Mechanisms of Viral Oncogenesis

1.            Malignant Transformation of Cells

a.            Oncology is the study of tumors:

i.          a benign tumor is a growth produced by abnormal cell proliferation which remains localized and does not invade adjacent tissue.

ii.          a malignant tumor is usually locally invasive and may also be metastatic; that is, spread by lymphatic and blood vessels to other parts of the body.

b.            Malignant tumors of epithelial cell origin are known as carcinomas, those arising from mesenchymal origin as sarcomas, and those from leukocytes as lymphomas.

c.         The process of development of tumors is termed oncogenesis.

d.            Malignant transformation refers to changes in the growth, properties, shape, and other features of the tumor cell.

e.            Malignant transformation can be induced by tumor viruses not only in animals but also in cultured cells.

f.            Features of Malignant transformation:

2.         Role of Oncogenes in Tumor Induction

a.            Oncogenes were originally found in retroviruses, where they are collectively referred to as v-onc genes.

b.         For each of the more than 60 v-onc genes so far identified there is a corresponding normal cellular gene, which is referred to as a c-onc gene, or as a protooncogene.

c.         The term oncogene is now applied broadly to any genetic element associated with cancer induction, including some cellular genes not known to have a viral homolog.

d.         The proteins they encode are assigned to four major classes: growth factors, growth factor receptors, intracellular signal transducers, and nuclear transcription factors.

e.         Cellular growth and control:

i.          after a growth factor binds to its receptor on the cell membrane, membrane-associated G proteins and tyrosine kinases are activated.

ii.          these, in turn, interact with cytoplasmic proteins to produce second messengers, which are transported to the nucleus and interact with nuclear factors.

iii.         DNA synthesis is activated, and cell division occurs.

iv.            overproduction of these factors can result in malignant transformation.

f.            Malignant transformation can be induced by a viral oncogene or the cellular oncogene itself.

g.            Mechanisms of Tumor production by Retroviruses:

i.          the transducing retroviruses introduce a v-onc gene, which is controlled by viral regulatory sequences present in the LTR (long terminal repeats) of the viral genome, into a chromosome of a normal cell.

ii.          Cis-activating retroviruses, which lack a v-onc gene, transform cells by integrating close to a c-onc gene and thus usurping normal cellular regulation of this gene.

iii.         Trans-activating retroviruses contain a gene that codes for a regulatory protein which may either increase transcription from the viral LTR or interfere with the transcriptional control of specific cellular genes.

iv.         the ‘oncoprotein’ products of all retroviral oncogenes act either by interfering with signal transduction or directly with the regulation of cellular genes.

h.            Mechanism of Tumor Induction by Cellular Oncogenes:

i.          DNA isolated from tumor cells can transform normal cells; this DNA has a c-onc gene with a mutation consisting of a single base change.

ii.            movement of c-onc gene to a new site on a different chromosome enhance expression of the gene.

iii.            increased numbers of c-onc genes, resulting in enhanced expression of their mRNA and proteins.

iv.         proviral DNA inserts near c-onc gene, which alters its expression and causes tumors.

v.         addition of an active promoter site enhances expression of the c-onc gene, and malignant transformation occurs.

3.            Viruses associated with Malignant Tumors in Humans

4.         Human T-cell Leukemia virus

a.         There are 2 human T-cell leukemia viruses, HTLV-1 and HTLV-2, both of which are associated with leukemias and lymphomas.

b.         In addition to cancer, HTLV is the cause of tropical spastic paraparesis, an autoimmune disease in which progressive weakness of the legs occurs.

c.         HTLV-1 has no viral oncogene and has 2 special genes called tax and rex that play a role in oncogenesis by regulating mRNA transcription and translation.

d.         The tax protein has two activities:

i.          it acts on the viral LTR sequences to stimulate mRNA synthesis.

ii.          it induces NF-kB, which stimulates the production of interleukin-2 and the IL-2 receptor.

e.         The increase in IL-2 and its receptor stimulates the T cells to continue growing, thus increasing the likelihood that the cells will become malignant.

f.          The rex protein determines which viral mRNA can exit the nucleus and enter the cytoplasm to be translated.

5.         Human Papillomavirus

a.         Certain genital HPV types, notably 16 and 18, induce cervical dysplasia which may progress to invasive carcinoma.

b.            Carcinogenesis by HPV involves 2 proteins encoded by HPV genes E6 and E7 that interfere with the activity of the proteins encoded by 2 tumor suppressor genes, p53 and Rb, found in normal cells.

c.         There are at least 60 different types of HPV each with a distinct clinical entity:

i.          HPV-1 through HPV-4 cause plantar warts on the soles of the feet.

ii.          HPV-6 and HPV-11 cause anogenital warts (condylomata acuminata) and laryngeal papillomas.

d.         In most of these tumor cells, the viral DNA is integrated into the cellular DNA and the E6 and E7 proteins are produced.

6.            Epstein-Barr virus

a.            Epstein-Barr virus is associated with Burkitt’s lymphoma, B cell lymphoma and nasopharyngeal carcinoma.

b.         The EBV genome DNA is present in multiple copies in each cell of most Burkitt’s lymphomas, in the form of closed circles of the complete viral DNA molecule, found free as autonomously replicating episomes.

c.            Burkitt’s lymphoma:

i.          a cellular oncogene, c-myc, which is normally located on chromosome 8, is translocated to chromosome 14 at the site of immunoglobulin heavy-chain genes.

ii.          this translocation brings the c-myc gene in juxtaposition to an active promoter, and large amounts of c-myc RNA are synthesized.

iii.            Burkitt’s lymphoma may develop as a consequence of differentiation arrest due to the translocation, and subsequent growth stimulation resulting from c-myc deregulation.

c.         B-cell lymphomas in immunocompromised patients, sometimes follows EBV primary infection or reactivation.

d.            Nasopharyngeal carcinoma:

i.          in NPC, the epithelial cells contain multiple copies of EBV DNA, in episomal form, in every cell.

ii.          EB produced by B lymphocytes traffick through copious lymphoid tissue in the pharynx binds to IgA to infect mucosal epithelial cells via the IgA transport pathway.

iii.         the EBV NPC cells produce EBNA-1 antigen consistently.