-by: university of South Carolina

Cancers are the result of a disruption of the normal restraints on cellular proliferation. It is apparent that the number of ways in which such disruption can occur is strictly limited and there may be as few as forty cellular genes in which mutation or some other disruption of their expression leads to unrestrained cell growth.

There are two classes of these genes in which altered expression can lead to loss of growth control: 
(a) Those genes that are stimulatory for growth and which cause cancer when hyperactive. Mutations in these genes will be dominant. These genes are called oncogenes.
(b) Those genes that inhibit cell growth and which cause cancer when they are turned off. Mutations in these genes will be recessive. These are the anti-oncogenes. Viruses are involved in cancers because they can either carry a copy of one of these genes or can alter expression of the cell's copy of one of these genes.

CLASSES OF TUMOR VIRUSES

There are two classes of tumor viruses:

• DNA tumor viruses
• RNA tumor viruses, the latter also being referred to as RETROVIRUSES.

We shall see that these two classes have very different ways of reproducing themselves but they often have one aspect of their life cycle in common: the ability to integrate their own genome into that of the host cell. Such integration is not, however, a pre-requisite for tumor formation.

If a virus takes up residence in a cell and alters the properties of that cell, the cell is said to be transformed.

TRANSFORMATION BY A VIRUS MAY BE DEFINED AS: CHANGES IN THE BIOLOGIC FUNCTIONS OF A CELL THAT RESULT FROM REGULATION OF THE CELL BY VIRAL GENES AND THAT CONFER ON THE INFECTED CELL CERTAIN PROPERTIES CHARACTERISTIC OF NEOPLASIA. THESE CHANGES OFTEN (BUT NOT ALWAYS) RESULT FROM INTEGRATION OF THE VIRAL GENOME INTO THE HOST CELL GENOME

Transformation often includes loss of growth control , ability to invade extracellular matrix and dedifferentiation. In carcinomas, many epithelial cells undergo an epithelial-mesenchymal transformation. Transformed cells often exhibit chromosomal aberrations.

The region of the viral genome (DNA in DNA tumor-viruses or RNA in RNA-tumor viruses) that can cause a tumor is called an oncogene. This foreign gene can be carried into a cell and cause it to take on new properties such as immortalization and anchorage-independent growth.

The discovery of viral oncogenes in retroviruses led to the finding that they are not unique to viruses and homologous genes (called proto-oncogenes) are found in all cells. Indeed, it is likely that the virus picked up a cellular gene during its evolution and this gene has subsequently become altered. Normally, the cellular proto-oncogenes are not expressed in a quiescent cell since they are involved in growth (which is not occurring in most cells of the body) and development; or they are expressed at low levels. However, they may become aberrantly expressed when the cell is infected by tumor viruses that do not themselves carry a viral oncogene.  We shall see later how this happens but it is clear that a virus may cause cancer in two ways: It may carry an oncogene into a cell or it may activate a cellular proto-oncogene.

The discovery of cellular oncogenes opened the way to the elucidation of mechanisms by which non-virally induced cancers may be caused. We shall investigate what the protein products of the viral and cellular oncogenes do in the infected cell and in cells in which cellular proto-oncogenes are expressed. We shall see that their functions strongly suggest mechanisms by which cells may be transformed to a neoplastic  phenotype. The discovery of cellular oncogenes led to the discovery of another class of cellular genes, the tumor repressor (suppressor) genes or anti-oncogenes. Initially, the involvement of viral and cellular oncogenes in tumors caused by retroviruses was much more apparent than the involvement of the DNA tumor virus oncogenes but the discovery of tumor repressor genes (as a result of our knowledge of how retroviruses cause cancer) led to the elucidation of the mode of action of DNA virus oncogenes. It should be noted that while viruses have been vitally instrumental in elucidation of the mechanisms of oncogenesis, most human cancers are probably not the result of a retroviral infection although retroviruses are important in cancers in some animals.