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with unscheduled DNA replication. It is possible that HPV LOWER GENITAL TRACT NEOPLASIAS:
infection mainly affects the cells located near the squamo- CERVICAL, VAGINAL AND VULVAR
columnar junctions that form the stratified epithelial layers CANCER
of the transformation zone as the cervix matures, such
as the epithelial reserve cells. [61,62] It is believed that the Neoplasias of the genital tract includes cervical (CIN),
formation of the lesion starts with the infection of the basal vaginal and vulvar intraepithelial neoplasias and a fraction
stem cell and the formation of a persistent lesion depends of these neoplasias progresses to invasive cancers. HPV
on the longevity of the stem cell. [6,63,64] This hypothesis is infection is detected in almost all cervical, half of the vulvar
especially convincing for the low-risk HPV types since and approximately 70% of vaginal tumors. [78]
they do not usually lead to neoplasia and do not particularly
stimulate the basal cell proliferation. The viral replication The organisation of the life cycle of HPVs in the
proteins E1 and E2 may play a role in the amplification of development of lower genital tract neoplasias is well
the viral genome. [63,65,66] One of the hypotheses suggests established. [79-82] Retrospective studies have reported that
that E2 may be possibly involved in genome partitioning almost all the women with cervical cancers are infected
where the viral transcription is regulated by E2. A with HPV and in the more severe cases, that are squamous
[67]
viral DNA helicase, such as E1, may separate the viral cell carcinomas, HPV16 is the most prevalent type observed
DNA replication from cellular DNA replication during in 90% of the cases [40,52,83,84] Ten percent of the cervical
establishment and amplification of the genome. [6,68] Of all cancers are adenocarcinomas that are mostly caused by
[40]
the HPV proteins, E6 and E7 are the key ones associated in HPV infections. Women with HPV16 (61%) and HPV18
cancers via eliminating the tumour suppressors p53 and Rb (10%) were shown to have 200 fold higher risks for the
leading to anti-apoptosis, genetic instability and formation development of cervical cancers. [1,85] The prevalence of
of skin or mucosa lesions. [22,23,69] In low-risk HPV types, the other HPV types are less observed in cervical cancer cases,
wound healing process may hold an important role in the in such HPV45 was observed in 6%, HPV31 in 4%, HPV52
initial proliferation of the infected cells. For the high- in 3%, HPV35 in 2% and HPV58 in 2% of cervical cancer
[70]
[86]
risk HPV types, viral proteins E6 and E7 function in the cases.
cell proliferation in the basal and parabasal cell layers. This
function is particularly important at cervical sites where The risk factors for cervical cancers follow the similar
parameters for the general HPV infection risks, such as
neoplasias may occur. The functions of viral proteins E6 high parity (more than 4 vaginal deliveries), full term
[6]
and E7 vary between the high and low-risk HPV types and pregnancy at earlier age (18 years old or earlier) and use
these are associated with different pathologies. The low of hormonal oral contraceptives. [83,87] Progression of the
[71]
risk HPV E6 and E7 proteins cause weak transformation cervical cancer can be affected by several factors including
or no transformation at all. RB1 is targeted and degraded coinfection with other sexually transmitted infection, such
by the high risk HPV E7 proteins, whereas E6 proteins as Chlamydia trachomatis, herpes simplex virus, HIV or
target TP53 and stimulate telomerase (TERT). Telomerase tobacco smoking and immune suppression. [55,83] Therefore,
activation is a fundamental stage for the high risk HPV type counselling adolescents at earlier age for avoiding tobacco
mediated cell immortalization in vitro. However, more use, initiation of sexual intercourse and limiting the number
[72]
studies involving animal models are required to understand of partners may help to reduce the cervical cancer.
the HPV integration in vivo. On the contrary, even though
the low risk HPV E7 proteins bind to RB1, it is not involved The HPV proteins E6 and E7 are proposed to play a role
in the degradation. Low risk E6 does not bind to TP53 and it in the pathogenesis of HPV associated cervical cancers. [88]
does not stimulate TERT. The mechanism of oncogenesis The phenotype of the cervical neoplasia was suggested to
[73]
associated with HPV is proposed to be through p16-INK4a vary depending on the expression levels of E6 and E7 were
expression. High risk HPV E7 triggers p16-INK4a through suggested to increase from cervical intraepithelial neoplasia
KDM6B histone demethylase causing p16-INK4a mediated grade 1 to 3 (CIN1 to CIN3). These interactions of HPV
CDK4/6 inhibition and RB1 mediated cell cycle arrest and proteins with cellular pathways of the host cell will give a
senescence. [74-76] More aberrations including abnormal chance for potential targets for HPV based cancer treatment
number of centromeres, multipolar mitotic spindles, strategies. Additionally, E2 gene is also believed to take a
chromosome lagging and anaphase bridges are also part in cervical cancer since in about 35% of HPV induced
observed in cells expressing HPV16 E6 and E7 genes. cervical cancers full length viral genomes are expressed. [89,90]
[77]
These aberrations may occur in cells with HPV infection at The regulation of gene expression is changed when the viral
the early stages, but they can be easily detected in invasive DNA integrates with the cell chromosomes. This integration
cancers. Therefore, these abnormalities that originates leads to a continuous expression of E6 and E7 proteins
during mitosis increases the risk of mutation accumulation causing accumulation of mutations of the cellular DNA
that may cause malignant transformation in vitro. One of and promoting malignancies. [77,91] These accumulations
these aberrations is the allelic loss, such as losses in 3p and of mutations, mostly monosomies, trisomies, structural
10p that are associated with telomerase activation. changes, chromatid gaps and breaks and double minutes,

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Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ June 15, 2016 ¦