Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

CANCER PREVENTION AND TREATMENT: PRESENT AND FUTURE
1131
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).
Better still, a vaccine has now been developed that protects against infection
with the relevant strains of human papillomavirus. This vaccine, given to girls
before puberty and thus before they become sexually active, has been shown
to greatly reduce their risk of ever developing cervical cancer. Because the virus
spreads through sexual activity, it is now recommended that both young males
and young females be routinely vaccinated. Mass immunization programs have
begun in several countries.
viral proteins mediate
the controlled replication
of the virus in outer
cell layers
host
chromosome
(A)
BENIGN GROWTH OR WART
chromosome of
papillomavirus
unregulated production of viral
proteins drives cell proliferation
in basal cell layer
Figure 20–40 How certain papillomaviruses are thought to give rise
to cancer of the uterine cervix. Papillomaviruses have double-stranded
circular DNA chromosomes of about 8000 nucleotide pairs. These
chromosomes are normally stably maintained in the basal cells of the
epithelium as plasmids (red circles), whose replication is regulated so as to
keep step with the chromosomes of the host. (A) Normally, the virus perturbs
the host cell cycle only when the virus is programmed to produce infectious
progeny, in the outer layers of an epithelium. This is relatively harmless.
(B) Rare accidents can cause the integration of a fragment of such a plasmid
into a chromosome of the host, altering the environment of the viral genes in
the basal cells of an epithelium. This can disrupt the normal control of viral
gene expression. The unregulated production of certain viral proteins (E6 and
E7) interferes with the control of cell division in the basal cells, thereby helping
to generate a cancer (bottom).
(B)
EVOLUTION OF
MALIGNANT TUMOR
integrated gene
encoding viral
proteins