The main culprits, as shown in Table 20–2, are the DNA viruses. The DNA tumor viruses cause cancer by the most direct route—by interfering with controls of the cell cycle and apoptosis. To understand this type of viral carcinogenesis, it is important to review the life history of viruses. Many DNA viruses use the host cell’s DNA replication machinery to replicate their own genomes. However, to produce a large number of infectious virus particles within a single host cell, the DNA virus has to commandeer this machinery and drive it hard, breaking through the normal constraints on DNA replication and usually killing the host cell in the process. Many DNA viruses reproduce only in this way. But some have a second option: they can propagate their genome as a quiet, well-behaved passenger in the host cell, replicating in parallel with the host cell’s DNA (either integrated into the host genome, or as an extrachromosomal plasmid) in the course of ordinary cell-division cycles. These viruses will switch between two modes of existence according to circumstances, remaining latent and harmless for a long time, but then proliferating in occasional cells in a process that kills the host cell and generates large numbers of infectious particles.
Neither of these conditions converts the host cell to a cancerous character, nor is it in the interest of the virus to do so. But for viruses with a latent phase, accidents can occur that prematurely activate some of the viral proteins that the virus would normally use in its replicative phase to allow the viral DNA to replicate independently of the cell cycle. As described in the example below, this type of accident can switch on the persistent proliferation of the host cell itself, leading to cancer.
Cancers of the Uterine Cervix Can Be Prevented by Vaccination Against human Papillomavirus
The papillomaviruses are a prime example of DNA tumor viruses. They are responsible for human warts and are especially important as a cause of carcinoma of the uterine cervix: this is the second commonest cancer of women in the world as a whole, representing about 6% of all human cancers. Human papillomaviruses (HPV) infect the cervical epithelium and maintain themselves in a latent phase in the basal layer of cells as extrachromosomal plasmids, which replicate in step with the chromosomes. Infectious virus particles are generated through a switch to a replicative phase in the outer epithelial layers, as progeny of these cells begin to differentiate before being sloughed from the surface. Here, cell division should normally stop, but the virus interferes with this cell-cycle arrest so as to allow replication of its own genome. Usually, the effect is restricted to the outer layers of cells and is relatively harmless, as in a wart. Occasionally, however, a genetic accident causes the viral genes that encode the proteins that prevent cell-cycle arrest to integrate into the host chromosome and become active in the basal layer, where the stem cells of the epithelium reside (see Figure 22–10). This can lead to cancer, with the viral genes acting as oncogenes (Figure 20–40).
The whole process, from initial infection to invasive cancer, is slow, taking many years. It involves a long intermediate stage when the affected patch of cervical epithelium is visibly disordered but the cells have not yet begun to invade the underlying connective tissue—a phenomenon called intraepithelial neoplasia. Many such lesions regress spontaneously. Moreover, at this stage, it is still easy to cure the condition by destroying or surgically removing the abnormal tissue. Fortunately, the presence of such lesions can be detected by scraping off a sample of cells from the surface of the cervix and viewing it under the microscope (the “Pap smear” technique).