BASIC MECHANISM OF CELL TRANSFORMATION BY ONCOGENIC VIRUSES

Read Also

Retroviruses are unusual RNA viruses which replicate by converting their genetic information into DNA form (the provirus), integrating this into the DNA of the host cell and producing new copies of the virus' RNA genome using this provirus as a master template. Very occasionally, the DNA provirus may integrate near a 'cellular oncogene' (a growth-promoting gene in the cell's own genome), liberating that gene from its usually tight control and causing it to drive the cell into growth (Figure 1.A). Such 'chronically oncogenic' viruses are found naturally in some animal species and produce tumours late in life. Very rarely, such viruses develop into 'acutely oncogenic' variants by capturing cellular oncogene sequences into the viral genome itself. These variants, so far only seen in the laboratory, produce tumours much more efficiently because they carry their own oncogene and can express it wherever they integrate in the cell genome. Yet a third mechanism of retrovirus-induced cell transformation exists and is described in the context of a human retrovirus HTLV1.

DNA viruses all possess one or more genes which are used early in the normal infectious cycle and transiently activate cell growth; this is important to these viruses because a transiently 'activated' cell becomes a much better factory for virus replication. Very occasionally, and with the exception of the herpesviruses, the viral genome accidentally integrates into the cell DNA and may do so in such a way that the early, growth-activating genes of the virus are permanently expressed. The normal infectious cycle is interrupted and the cell permanently activated into growth. The viral genome of the cancer-associated herpesviruses is much larger. It can be stably maintained in the cell and express growth-activating latent genes without integration.

Multistep Carcinogenesis. Carcinogenesis is a multistep process, ie, multiple genetic changes must occur to convert a normal cell into a malignant one. Intermediate stages have been identified and designated by terms such as "immortalization," "hyperplasia," and "preneoplastic." Tumors usually develop slowly over a long period of time. The natural history of human and animal cancers suggests a multistep process of cellular evolution, probably involving cellular genetic instability and repeated selection of rare cells with some selective growth advantage. The number of mutations underlying this process is estimated to range from five to eight. Observations suggest that activation of multiple cellular oncogenes and inactivation of tumor suppressor genes are involved in the evolution of tumors whether or not a virus is involved.

It appears that a tumor virus usually acts as a cofactor, providing only some of the steps required to generate malignant cells. Viruses are necessary—but not sufficient—for development of tumors with a viral etiology. Viruses often act as initiators of the neoplastic process and may do so by different mechanisms.