Viruses and Cancer

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Viruses and Cancer
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Cancers of viral aetiology

• Hepatocellular carcinoma (HBV and HCV)
• Burkitts lymphoma (EBV)
• nasopharyngeal carcinoma (EBV)
• Hodgkins disease (EBV)
• cervical carcinoma (HPV)
• Kaposis sarcoma (HHV-8)
• adult T cell leukaemia/lymphoma (HTLV-1)

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Criteria

• epidemiology
• virus in tumour tissue
• viral genes and oncogenesis

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Mechanisms of Oncogenesis

1. modulation of cell cycle control (The virus may
   alter the regulatory mechanisms controlling the
   progress of the cell cycle and cell division)
2. modulation of apoptosis (the virus must prevent
   the host cell from undergoing apoptosis, a normal
   cellular response to viral-induced injury, which
   would otherwise abort the further development of
   uncontrolled cell proliferation)
3. ROS (Reactive oxygen species) mediated damage

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Cell Cycle Control

• pRB ( a tumor suppressor protein that is
  dysfunctional in several major cancers. One
  function of pRb is to prevent excessive cell growt
  h by inhibiting cell cycle progression until a
  cell is ready to divide)
• cyclin D1 (cell cycle control)

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Modulation of Apoptosis

• P53 (transcription factor activated by DNA damage
  that can induce growth arrest and apoptosis)
• Bcl-2 (supress apoptosis)
• FLICE inhibitory proteins (FLIPs) (inhibit
  apoptosis signalling)

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ROS Damage

• inflammatory responses generate radicals,
  including OH. and NO.
• free radicals target
• DNA (mutation)
• protein (nitration, nitrosation)
• RNA
• lipids (lipid peroxidation)

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ROS Damage

• Free radicals may promote cancer by
• mutating cancer related genes
• activating signal transduction pathways
• promoting angiogenesis
• exerting selective pressure (p53 and NO.)

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Hepatocellular Carcinoma
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Hepatocellular Carcinoma

• HCC is one of the most prevalent malignant
  diseases in the world
• chronic infection with HBV or HCV accounts for
  more than 80 of HCC cases
• other risk factors include aflatoxin B1, heavy
  alcohol consumption and smoking

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HCC and HBV

• insertional activation
• HBx
• transactivation of proinflammatory genes
• interaction with p53
• generation of ROS

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HCC and HCV

• HCV sequences are present in HCC tissue
• HCV antigen expression in HCC (or other tissue)
  cannot be assessed
• HCV contains genes with potential oncogenic
  function

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HCV genes

• HCV core protein has been shown to
• cause HCC in transgenic mice
• modulate apoptosis
• drive cells to proliferation
• generate ROS

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HCC and hepatitis viruses

• mass vaccination against HBV will radically
  reduce the incidence of HCC in SE Asia
• elimination of HCV or HBV reduces the risk of
  developing HCC

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Human Herpesvirus 8 and Kaposis Sarcoma
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Kaposis Sarcoma

• Kaposis sarcoma (KS) is a mesenchymal tumour
  involving blood and lymphatic vessels
• KS occurs in three forms
• classical
• endemic
• epidemic

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Pathology of KS

• Multicentric lesions composed of interweaving
  bands of spindle cells that form irregular
  vascular channels
• Spindle cells express markers of endothelial
  cells (CD34 and Factor VIII)

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KS and HIV

• The incidence of KS in HIV positive gay men is
  20,000 fold that of the general population
• KS is 20 times more common in homosexual men with
  AIDS than other risk groups
• the risk of KS in HIV positive men increases with
  the frequency and risk of sexual activity

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Herpesviruses and KS

• In 1994 RDA isolated viral sequences from KS
  tissue
• these sequences were identified as a new
  herpesvirus, designated HHV-8
• HHV-8 has now been found in almost 100 of
  tissues from all forms of KS

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Epidemiology

• HHV-8 seropositivity in various populations is
  correlated with the population risk of KS
• Longtitudinal surveys have shown infection with
  HHV-8 precedes the onset of KS

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Virus and Tumour Tissue

• In individuals with KS, HHV-8 sequences are found
  in tumour but not in adjacent tissue
• within KS lesions, HHV-8 DNA and antigen
  expression is localised to spindle cells

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Genes and oncogenesis

• HHV-8 encodes homologues of human proteins
• (examples)
• cyclin D1
• G-protein coupled receptor
• bcl-2
• FLICE inhibitory protein
• And others

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v-cyclin D1

• HHV-8 v-cyclin is expressed in KS lesions and
  interacts with CDK6
• v-cyclin in complex with CDK6 is not inhibited by
  p16 INK4a or p27Kip1

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HHV-8 (G protein-coupled receptor) GPCR

• HHV-8 encodes a viral G protein-coupled receptor
  (vGPCR).
• v-GPCR is homologous to the IL-8 receptor
• v-GPCR has been shown to transform cells and
  tumour formation.

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HHV-8 bcl-2

• the viral protein has both sequence and
  structural homology to bcl-2 family proteins
• v-bcl-2 is functional
• the role of v-bcl-2 in the viral life cycle is
  not yet clear

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v-FLIP

• v-FLIPs inhibit apoptosis signalling through
  death receptors
• HHV-8 v-FLIP physically interacts with
  pro-caspase-8 and prevents recruitment to DISC

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Non-homologous Viral Genes

• Latency -associated nuclear antigen (LANA) is
  essential to the maintenance of HHV-8
• LANA interacts with p53 and suppresses its
  transcriptional activity