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Some viruses cause cancer Viruses are one of the main factors that cause
normal cells to proliferate and to become malignant: up to 15% of all human cancers are associated with single or multiple virus infections
Viruses have evolved many strategies to prevent infected cells from becoming apoptotic and to evade the innate and adaptive immune responses of their hosts.
Changes in critical cellular funtions such as cell cycle control, cellular signalling, DNA repair, apoptosis or tumour supression lead to cancer
Viruses associated with cancers
Viruses associated with cancers
How do viruses cause cancer?
1. Transducing viruses
Oncogenes of retroviruses arose by transduction of cellular genes by recombination events.
Originally recognized from studies of the oncogene (v-src) of Rous sarcoma virus (RSV) and its cellular progenitor (c-src).
Transducing virus oncogenes
EGF receptor and transducing virus version
The ErbB protein family or epidermal growth factor receptor (EGFR) family is a family of four structurally related receptor tyrosine kinases.
Excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor.
Non- transducing viruses and cancer
2. Non transducing viruses: Retroviruses integrate into host genomes and can
disrupt coding regions of host genes (deletions truncations, rearrangements)
Integration into the host genome alters host genome expression (eg. LTR can act as enhancers or repressors of host gene expression). Cis acting viral sequences.
Produce changes in cell metabolism through the action of viral proteins acting as trans-acting factors (protein-protein and protein-DNA interactions
Insertional activation of cellular oncogene (c-onc)
Insertional activation can be by action of promoter or enhancer
c-onc can be a host protein critical for cell cycle control/cellular signalling/apoptosis
Eg. Ras ., myc activation
Human papillomavirus E5 protein
Human papillomavirus E5 protein increases the EGF cell surface receptor concentration of infected cells
Inhibits the endosomal H+ ATPase thus slowing degradation of EGF
p53- a master tumour supresor
Inactivation of the p53 protein by adeno- and papo- viral proteins
Normal response to remove infected cells….
Viral proteins inactivate or remove p53 (tumour repressor) thereby causing oncogenesisis
EBV
Epstein-Barr virus (EBV), is a herpesvirus family and very common. The virus occurs worldwide, and most people become infected with EBV sometime during their lives. > 95% of adults between 35 and 40 years of age have been infected.
Many children become infected with EBV, usually cause no symptoms or are indistinguishable from the other mild, brief illnesses of childhood. When infection with EBV occurs during adolescence or young adulthood, it causes infectious mononucleosis 35% to 50% of the time.
Also called glandular fever or the “kissing disease”
Diseases Driven by Epstein-Barr Virus (EBV)
Infectious mononucleosis
Chronic Active EBV
X-linked lymphoproliferative disease
Lymphoproliferative disease
Oral hairy leukoplakia
Hodgkin disease EBV EBV-Driven
Nasopharyngeal carcinoma Gene Cell
T cell lymphoma Expression Proliferation
Burkitt lymphoma
EBV Viral Load is Increased in Patients
with Lymphoproliferative Disease
Riddler, Blood 1994
Viral Load Used to Monitor Transplant Patients:Increased EBV load at onset of LPD
Used to initiate preemptive therapy
Burkitt Lymphoma
EBV+: 90% of cases in developing countries – jaw tumors 20% cases in US – children with abdominal tumors AIDS patients – tumors in lymph nodes
Dysregulation of c-myc oncogeneOnly EBV EBNA-1 expressed
EBV-Associated Smooth Muscle Tumors
Occur in transplant recipients, AIDS patients, congenitial immunodeficiency
Pathology: leiomyosarcomas and leiomyomas in various organs and lymph nodes
EBV Lymphoproliferative Disease
Occurs with immunodeficiency (AIDS, congenital) or after
transplantation, RA and MTX
Symptoms: Infectious Mononucleosis
Mass lesions in organs (less often lymph nodes)
Cohen NEJM 2000
LMP-1 is the EBV Oncogene
LMP-1 mediates signaling through the Tumor necrosis factor-alpha/CD40 pathway.
LMP-1 Expression in transgenic mice leads to B cell lymphoma; expression in fibroblasts leads to tumors in nude mice
B Cell Proliferation : Upregulates adhesion molecules, CD23, CD40,
IL-6, IL-10, etc. Activates NF-B Inhibition of apoptosis: Upregulates Bcl-2, A20, Mcl-1
Signalling pathway of TNF
TNF stimulates the inflammatory response and causes apoptotic
cell death…
SummaryViruses can cause cancer (uncontrolled cell growth).
Either through the recombination and capture of host oncogenes (transducing viruses) or by several mechanisms to alter cellular growth, differentiation and/or signalling (non-transducing viruses) including:
Retroviruses integrate into host genomes and can disrupt coding regions of host genes (deletions truncations, rearrangements)
Integration into the host genome alters host genome expression (eg. Cis acting viral sequences act as repressors of host gene expression).
Produce changes in cell metabolism through the action of viral proteins acting as trans-acting factors (protein-protein and protein-DNA interactions
The associations beweeen viruses and cancers are becoming clearer with better epidemiology and methods to isolate and study viruses.
