The Cell: Basic Structure and Function
Fig. 1.14
Schematic representation of the
different phases of an HR-HPV infection.
After infection of basal cells of the epithelium the virus may persist
in a latent state. Upon differentiation and maturation of the cells, the viral genome may be replicated and novel virus particles are produced and released at
the surface of the epithelium. This stage is often characterized by typical koilocytes as a morphological hallmark of virus production. If transcriptional control of
the viral genome in the basal and parabasal cells fails, expression of the viral oncogenes in these replicating cells may induce chromosomal instability and thus
initiate transformation. Later in the progression to invasive cancers the viral genome often becomes integrated into the host cells' chromosomes as a sign of
increasing chromosomal instability.
aberrations.27 As a result of chromosomal instability induced by
E6 and E7, HPV genomes may become integrated into the host
genome.28 Both viral oncoproteins interact with many more
proteins of epithelial cells that are summarized in Fig. 1.15.
These interactions further support that central role of E6 as
anti-apoptotic protein and of E7 as proliferation inducing and
cell cycle deregulating factor.
Progression of HPV-Infected Epithelial Cells
to Invasive Cancer Cells
The progression of pre-neoplastic lesion of the uterine cervix to
invasive cancer cells is a well-described process usually subdi-
vided into three main stages referred to as cervical intraepithe-
lial neoplasia 1, 2, and 3 (Figs. 1.13, 1.14). This classification is
based on histopathological criteria that are essentially describing
the pathogenic effects of persisting HR-HPV infection in the cer-
vical epithelium. CIN 1 is characterized by minor activation of
the proliferation rate of the basal cells, whereas the proliferat-
ing cells are still restricted to the lower third of the epithelium.
The abundant presence of koilocytes in the more superficial cell
layers document the massive production and release of HPV.
In CIN 2 lesions the proliferating cells extend to the two lower
thirds of the epithelium. In these lesions the number of koilo-
cytes decreases gradually. CIN 3 lesions are characterized by
proliferating cells that extend now into the upper third of the
epithelium or in case of the carcinomata in situ lesions (CIS)
extend through the full thickness of the epithelium. These diag-
nostic categories are very useful in clinical practice since they
make it possible to subdivide precancerous stages according to
their likelihood to progress to invasive cancer. However, since
they do not make it possible to visualize the molecular events
induced by the deregulated expression of the viral oncogenes
in these cells, they do not formally make it possible to subdi-
vide the preneoplastic lesions according to the molecular events
involved in the carcinogenic processes.
As discussed above, the expression of HPVs is tightly regu-
lated in basal and parabasal cells of the epithelium. Thus, the
initiation of the carcinogenic process is not the infection of basal
epithelial cells by HR-HPVs but rather the emergence of epithe-
lial cell clones that fail to downregulate the expression of the
viral oncogenes in the basal cell layer.29 According to this model,
preneoplastic HPV-induced lesions can be subdivided into
acute virus-producing lesions (CIN 1, acute or replicating HPV
infection) and transforming HPV infections that emerge from
CIN 1 lesions but may progress via CIN 2 finally to CIN 3/CIS
lesions into invasive cervical carcinomas.30 In terms of the rela-
tive risk that each of these different stages carries for progres-
sion, this revised molecular model of the pathogenesis of the
HPV-induced cancers strongly suggests that as long as no dereg-
ulated expression of the viral genes has occurred in the basal
cells, the risk for progression to high-grade lesions or even can-
cer is comparably low. This situation dramatically changes once
individual HR-HPV infected basal cells lose the control over the
expression of the viral genes and start to express the viral E6
and E7 genes that then may initiate their deteriorating activi-
ties and initiate the carcinogenic process. Expression of the HR-
HPV type E7 protein interferes with the regulation of the G1/S
phase control of the cell cycle and permits proliferation of cells
even if the complete cell cycle machinery is not yet prepared to
replicate the DNA of the chromosomes. This results in fixation
of unrepaired mutation but also in damage of the genome by
itself. In normal cells this would have been counteracted by the
activation primarily of p53 mediated control mechanisms that
either would have resulted in stoppage of cell cycle progression
or, if the genomic damage is already too severe, induction of
the cellular suicide mechanisms (apoptosis) that prevent sur-
vival and expansion of cells with damaged genomes. During
the normal life cycle this never occurs since the expression of
the viral early genes is restricted to terminal differentiated cells
of the intermediate or superficial cell layers (Fig. 1.14).
Cells that display chromosomal instability under the influ-
ence of the papillomavirus genes E6 and E7 rapidly accumulate
numerous morphological alterations. First aberrant mitotic fig-
ures are seen in dividing cells, then enlarged nuclei with altered
chromatin structures appear, and finally severe changes of the
DNA content of the cells results in aneuploidy and anisonu-
cleosis. All these criteria are classical features that build up the
cytological classification system to score the degree of abnor-
malities induced by HPV infections in cervical cells.
One important aspect in the pathogenesis of HPV-induced
cancers in the female anogenital tract is its typical anatomical
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