1. Viruses and Cancer

2. Cancers of viral aetiology
Hepatocellular carcinoma (HBV and HCV)
Burkitt’s lymphoma (EBV)
nasopharyngeal carcinoma (EBV)
Hodgkins disease (EBV)
cervical carcinoma (HPV)
Kaposi’s sarcoma (HHV-8)
adult T cell leukaemia/lymphoma (HTLV-1)

3. Criteria epidemiology virus in tumour tissue
viral genes and oncogenesis

4. Mechanisms of Oncogenesis
modulation of cell cycle control (The virus may alter the regulatory mechanisms controlling the progress of the cell cycle and cell division)
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)
ROS (Reactive oxygen species) mediated damage

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

6. 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)

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

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

9. Hepatocellular Carcinoma

10. 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

11. HCC and HBV insertional activation HBx
transactivation of proinflammatory genes
interaction with p53
generation of ROS

12. 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

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

14. 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

15. Human Herpesvirus 8 and Kaposi’s Sarcoma

16. Kaposi’s Sarcoma
Kaposi’s sarcoma (KS) is a mesenchymal tumour involving blood and lymphatic vessels
KS occurs in three forms:
classical
endemic
epidemic

17. 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)

18. 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

19. 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

20. 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

21. 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

22. Genes and oncogenesis HHV-8 encodes homologues of human proteins
(examples):
cyclin D1
G-protein coupled receptor
bcl-2
FLICE inhibitory protein
And others

23. 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

24. 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.

25. 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

26. 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

28. 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