General Cytology
that encode components of the DNA-MMR complex. MSI may,
however, also occur in sporadic cancers without distinct inher-
ited background. In most of these cases accidental failure of the
epigenetic regulation of the genes that encode the components
of the MMR complex may fail usually due to altered methyla-
tion of the respective promoter sequences.
The third emerging major mechanism of carcinogenesis is
referred to as
CpG island methylator phenotype.12
Cancer cells that
emerge in frame of this molecular phenotype initially experi-
ence alterations of the epigenetic control mechanisms that tell
genes of specific cells where and when they should be active
or silent. In many instances this is regulated by methylation of
specific sites within the DNA by the addition of methyl groups
particularly to CpG sites frequently found throughout the whole
genome. The addition of these methyl groups either completely
blocks the expression of the respective gene by condensing it
chromatin structure or may just modify the binding proper-
ties of activating or inhibitory factors that activate or repress
transcription of the respective gene. The CIMP phenotype is
clearly the less well-characterized cancer phenotype so far.
Because of the basic mechanism it may end up finally in cancer
cells that impress as CIN phenotype due to the transcriptional
inactivation of genes involved in chromosomal homeostasis or
alternatively as MSI cancers due to the inactivation of genes that
maintain the DNA-MMR functions; here the most pronounced
example is the hMLHl gene frequently inactivated via the CIMP
phenotype in MSI-positive sporadic colorectal cancers.
Carcinogenesis Induced by
Papillomavirus Infections
Human papillomavirus infections play the predominant carci-
nogenic role for cancers of the lower female genital tract, and
in particular cervical cancer.13 Molecular pathways of how these
viruses contribute to neoplastic transformation of epithelial cells
have to a large extent been clarified and thus will be considered
in more detail in the following paragraphs.
Published reports on the concept that infectious agents may
be involved in the pathogenesis of cancers of the female lower
genital tract dates back to the middle of the nineteenth century.
Domenico Rigoni Stern described his observation that women
with frequent sexual contacts with various partners are at sub-
stantially higher risk to develop cervical cancer than women
who did not have sexual contacts. Since then sexually transmit-
table agents that may explain this peculiar epidemiological fea-
ture of these cancers have been extensively investigated. It lasted
until the end of the 1970s when the first truly important clues
that made it possible to delineate the formal molecular patho-
genesis of cervical cancers were put forward. In 1976 Harald zur
Hausen published his hypothesis that cervical cancer and its
precursor lesions may be caused by agents similar to those that
cause hyperproliferative lesions in the genital tract, the condy-
lomata acuminata or genital warts.14 This hypothesis initiated
an intense chase to track down the putative agents. Genomes
and viral particles of a new type of human papillomavirus were
identified in biopsies of genital warts and labeled as HPV 6.15
Shortly later a related HPV type was cloned from DNA samples
isolated from laryngeal papillomas and referred to as HPV 11.16
This HPV type showed substantial homologies with HPV 6 and
in subsequent studies both HPV types were found in laryngeal
as well as in genital papillomas.17
Both HPV types were used as probes to look for related DNA
sequences in DNA extracted from tumor biopsies and cell lines
derived from cervical cancers in further hybridization experi-
ments. These experiments led to the identification of related
but clearly distinct HPV sequences in cervical cancer cells. Sub-
sequent cloning and detailed characterization has revealed that
these sequences are indeed new types of the HPV group that
have since then been referred to as HPV 16 and 18.18, 19
Basic Structure of the Virus and Its Genome
Human papillomaviruses are small viral particles that constitute
viral capsids built up by self-assembling proteins encoded by the
L1 and L2 genes of the virus (Fig. 1.12). They lack an envelope
and are thus relatively resistant toward environmental hazards.
Viral capsids measure about 55 nm in diameter and include an
about 8,000-bp-long circular episomal genome that is highly
twisted (supercoiled circular genomes). This circular genome
encompasses three major genetic and functional regions:
• Early region E, which includes about eight different
genes (E1-E8);
• Late region L, which includes the two genes that encode
the proteins that make up the capsids (L1 and L2); and
• Upstream regulatory regions of the early region (URR),
which includes the important regulatory sequences
of the early promoter and enhancer that mediates the
highly complex regulation of the viral gene expression
pattern in their host cells that is so important for all
processes related to HPV-related carcinogenesis and
that we will discuss later.
A second regulatory element that regulates the expression of
the late genes is included in sequences that are part of the E7
gene (late promoter).
Papillomavirus types are differentiated in HPV genotypes
based on distinct variations of their nucleic acid sequences.
A certain stretch within the L1 gene is used as a reference to
differentiate types according to an international agreement on
the classification of HPV types.20
Meanwhile more than 120 different HPV types have been
characterized, but it is estimated that the true number of pap-
illomaviruses that may infect humans exceed 200. Papilloma-
viruses are strict epitheliotropic viruses that exclusively infect
epithelial cells of the outer surfaces of the human body. Most
of the HPV types infect the cutaneous parts of the skin (skin
types), whereas about 40 HPV types are preferentially found
in lesions in the mucosal surfaces in the lower anogenital
tract (mucosa types).21 Among the mucosa types two different
classes of HPV types are distinguished (Table 1.1): (a) the low-
risk HPV (LR-HPV) types that cause massive exophytic, hyper-
plastic wart-like lesions, and (b) the high-risk HPV (HR-HPV)
types associated with cancer particularly of the uterine cervix
(Fig. 1.13). The latter, however, usually cause only very minor
lesions without massive hyperplasia. These lesions rarely exceed
the surface of the epithelium in the early stages of the infection.
They commonly occur and regress without the infected person
realizing the infection. Thus although these infections occur in
men and women apparently with the same incidence, clinical
consequences that would trigger follow-up usually only occur
in women who have developed cervical lesions as part of a car-
cinogenic process, whereas in men the infections usually occur
and regress unnoticed.
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