Viruses and Cancer. Cancers of viral aetiology n Hepatocellular carcinoma (HBV and HCV) n Burkitt’s lymphoma (EBV) n nasopharyngeal carcinoma (EBV) n.

Viruses and CancerViruses and Cancer

Cancers of viral aetiologyCancers of viral aetiology

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

1)1)

CriteriaCriteria

epidemiologyepidemiology virus in tumour tissuevirus in tumour tissue viral genes and oncogenesisviral genes and oncogenesis

Mechanisms of Mechanisms of OncogenesisOncogenesis

1.1. modulation of cell cycle control modulation of cell cycle control (The virus may alter the regulatory mechanisms controlling the progress of the cell cycle and cell division)

2.2. modulation of apoptosis 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)

3.3. ROS (Reactive oxygen species) mediated ROS (Reactive oxygen species) mediated damagedamage

Cell Cycle ControlCell Cycle Control

pRB (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)cyclin D1 (cell cycle control)

Modulation of ApoptosisModulation of Apoptosis

P53 (transcription factor activated P53 (transcription factor activated by DNA damage that can induce by DNA damage that can induce growth arrest and apoptosis) growth arrest and apoptosis)

Bcl-2 (supress apoptosis)Bcl-2 (supress apoptosis) FLICE inhibitory proteins (FLIPs) FLICE inhibitory proteins (FLIPs)

(inhibit apoptosis signalling)(inhibit apoptosis signalling)

ROS DamageROS Damage

inflammatory responses generate inflammatory responses generate radicals, including OHradicals, including OH.. and NO and NO..

free radicals target free radicals target

DNA (mutation)DNA (mutation)

protein (nitration, nitrosation)protein (nitration, nitrosation)

RNA RNA

lipids (lipid peroxidation)lipids (lipid peroxidation)

ROS DamageROS Damage

Free radicals may promote cancer byFree radicals may promote cancer by mutating cancer related genesmutating cancer related genes activating signal transduction pathwaysactivating signal transduction pathways promoting angiogenesispromoting angiogenesis exerting selective pressure (p53 and exerting selective pressure (p53 and

NONO..) )

Hepatocellular CarcinomaHepatocellular Carcinoma

Hepatocellular CarcinomaHepatocellular Carcinoma

HCC is one of the most prevalent HCC is one of the most prevalent malignant diseases in the worldmalignant diseases in the world

chronic infection with HBV or HCV chronic infection with HBV or HCV accounts for more than 80% of HCC accounts for more than 80% of HCC casescases

other risk factors include aflatoxin Bother risk factors include aflatoxin B11, , heavy alcohol consumption and heavy alcohol consumption and smokingsmoking

HCC and HBVHCC and HBV

insertional activation insertional activation HBxHBx

transactivation of proinflammatorytransactivation of proinflammatorygenes genes

interaction with p53 interaction with p53 generation of ROS generation of ROS

HCC and HCVHCC and HCV

HCV sequences are present in HCC HCV sequences are present in HCC tissuetissue

HCV antigen expression in HCC (or HCV antigen expression in HCC (or other tissue) cannot be assessedother tissue) cannot be assessed

HCV contains genes with potential HCV contains genes with potential oncogenic functiononcogenic function

HCV genesHCV genes

HCV core protein has been shown toHCV core protein has been shown to cause HCC in transgenic micecause HCC in transgenic mice modulate apoptosismodulate apoptosis drive cells to proliferationdrive cells to proliferation generate ROSgenerate ROS

HCC and hepatitis virusesHCC and hepatitis viruses

mass vaccination against HBV will mass vaccination against HBV will radically reduce the incidence of HCC in radically reduce the incidence of HCC in SE AsiaSE Asia

elimination of HCV or HBV reduces the elimination of HCV or HBV reduces the risk of developing HCCrisk of developing HCC

Human Herpesvirus 8 and Human Herpesvirus 8 and Kaposi’s SarcomaKaposi’s Sarcoma

Kaposi’s SarcomaKaposi’s Sarcoma

Kaposi’s sarcoma (KS) is a Kaposi’s sarcoma (KS) is a mesenchymal tumour involving blood mesenchymal tumour involving blood and lymphatic vesselsand lymphatic vessels

