Certain viruses have the ability to induce tumors in the animals they infect; such viruses are termed oncogenic viruses. When such viruses infect cultured cells, they cause transformation.
Examples of oncogenic viruses:
- Human Papilloma Virus: Genital warts, squamous cell carcinoma
- Epstein Barr Virus: Nasopharyngeal carcinoma, African Burkitt's lymphoma, B cell lymphoma
- Human Herpes Virus 8 (HHV8): Kaposi's sarcoma
- Herpes simplex type II: Cervical carcinoma
- Hepatitis B virus: Hepatocellular carcinoma
Carcinogenesis: It is a multistep process where multiple genetic changes must occur to convert a normal cell into a malignant one. As many as 5-8 independent steps may required for the malignant cell to emerge. Intermediate stages have been identified in various systems as "immortalization", "hyperplasia" and "pre-neoplastic".
- Human T cell lymphotropic virus (HTLV-1): adult T cell leukemia
Transformation: It may be defined as stable, heritable change in the growth control of the cells in culture. Transformation is a change in the morphological, biochemical or growth parameters of the cell, which may or may not result in production of tumors in experimental animals. Characteristics associated with transformed cells include:
- Increased metabolic rate, growth rate and growth to higher cell density
- Decreased requirement of serum growth factors
- Decreased cell adhesion to substrate
- Loss of contact inhibition
- Increased rate of transport of nutrients
- Increased secretion of activators
- Expression of virus coded proteins
- Changes in glycoproteins and glycolipids
- Expression of foetal antigen
- Altered levels of nucleotides
- Activation or repression of cellular genes
- Presence of viral nucleic acid
- Changes in cytoskeleton, often making the cell round
- Production of tumors when transformed cells are injected into appropriate animals
It is not necessary for a transformed cell to exhibit all of these features.
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Mechanism of transformation:
Not all cells are susceptible to infection by viruses. Those cells that resist viral infection are called non-permissive and those, which get infected, are called permissive cells. Cells that are permissive for one virus may be non-permissive for another virus. DNA viruses don't transform permissive cells but may transform non-permissive cells. In contrast to DNA viruses, RNA viruses can transform both permissive and non-permissive cells.
Transformation of normal cells into neoplastic cells involves integration of certain viral genes. In DNA viruses, the DNA integrates into the chromosome of the host cell. In RNA viruses, the RNA serves as template for the synthesis of DNA by viral enzyme reverse transcriptase. This DNA copy (known as provirus) of the viral RNA is then integrated into the host chromosome at any site. Transformed cells usually don't produce viruses. Retroviruses are not cytolytic (they don't kill the cells in which they replicate). The provirus remains integrated within the cellular DNA for the life of the cell.
Two common mechanisms of tumor induction are:
1. Tumor virus may introduce a new transforming gene (oncogene) in to the cell
2. The virus induces or alters the expression of pre-existing cellular gene
Transformation by RNA viruses:
RNA tumor viruses are of two general types with respect to tumor induction. The highly oncogenic viruses carry an oncogene. They are referred as direct transforming or acute transforming viruses because they induce tumors in vivo and transformation in vitro after very short latent period. These induce varieties of tumors such as sarcoma, carcinoma and leukemia. The weakly oncogenic (slow transforming) viruses do not contain an oncogene and induce leukemia after long incubation period by indirect mechanisms. Neoplastic transformation by retroviruses is the result of activation and over expression of a normal cellular gene that is normally tightly regulated. In acutely transforming viruses, a cellular gene becomes a part of viral genome by recombination, which is then expressed under the control of virus. In leukemia virus, the viral promoter gets inserted adjacent to a cellular gene, thereby continuously activating it. Cells transformed by many oncogenes produce excess of various growth factors.
Transformation by DNA viruses:
The genes responsible for transformation in DNA viruses have no cellular homologues. The transforming genes carried by DNA tumor viruses encode functions responsible for viral replication. The proteins coded by the transforming genes of DNA viruses forms complexes with normal cellular proteins and alter their functions. Certain DNA viruses can induce transformation by repression of anti-oncogenes or tumor suppressor genes. Proteins coded by these genes are negative regulators of cell growth. Inactivation of these genes may lead to loss of control over cell growth and may result in tumor formation. The transforming proteins of certain DNA viruses (eg. Adenovirus, SV40) can bind and inactivate the products of tumor suppressor genes and induce tumors.