Viral Viral OncogenesisOncogenesis

What is Cancer?What is Cancer?Definit ion: Definit ion: Any disorder of cell growth that results in invasion and destruction of surrounding healthy tissue by abnormal cells.

Cancer cells arise from normal cells whose nature is permanently changed.

They multiply more rapidly than healthy body cells and do not seem subject to normal control by nerves and hormones.

They may spread via the bloodstream or lymphatic system to other parts of the body, where they produce further tissue damage (metastasis).

Regulation of Cell Division In Normal Regulation of Cell Division In Normal CellsCells

Cellular Transformation►When the cell fails to respond to suchsignals, it is “out of control”, and can continue to

divide.

►The daughter cells will also continue to divide.

►Ultimately, might result in cancer.

Carcinoma (Skin Cancer)Carcinoma (Skin Cancer) Basal skin carsinoma.Basal skin carsinoma.

Sarcoma (In bone , Muscle or other Sarcoma (In bone , Muscle or other Soft Tissue)Soft Tissue)

Leukemia (Cancer of the bone marrow)

Too many Too many leucocytes are produced.

Lymphoma (cancer of the lymph tissue)

Myeloma (Cancer of The Myeloid Tissue)

Myeloid tissue is where blood forms in the red bone marrow in vertebrates. It is important in the immune system.

Oncogenes A gene that is capable of transforming a normal

cell into a cancerous cell.

Oncogenes result from the mutation of normal genes (proto-oncogenes).

Oncogenes are also seen in oncogenic viruses.(Viral oncogenes are derived from normal host genes that have

become incorporated into the viral genome and subsequently undergo mutation.)

Genes and Cancer►Mutations that result in cancer typically occurin 3 types of genes. – Proto-oncogenes: (genes whose products

stimulate cell multiplication)

– Tumor-suppressor genes: (genes whose products inhibit cellmultiplication)

– Mutator genes: (genes whose products ensure accurate DNA replication and DNA repair)

Genes and Cancer Retinoblastoma

Tumor Viruses For most viruses: Genome Viral Proteins

Replication Lysis Progeny virions

Lytic Life Cycle

Tumor Viruses Latent Life Cycle

Virus Cell Integration (usually) Transformation

►Virus-specific proteins expressed - No mature virus changes in the properties of host cell – TRANSFORMATION!

Tumor Viruses

Transformation:

Loss of growth control Abil ity to form tumors - viral genes interfere with

control of cell replication.

TRANSFORMATION

►Both DNA and RNA tumor viruses can transform cells. Integration occurs (usually).

Similar Mechanisms

VIRAL TRANSFORMATIONThe changes in the biological functions of a cell

that result from REGULATIONof the cell’s metabolism by viral genes and that

confer on the infected cell certain properties characteristic of

NEOPLASIAThese changes often result from the integration

of the viral genome into the host cell DNA.

TRANSFORMATION Among the many altered properties of the

TRANSFORMED CELL are:►Loss of growth control ( loss of contact

inhibit ion in cultured cells).►Tumor formation.►Mobility.►Reduced adhesion.►Transformed cells frequently exhibit

chromosomal aberrations.

DNA Tumor Viruses Papil loma Viruses:• Cause natural cancers in animals.

• Cause benign warts.

• Ubiquitous.

• Epitheliotropic - most human tumors are malignancies of epithelial cells.

DNA Tumor Viruses Epidermodysplasia verruciformis

Papilloma virus

DNA Tumor Viruses Polyoma Viruses

• Simian virus 40 - juvenile hamster sarcomas, transformation.

• Polyoma - mouse leukemia, in vitro transformation.

• Human polyomas (JC and BK) – monkey sarcoma , transformation

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Polyoma virus transforms cells when the genome is incomplete.

Early functions are necessary.

DNA Tumor Viruses Adenoviruses

►Highly oncogenic in animals.

►Only part of virus integrated.

►Always the same part.

DNA Tumor Viruses Herpes VirusesConsiderable evidence for role in human

cancer.• Some very tumorigenic in animals.• Viral DNA found in small proportion of tumor

cells: “hit and run”.► Epstein-Barr Virus.► Burkitt ’s Lymphoma.► Nasopharyngeal cancer.► Infectious mononucleosis.► Transforms human B-lymphocytes in vitro.

DNA Tumor Viruses Hepatit is B Virus

DNA genome RNA Provirus DNA genome

RNA polymerase II Reverse transcriptase Host enzyme Viral enzyme

RNA Tumor Viruses RNA Genome – (Retroviruses)

RNA-dependent DNA Polymerase encoded by virus.

RNA Genome DNA Genome Integrates RNA Genome

Reverse transcriptase Integrase Host RNA polymerase II

Virus Virus Host

RNA Tumor Viruses A normal retrovirus has 3 genes :

GAG : Internal proteins.ENV: Envelope glycoproteins.POL: Enzymes Reverse transcriptase Integrase Protease

RNA Tumor Viruses

RNA Tumor Viruses Groups of Retroviruses• OncovirinaeTumor viruses and similar

• LentivirusesLong latent periodProgressive chronic diseaseVisna HIV

• Spumavirinae

RNA Tumor Viruses Viral Oncogene V-onc

Cellular Proto-oncogene C-onc

RNA Tumor Viruses Proto-oncogeneA cellular (host) gene that is homologous with a

similar gene that is found in a transforming virus.

A cellular oncogene can only induce transformation after:

• mutation • some other change in the cell’s

genome.

RNA Tumor VirusesThe discovery of the acutely transformingretroviruses that contain v-oncs explains how

cancers may arise as a result of infection.

These viruses cause rapid cancer in animals inthe laboratory.

RNA Tumor VirusesALV can integrate into the host cell genome at

MANY locations but in tumor it is always at the SAME site (or restricted number of sites).

Suggest tumor arose from one cell.• Something must be important about this site for

transformation.• Crucial event must be rare.