells in animals, but that have not yet been linked to human cancers?

A
  1. Adenovirus
  2. Polyomavirus
  3. Poxvirus
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10
Q

What is the difference between immortalized and transformed cells? List 5 characteristics of transformed cells.

A
  • Immortalized: retain original properties, but grow indefinitely
  • Transformed: immortalized, but lose many growth props
  1. Reduced need for serum growth factors
  2. Loss of contact inhibition
  3. Anchorage independent (can grow in soft agar)
  4. Appear round as opposed to typical morphology
  5. May cause tumors when introduced into suitable animal
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11
Q

What are v-oncogenes?

A
  • Part of viral genome
  • Derived from cellular oncogenes (aka, c-oncogene, or proto-oncogene)
  • Picked up by ancestors, likely result of integration of viral genome into host chromosome during normal replication cycle of retroviruses
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12
Q

What are the 3 classifications of oncogenic retroviruses?

A
  1. Transducing oncogenic (e.g., Rous sarcoma virus):

a. Contain v-oncogene
b. 100% rate of tumor formation
c. Rapid tumor formation (days)

  1. Non-transducing onocogenic (e.g., some non-human agents)

a. No v-oncogene, but can activate c-oncogene via integration
b. High rate of tumor formation
c. Intermediate time to tumor (weeks to months)

  1. Nontransducing, long latency oncogenic (e.g., HTLV1)

a. V-oncogene unrelated to c-oncogenes
b. Low (<5%) rate of tumor formation
c. Months or years to tumor formation

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13
Q

What kinds of viruses can be oncogenic? What is their typical mechanism?

A
  • Both RNA and DNA tumor viruses can be oncogenic
    1. Often the net result is an increase/dysregulation in kinase (phosphorylation) cascades that increase gene expression related to cell division
    2. Other times the gene expression is upregulated by the introduction of new transcription factors
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14
Q

What is the difference between v-oncogene and c-oncogene function?

A
  • V-oncogenes are always active (constitutive)
  • Results in loss of signaling control and inappropriate growth
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15
Q

What kind of v-oncogenes are carried by transducing retroviruses?

A
  • V-oncogenes that control signal transduction related to cell growth/regulation in a variety of ways, i.e.,:

a. Tyrosine kinases
b. Tyrosine kinase growth factor receptors
c. Serine/threonine kinases
d. Transcription factors
e. Hormone receptors

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16
Q

What is the mechanism of non-transducing retroviruses?

A
  • Operate by insertional activation: virus genome (or part of it) randomly inserts in host chrom -> strong promoters or transcriptional enhancers in viral genome lead to unregulated overexpression of nearby c-oncogenes
  • Because integration events next to c-oncogenes and subsequent alterations that lead to increased expression are rare, there is an intermediate-to-long lag time for tumor induction and tumors are monoclonal
  • No naturally occurring human examples, but a recent retroviral gene therapy trial resulted in leukemias due to an unfortunate integration site of the vector
17
Q

What is the human example of a long latency retrovirus leading to cancer? Which cancer? What is the mechanism?

A
  • HTLV-1: only human example
  • Causes adult T cell leukemia and lymphoma (ATL), an aggressive non-Hodgkin’s lymphoma that is fatal
  • Infects and transforms CD4+ T cells

a. Tax (oncogene) stimulates Ikk complex -> IkB degradation, freeing NF-kB to direct transcription in nucleus of T cells
c. Dysregulation of NF-kB func -> immortalization and subsequent transformation of the T cells

18
Q

Describe the pathogenesis of EBV related to cancer, and the cancers it is implicated in.

