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Oncogenesis
Unidad
de Oncología Molecular, Instituto de Estudios
Celulares y Moleculares Policlínico de
Lugo, Lugo, Galicia, Spain
Introduction
Cervical
carcinoma supposes, in global terms, the second cause
of death by cancer in women after the breast carcinoma.
During year 2002, in spite of the progressive implantation
of the cytological screening programs, they will die
more than 550,000 women worldwide by this cause, although
the distribution of these cases will be very different
being developing countries those that agglutinate
most of such cases (Baker P. Et al). Very well-known
is the existing relation between certain human types
of papillomavirus and the development of cervical
preneoplasic and neoplasic pathologies (Dilner J et
al.). The last studies (Boch FX et al.) establish
with certainty the implication of high risk HPVs as
casual agents of the tumoral transformation in almost
the totality of cervical carcinomas.
In spite of this certainty, the fundamental question
can be formulated under three premises: Could determination
of the casual agent improve diagnosis of the cervical
pathologies? Or, does this knowledge changes the therapeutic
attitude if a patient is infected by a high risk HPV?
Or, could allow typification to establish the bases
for a definitive treatment?
The answer to these questions continues being debate
object; in the first place the HPV is, without a doubt,
necessary for the tumoral transformation but non sufficient,
since the fact to find discharges rates of spontaneous
regression of these infections, mainly in pathologies
of low grade as CIN I, seems to indicate that another
series of cofactors must collaborate with the virus
in this process of transformation. With regard to
the second question, it is doubtless that the knowledge
of the casual agent in other pathologies have to lay
the basis of a clinical attitude, thus in the cases
of HIV, HCV, HBV …, the determination of the
presence of the viral agent is determining in the
handling of the patient (Jennings-Dozier K et al).
Perhaps in HPV infection, due to its wide distribution
in the different degrees of cervical pathologies (low
grade SIL, high grade SIL, “in situ” and
invasive Ca and even ASCUS and AGUS) does that the
determination of the simple presence of HPV, without
additional cytohistologic data, is not a sufficient
marker that allows to clinical to distinguish between
taking an interventional attitude (escisional or destructive
treatment) or an expectant attitude, with minimal
guarantees of security that avoid the overtreatment.
Finally with regard to the third question, in the
basis of knowledge of the complex biology of the viral
infection and the cellular processes which leads to
the transformation of the cells to a tumoral state,
and taking into account that the maintenance of infection
throughout the cellular generations is the basis of
the invasive process, makes crucial the finding of
effective chemotherapeutic agents or vaccines for
this infections. Is very difficult, however, that
its spectrum of action completely covers all the variants
that the infection presents at clinical level.
Biology of Viral Infection and Oncogenesis
Of the more than one hundred known HPV types, single
few (around a twenty) are associate to the infection
of anogenital tract. Remarkable population differences
in the distribution of the infection exist and certain
types are even mainly associated to histologic types
of tumors, for example is well-known the strong association
between the HPV the 18 and the adenocarcinoma, being
those scuamous lesions preferably associated to types
like HPV 16,31 or 33. We will focus our attention
on the types 16 and 18 that are responsible for most
of the cervical tumours in our population. All the
HPVs are encapsulated double stranded DNA viruses
of approximately 8000 base pairs, their architecture
does not defer between types, sharing a structure
from ORFs (open reading frames) of which E6 and E7
will be, in the high risk types, implied directly
in the process of tumoral transformation to this end
as oncogenes. (Table 1.)
The HPVs, after being inoculated, infects the basal
cells of cervical epithelium and takes advantage of
the differentiation process of this epithelium, to
be producing the proteins that will allow him to assemble
new viral particles. The infected epithelial cells
activate their mechanism of cellular defence including
a revision of the DNA sequence before dividing themselves.
This process of revision happens during a phase of
the cellular cycle and is directed by a protein cascade
of which they emphasize p53 and the Rb protein, When
the cell locates the viral DNA, in a perfectly regulated
process, it tries to repair the error and since this
DNA is excessively long like being
Table 1. - Structure of viral genome
------------URR-----------ORFE6--------ORF E7---------
Viral DNA
---------------------------ORF E2-----------------------
Eliminated,
p53 and Rb direct to the infected cell to programmed
cellular death by apoptosis, avoiding so this cell
serves as propagator of the infection. The high risk
HPV types, protecting himselves of this cellular mechanism
and are able to synthesize proteins that block this
system of cellular defence. The ORFs E6 and E7, transcribe
a product whose translation will result in the production
of proteins of the same name (E6 and E7) which respectively
they will be able to block to p53 and Rb of the cellular
cycle and to hinder the death of the cell by apoptosis,
being able to continue this way using the cell as
centre of production of viral particles. By this,
E6 and E7 they must be considered, to all the effects,
like viral oncogenes. The process of blockade of p53
and Rb by the proteins E6 and E7 would not have greater
problem if it were not resulted in a cellular immortalization.
As a result of the blockade of the system of repair
of errors, the cell is not only incapable to eliminate
the viral DNA, but that also is disabled to fix intrinsic
errors to the cellular DNA, so that it is accumulating
genetic alterations and in addition, as either can
not “to death” since the apoptosis process
also has been blocked, o what is the same, in a cell
with neoplasic phenotype will become a cell immortalized
with DNA in progressive decay. It seems sure, at sight
of these processes, that the HPV mediated oncogenesis
mechanism begins with the expression of E6 and E7
which they block to p53 an Rb and which they immortalize
to the cell restricting, with it, the functionality
of its DNA; nevertheless, certain experiments have
demonstrated that the basal expression of E6 and E7
in the HPVs is very low since the E2 protein, by means
of regulating region URR (Table 1.) it practically
maintains silenced the expression of the same ones.