KS occurs in three forms:KS occurs in three forms:

classicalclassical

endemicendemic

epidemicepidemic

Pathology of KSPathology of KS

Multicentric lesions composed of Multicentric lesions composed of interweaving bands of spindle cells that interweaving bands of spindle cells that form irregular vascular channelsform irregular vascular channels

Spindle cells express markers of Spindle cells express markers of endothelial cells (CD34 and Factor VIII) endothelial cells (CD34 and Factor VIII)

KS and HIVKS and HIV

The incidence of KS in HIV positive gay The incidence of KS in HIV positive gay men is 20,000 fold that of the general men is 20,000 fold that of the general populationpopulation

KS is 20 times more common in KS is 20 times more common in homosexual men with AIDS than other homosexual men with AIDS than other risk groupsrisk groups

the risk of KS in HIV positive men the risk of KS in HIV positive men increases with the frequency and risk of increases with the frequency and risk of sexual activitysexual activity

Herpesviruses and KSHerpesviruses and KS

In 1994 RDA isolated viral sequences In 1994 RDA isolated viral sequences from KS tissuefrom KS tissue

these sequences were identified as a these sequences were identified as a new herpesvirus, designated HHV-8new herpesvirus, designated HHV-8

HHV-8 has now been found in almost HHV-8 has now been found in almost 100% of tissues from all forms of KS100% of tissues from all forms of KS

Epidemiology Epidemiology

HHV-8 seropositivity in various HHV-8 seropositivity in various populations is correlated with the populations is correlated with the population risk of KSpopulation risk of KS

Longtitudinal surveys have shown Longtitudinal surveys have shown infection with HHV-8 precedes the onset infection with HHV-8 precedes the onset of KSof KS

Virus and Tumour Tissue Virus and Tumour Tissue

In individuals with KS, HHV-8 sequences In individuals with KS, HHV-8 sequences are found in tumour but not in adjacent are found in tumour but not in adjacent tissuetissue

within KS lesions, HHV-8 DNA and within KS lesions, HHV-8 DNA and antigen expression is localised to antigen expression is localised to spindle cellsspindle cells

Genes and oncogenesisGenes and oncogenesis

HHV-8 encodes homologues of human HHV-8 encodes homologues of human proteins proteins

(examples):(examples): cyclin D1cyclin D1 G-protein coupled receptorG-protein coupled receptor bclbcl-2 -2 FLICE inhibitory proteinFLICE inhibitory protein And others And others

v-cyclin D1v-cyclin D1

HHV-8 v-cyclin is expressed in KS HHV-8 v-cyclin is expressed in KS lesions and interacts with CDK6 lesions and interacts with CDK6

v-cyclin in complex with CDK6 is not v-cyclin in complex with CDK6 is not inhibited by p16 INK4a or p27Kip1inhibited by p16 INK4a or p27Kip1

HHV-8 (HHV-8 (G protein-coupled G protein-coupled receptor) receptor) GPCRGPCR

HHV-8 encodes a viral G protein-HHV-8 encodes a viral G protein-coupled receptor (vGPCR).coupled receptor (vGPCR).

v-GPCR is homologous to the IL-8 v-GPCR is homologous to the IL-8 receptor receptor

v-GPCR has been shown to transform v-GPCR has been shown to transform cells and tumour formation. cells and tumour formation.

HHV-8 bcl-2HHV-8 bcl-2

the viral protein has both sequence and the viral protein has both sequence and structural homology to bcl-2 family structural homology to bcl-2 family proteinsproteins

v-bcl-2 is functional v-bcl-2 is functional the role of v-bcl-2 in the viral life cycle the role of v-bcl-2 in the viral life cycle

is not yet clearis not yet clear

v-FLIPv-FLIP

v-FLIPs inhibit apoptosis signalling v-FLIPs inhibit apoptosis signalling through death receptorsthrough death receptors

HHV-8 v-FLIP physically interacts with HHV-8 v-FLIP physically interacts with pro-caspase-8 and prevents recruitment pro-caspase-8 and prevents recruitment to DISCto DISC

Non-homologous Viral Non-homologous Viral GenesGenes

Latency -associated nuclear antigen Latency -associated nuclear antigen (LANA) is essential to the maintenance (LANA) is essential to the maintenance of HHV-8of HHV-8

LANA interacts with p53 and suppresses LANA interacts with p53 and suppresses its transcriptional activityits transcriptional activity