A
  • Epstein-Barr Virus (EBV): herpesvirus (DNA virus) latent in B-cells -> leads to Burkitt’s, Hodgkin’s, and post- transplantation lymphoma, & nasopharyngeal carcinoma (NPC), but only in the presence of contributing factors
  • Encodes a multi-spanning transmembrane protein

a. Latency membrane protein-1 (LMP-1) analogous to PM signaling proteins, but oligomerizes independent of ligand and is always active
c. LMP-1 activates kinase cascade localizing NF-kB to the nucleus in B-cells, leading to immortalization

  • Burkitt’s lymphoma arises from chrom translocations: in years post-infection and B cell immortalization, errors are made in B cell division
    1. Translocation puts c-myc under control of a very powerful Ig heavy chain promoter, and c-myc over-expression -> further loss of cell division control
19
Q

Describe the pathogenesis of HHV8 related to cancer, and the cancers it is implicated in.

A
  • Human herpesvirus 8 (KSHV): leads to Kaposi’s sarcoma (lymphatic endothelial cancer), pleural effusion lymphoma (non-Hodgkin’s body cavity lymphoma), and Castleman’s disease (lymph node tumors, not strictly a cancer)
  • KSHV encodes several potential oncogenes, including:

a. Cytokine and chemokine homologues that stimulate transformation
b. vGPCR (most significant): G protein-coupled receptor that induces growth and transformation; differs from cellular GPCRs b/c constitutively active due to amino acid substitutions

  • KSHV also alters cell cycle control (+ signaling, above):
  1. Produces cyclin homologue, v-cyclin, that binds and activates cyclin-dependent kinase 6 (CdK6)
    a. v-cyclin/CdK6 complex immune to inhibition by CdK inhibitors such as Cip or Ink4 -> cell cycle progression maintained rather than regulated
20
Q

Describe the pathogenesis of SV40 related to cancer, and the cancers it is implicated in.

A
  • Simian virus 40 (DNA polyomavirus): non-human pathogen found in early preps of the live polio vaccine
  • Encodes 2 versions of a “T” (transforming) Ag that functions in replication of the viral genome
  • Small (sT) antigen binds protein phosphatase 2A, a serine/threonine phosphatase abundant in cells
    i. Bond inactivates phosphatase, increasing half-life of phosphorylation events -> sustains cascades longer, so uncontrolled stimulation of cell division
  • Lg (LT) T Ag expression inhibits (-) cell cycle regulation
  1. . LT binds Rb protein, inactivating it, and inducing E2f-dependent transcription and cell division
  2. Also binds p53 -> inactive; prevents apoptosis
21
Q

Is inactivation of TSGs a necessary part of oncogenic viral replication?

A
  • NO: while this is a process that involves viral proteins required for viral replication, inactivation of TSGs is a side effect NOT required for viral replication
22
Q

Describe the pathogenesis of HPV related to cancer.

A
  • Undergoes lytic replication in permissive cells, but transforms non-permissive cells (NO replication in them)
  1. Low-risk HPV (6, 11) causes warts (benign tumors)
    b. High-risk HPV (genotrypes 16, 18, 35) cause cervical, penile, and oral cavity/throat cancers
  • Metastatic tumors: part of HPV genome integrated into host chromosome, disrupting viral regulatory gene, E2,
    which normally dampens expression of E6 and E7     (E = early proteins needed for viral replication)
  1. E6 and E7 expressed at high levels
  2. High risk HPV: E6 binds p53 and leads to p53 degradation; E7 binds Rb protein and inactivates it
  • Closely related to SV40 and other polyomaviruses
23
Q

Describe the pathogenesis of HBV/HCV related to cancer.

A
  • HBV/HCV leading caus of hepatocellular carcinoma (HCC), but do not directly alter cell division pathways
  • HCC: result of long-term (decades) chronic liver INF
  • Constant clearance of infected hepatocytes leads to unintended replication of hepatocytes and subsequent mutations, leading to uncontrolled proliferation & cancer
  • HBV, a very simple DNA virus, encodes a protein “X,” implicated in transformation; evidence not complete, but X protein is a liver-specific transcription factor that may play a role in dysregulation of cell division

Block 2 Microbiology (4 decks)

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