Figure 1
Before this, it seems clear that solely an infection
with great amount of virus would be able to produce
the sufficient units of E6 and E7 like initiating
this process. Indeed, the infections with high viral
load, in which the immune system is not competent
to eliminate the infection, have a higher risk of
neoplasic transformation. Nevertheless, it has been
demonstrated that certain persistent infections with
low viral load, are able to generate tumoral phenotypes.
Which is, then, the mechanism of immortalization with
so low viral load? The demonstration of which in most
of the carcinomas the viral DNA it was fragmented
and it integrated in the cellular genome, gave answer
to this question. In most of the cases a viral DNA
is fragmented by the E2 region (Fig. 1.) losing its
capacity to act on URR and to issue the order of which
this one maintains repressed the expression of E6
and E7, this way, a small amount of virus will be
deregulated and will produce great amounts of protein
E6 and E7 which they will initiate the process of
blockade of p53 and Rb in a highly effective way.
Definition
of HPV Associated High Risk Biological Lesion
Under the basis of the knowledge of viral biology,
we can distinguish between initial lesions in which
those that the infection, independently of the viral
load, it is going to be solved by immunological mechanisms
(Cucick J et al), and infections in which there is
no immunological response originating, with it, persistence
of the associated infection and resulting frequently
in viral integration.
This process will produce immortal cellular clones
that will be the basis of the neoplasic transformation.
With these premises we can define a high risk biological
lesion associated to HPV (BHR-HPV) that defines different
capacities from neoplasic transformation on the basis
of the biology of the HPV infection (Alba a. et al.)
(Fig. 2).
Biological
Markers Associated to Oncogenesis
An infection by HPV, even by types of high risk, has
a capacity of neoplasic transformation that is variable
based on the physical state of the virus (integrated
or not in the genome) and of the local immunological
status of the tissue. These variables, altogether,
are going to define different characteristics as persistence,
cellular immortalization and local capacity of transformation
that are those that will affect the clinical evolution
of the patient. Once established an immortalized cellular
clone a progressive alteration of its genetic patrimony
will begin and will be appearing alterations that
will serve as tracers of the pathology. Recently it
has been described (Nuovo GJ et al.) a process of
inactivation by hipermetilation of the p16 protein
, as responsible of the maintenance of the established
tumoral phenotype, besides to produce an antiapoptotic
effect, added to which E6 causes on p53 and that is
mediated by the Bag-1/rap46 protein (Yang X et al.)
.As one scored in the beginning, it seems that certain
cofactors act the HPVs along with, in the initiation
of the process of neoplasic transformation; one of
these cofactors, still widely discussed, is the presence
of coinfection by Clamydias (Edelman M et al), preferredly
of G serotype. Another interesting discovery is the
one that describes to the inactivation of the endogenous
interferon expression by interaction between the E7
protein and regulating factor Irf-1, which would explain
the mechanism of immune evasion which they present/display
certain infected patients. Another important finding
is the one that describes a phenotype of predisposition
to the development of carcinomas in patients infected
by HPV and that is bound to a polymorphism of p53
(Matsumoto Y. et al; Pegoraro R et al). Thus the patients
homocigous for Arg alelle (it codes for arginin in
codon 72) would have 7 times more possibilities of
developing a cervical cancer that those homocigous
for alelle Pro (it codes proline) in the same position.
This genetic pattern could explain, partly, the known
fact by which certain women solve the infections by
HPV spontaneously or being infected they do not even
make debut with citohistologica alterations, unlike
which in a short space of time they develop invasive
carcinomas.
Conclusions
Like all the neoplasic processes, the cervical carcinomas
are originated by a succession of extracellular and
intracellular events that affect to the genetic pattern
of cervical epithelium. Doubtlessly the infection
by HPVs of high risk acts like detonating of this
cascade of events in which the mechanisms of cellular
repair, mediated by p53, Rb, Bag-1, MDM2, etc, are
disqualified for, later, in a clastogenetic process
(accumulation of genetic alterarions) are p16 (Nuovo
GJ et al), Telomerasa, PTEN, MMACl and other genes
those that take care of the maintenance of this tumoral
phenotype. Other predisponentes factors as the polymorphisms
of codon 72 of p53 (Tenti P et al) or confactors as
the infection by certain serotypes of Chlamydia (Hakama
M et al) seems to collaborate in the establishment
of the alterations that lead to the tumour maintenance
and progression. At sight of all these data, we have
defined a high risk biological lesion associated to
HPV (BHR-HPV) that helps the clinical ones to value,
non single the presence of the casual agent of the
pathology, but that identifies and distinguishes certain
biological states (integration, viral load, etc) which
they allow, in conjunction with the cytohistological
data, to take a different therapeutic attitude based
on the pattern from viral infection. This method defers
of the habitual ones (PCR-RFLP, Hybrid Capture , ETC)
in that, although with value in primary screening,
they only inform about the presence or absence of
HPV but they do not allow to value the short are half
term risk of the HPV positive lesions, and determination
of BHR-HPV could induce to the clinician to change
the therapeutic attitude from the knowledge of which
the lesion has biological characteristics of persistence
more or an elevated potential of short term tumoral
transformation.
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