Cervical cancer are the most common female's cancer in the developing countries. On the world, about 500 000 women have the disease annually and about 75% are from developing countries. The pathogenesis of cervical cancer is linked to human papilloma virus(HPV), HPV is a sexually transmitted disease with particular types being highly oncogenic. HPV is regarded as the vector that confer susceptibility to neoplastic conversion or directly incites transmutation to are malignant phenotype in some infected epithelial cells. The IARC had classified the HPV into three groups, one are carcinogenic (HPV type of 16 / 18), one are probably carcinogenic (HPV type of 31 / 33) and the last one are possibly carcinogenic (the other types of HPV except 6 and 11).
The structure of HPV
HPV are double stranded DNA virus, it also are diameter of 47-55 nm. It are in protein caps with the viral genome in the circular configuration. The viral genome can be divided into 3 part, the first one are Upstream Regulatory Region (URR),the second one are the Early Region (E) and the last one are Late Region (L), and I will explain the function of those part in the following:
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Upstream Regulatory Region (URR): The URR are involved in viral replication and also control of transcription in some sequences in the Early region.
Early Region (E): The Early Region encode for the protein that are responsible for viral replication which occurs early in the viral life cycle.
Late Region (L):
The late region are encode for viral structural protein necessary for the caps production late in the viral life cycle.
The Early Region are responsible for the maintaining high numbers of the HPV and the oncogenic types also encode for the proteins that promote the transformation of the host cell to the cancer cell (call immortalisation).
There are some area in the Early Region that can encode for the proteins and are designated as E1/ E2/ E3/ E4/ E5/ E6 and E7. The E6 and E7 regions are responsible for the oncogenic properties of the HPV.
Pathogenesis of Cervical cancer
The reason of cervical cancer is come from HPV. That is usually are sexually transmitted disease. The mode of inhibition of cervical cellular p53 and Rb anti-ongenes by the production of the proteins from the viral genome E6 / E7 regions, the integration of the viral DNA into the host's cell and mutation of the host cell nucleus resulting in uninhibited proliferation of the cervical cells with subsequent cancer formation.
As the virus invades the genital cell in the HPV loses its protein capsule but to be infective the capsule are required. The HPV DNA therefore exists in the host's cell without this shell. Infective HPV may be found only in the upper layers of the epithelium where infective genomes of HPV are released as dying koilocytes. A Koilocyte is a squamous epithelial cell that has undergone a number of the structural changes, which occur as a result of infection of the cell by HPV.
group of normal cervical cells on left and HPV-infected cells showing features typical of koilocytes (wiki)
The late regions of the HPV are responsible for the proteins involved in the construction of the caps of the infective HPV genome. The infection is usually found at the basal cell layer and it is doesn't go to through the basement membrane of the epithelium. The infection of the female genital tract may take two main courses , one are transient infection, the other one are persistent infection. When the virus escapes the host's immune reaction the infection becomes persistent. Persistence of the viral genome in the host's cells may ultimately result in the cervical changes leading to the carcinoma.
The Pathogenesis of Cervical cancer is related to two viral proteins E7 and E6,
The E6 and E7 proteins, which in laboratory studies can immortalize human keratinocytes, are invariably expressed in HPV-associated cancers. that respectively bind to host tumor suppressor gene products Rb and p53 lead to disturbance in the regulation of the repair, DNA replication, and also the cellular growth. The host's cell genes p53 and Rb are responsible for the repair damage (mistakes or mutations) during the cell replication. If the damage is irreparable the cell are destroyed by the process, it is called apoptosis. In most cancers, the HPV genome are integrated into the cellular DNA. That genomic integration allows transcription of the E6 and E7 protein with the following increase of HPV oncogenic potential. In the persistent of HPV infection the anti oncogenic activity of the p53 and Rb there are blocked by the production of the proteins by E6 and E7 from the HPV result in the uninhibited host cellular growth and also lack of repair of the damaged cells. The integration of the virus disrupts the E2 region of the HPV genome and increases expression of the E6 and E7 oncoproteins.
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In the Abnormal cell proliferation then result with integration of the viral DNA into the host's cellular DNA with the resultant immortalisation of the host's cell which then become capable of the invasion. The oncoproteins exert their effect by forming complexes with the cellular tumor-suppressor proteins,E6 with p53, and E7 with Rb. The E6 and E7 proteins of high-risk HPVs bind the tumor-suppressor proteins more efficiently than do the E6 and E7 proteins of low-risk HPV. So that I think some of the loss of control of growing cells may develop irreparable, permanent change on the genetic structure (mutation). The inactivation of the tumor-suppressor proteins presumably distorts the cell cycle and results in the genetic instability and additional cellular genetic alterations. This eventually result in the production of the cancerous cells.
As the HPV cells occupy the host's cells various cellular change in the epithelial squamous cells detectable by cytology. The first to occur are koilocytic atypia in which the host cellular nucleus are displace to the side with the 'hollow' appearance of the cytoplasm. The squamous cells, as the disease advance, then begin to show signs of change size and shape with sometimes nuclear change. The cellular atypia resulting are termed Atypical Squamous Cells of the Undetermined Significance (ASCUS). The equivalent in the cervical glandular cells is the Atypical Glandular Cells of the Undetermined Significance (AGUS).
About 60% of such cases will be regress spontaneously, and the percentage of 20-35% would be persist unchanged and the percentage of 10% are likely to develop High Grade Intra epithelial Lesion (HGIL) with increased cellular changes, reduced nuclear or cytoplasmic ratio and the mitotic. As the whole epithelium is replaced with the mutant cells cervical intra-epithelial neoplasia (CIN) or carcinoma in the situ develops.
So as the conclusions, we know that the pathogenesis of cervical cancer is linked to human papilloma virus. The main support for HPV in cancer etiology came from the finding that DNA sequences of HPV were integrated into the cell genome of most cervical cancers. The main production of the cancerous cell is inactivation of the E2 region, with loss of the repression and consequent overexpression of the E6 and E7 oncoproteins; and inactivation of p53 and the pRb tumor suppressor factors by those oncoproteins, which in turn promotes unrestricted cell proliferation.