Infectious HPV particles introduced into the vagina upon sexual intercourse can reach the basement cells of the squamous cell epithelium of the cervix uteri through micro-lesions (von Knebel Doeberitz, M. 1994).
Once infection is initiated in the basal cell layer, the viral DNA genome is maintained as a low copy circular episome. Basal cells are the only dividing cells in this epithelial tissue, which generate other basal cells by lateral division and keratinocytes by upward division (K. Munger et al., 2004)
In differentiating keratinocytes in the lower mid-zone, which derive from HPV-infected basal cells, the episomal viral genome expresses early (E) and late (L) genes and amplifies the viral genome. Once in the upper mid-zone and superficial zone, only late gene expression of the L1 and L2 capsid forming proteins occurs in terminally differentiated squamous keratinocytes (S.A. Southern and C.S. Herrington, 1994). Subsequently progeny virus is released into the vagina from desquamated cells, which can be further transmitted upon intercourse.
The presence of the virus in the squamous epithelium causes morphological abnormalities, including papillomatosis, parakeratosis, and koilocytosis Such abnormalities corresponds histologically to Grade 1 cervical intraepithelial neoplasia (CIN 1).
HPV disease progression
HPV infection causes epithelial abnormalities
HPV infection can cause invasive cancer
In some keratinocytes in the midzone, viral replication does not occur. In this situation, the viral episome persists as either an extra-chromosomal element or becomes integrated into the host cell chromosome at a random site .(C. Popescu and J.A. DiPaolo 1989). Viral integration into the host cell DNA is believed to be a necessary step in cellular transformation in mucosal HPV. The effect is deregulated cell cycle control and uncontrolled cellular proliferation, dependent on constitutive expression of the viral oncogenes E6 and E7 (von Knebel M. et al., 1994).
Through cell division, more and more cells in the are transformed and form high grade squamous epithelial lesions that histologically correspond to Grade 2 and Grade 3 cervical intraepithelial neoplasia (CIN 2 & CIN 3). When all cells are transformed, cervical cancer is diagnosed. This cancer becomes invasive when the tumour mass disrupts the basement membrane and spreads through the body.
A diagram representing HPV disease progression is given below.
Through cell division, more and more cells in the are transformed and form high grade squamous epithelial lesions that histologically correspond to Grade 2 and Grade 3 cervical intraepithelial neoplasia (CIN 2 & CIN 3). When all cells are transformed, cervical cancer is diagnosed. This cancer becomes invasive when the tumour mass disrupts the basement membrane and spreads through the body.
A diagram representing HPV disease progression is given below.
Symptoms of cervical cancer and its treatment
The classic symptoms of early stage cervical cancer include vaginal discharge, bleeding, pain and in more advanced stages, bowel obstruction and obstructive uropathy. Pelvic examination may show a tumour mass, ulceration, cervicitis, and bleeding.
The basis of the treatment of Cervical Cancer is surgery, complemented with radiotherapy and chemotherapy according to stage of the disease, patient age, and health status. Because of the poor prognosis following invasive cervical cancer (58% of patients die), it is very important to detect HPV infection as early as possible.
The basis of the treatment of Cervical Cancer is surgery, complemented with radiotherapy and chemotherapy according to stage of the disease, patient age, and health status. Because of the poor prognosis following invasive cervical cancer (58% of patients die), it is very important to detect HPV infection as early as possible.
References
Munger K., A. Baldwin, K.M. Edwards, H. Hayakawa, C.L. Nguyen, M. Owens, M. Grace and K. Huh, Mechanisms of human papillomavirus-induced oncogenesis, J Virol 78 (2004), 11451–11460.
Lowy D.R. and P.M. Howley, Papillomaviruses, in: Fields Virology, D.M. Knipe, P.M. Howley, D.E. Griffin, R.A. Lamb, M.A. Martin, B. Roizman and S.E. Straus, eds, Lippincott Williams & Wilkins, 2001.
Popescu N.C. and J.A. DiPaolo, Preferential sites for viral integration on mammalian genome, Cancer Genet Cytogenet 42 (1989), 157–171.
Southern S.A. and C.S. Herrington, Differential cell cycle regulation by low- and high-risk human papillomaviruses in lowgrade squamous intraepithelial lesions of the cervix, Cancer Res 58 (1998), 2941–2945.
von Knebel Doeberitz, M., C. Rittmuller, F. Aengeneyndt, P. Jansen-Durr and D. Spitkovsky, Reversible repression of Papillomavirus oncogene expression in cervical carcinoma cells: consequences for the phenotype and E6-p53 and E7-pRB interactions. J Virol 68, (1994), 2811-2821.
Lowy D.R. and P.M. Howley, Papillomaviruses, in: Fields Virology, D.M. Knipe, P.M. Howley, D.E. Griffin, R.A. Lamb, M.A. Martin, B. Roizman and S.E. Straus, eds, Lippincott Williams & Wilkins, 2001.
Popescu N.C. and J.A. DiPaolo, Preferential sites for viral integration on mammalian genome, Cancer Genet Cytogenet 42 (1989), 157–171.
Southern S.A. and C.S. Herrington, Differential cell cycle regulation by low- and high-risk human papillomaviruses in lowgrade squamous intraepithelial lesions of the cervix, Cancer Res 58 (1998), 2941–2945.
von Knebel Doeberitz, M., C. Rittmuller, F. Aengeneyndt, P. Jansen-Durr and D. Spitkovsky, Reversible repression of Papillomavirus oncogene expression in cervical carcinoma cells: consequences for the phenotype and E6-p53 and E7-pRB interactions. J Virol 68, (1994), 2811-2821.
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HPV disease progression