Viruses and Cancer

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

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

Cell Cycle Control • pRB ( a tumor suppressorprotein 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)

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)

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

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

Hepatocellular Carcinoma

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

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

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

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

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

Human Herpesvirus 8 and Kaposi’s Sarcoma

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

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)

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

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

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

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

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

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

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.

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

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

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

Viruses and Cancer