The evidence for a viral aetiology in cervical cancer

Critically appraise the evidence for a viral aetiology of human cervical cancer

Human cervical cancer ranks as one of the most important cancers. In the West, cervical cancer is the fourth most common cancer in women. In developing countries though, it is the most common cancer, with 1/2 million new cases per year. Overall, it is the most common cancer with a possible viral aetiology worldwide, followed by hepatocellular carcinoma, nasopharyngeal carcinoma and Burkitt's lymphoma. There is now a lot of evidence for an aetiological role of HPV in cervical cancers.

Epidemiological Evidence;- it has been known for a long time that the incidence of cervical carcinoma. is related to sexual activity. Promiscuous women are far more likely to develop cervical Ca. The disease is common among prostitutes whereas it is virtually unknown in nuns. Several sexually transmitted agents have been implicated including Herpes Simplex and human papilloma viruses. However it is now fair to say that evidence of a role for HSV is very slim and now very much discounted.

Virological Evidence ;-

1. Certain HPV genomes can be detected in 90 - 95% of cervical tumour cell lines. HPV genomes can be found at a lower frequency in pre-cancerous state such as CIN (cervical intraepithelial carcinoma) 1, CIN2 and CIN3. HPV 16 and 18 are the most commonly found. However, other strains may be present, especially in the less dysplastic lesions.

2. HPV DNA persists in an episomal form in normal infected cells but is integrated in the host cell chromosome in malignant cells. The site of integration of HPV DNA appears to be random.

3. HPV-16 and 18 DNA is biologically active in vitro. It is able to transform human fibroblasts and keritinocytes. It has effects on epithelial cell differentiation and induces DNA replication in the fibroblast. All the above effects can be nailed down to the E7 reading frame. The constant expression of the E7 and perhaps the E6 reading frames products are essential for the maintenance of transformation.

4. Antibodies to HPV gene products E4 and E7 are more prevalent in patients with CIN or invasive carcinoma. Although the prevalence of Abs to both E4 and E7 were increased in patients with Ca.Cervix compared to the controls. The prevalence of Ab to E7 was much higher ; There was only a 2 fold difference in the prevalence of Ab to E4 between the cancer patients and the normal controls. However there was a 7 fold difference in the prevalence of Ab to E7. This suggest that there may be a role for testing for Ab to the E7 protein in future for use as a marker in monitoring the effectiveness of treatment. However, it is very important to have the correct protein antigen of the particular strain of HPV involved.

5. It has now been proven that certain precancerous conditions for cervical and vulval Ca, namely CIN and VIN, are caused by HPV. Normal human epithelium from the cervix and epithelium purposefully exposed to HPV 16 were transplanted to immunologically nude mice. Weeks later, lesions that resemble CIN histologically were detected in the epithelium which was infected by HPV.

Possible molecular_mechanism

All the oncogenic effect of HPV-16 and 18 can be attributed to the E6 and E7 reading frames. Only the E6 and E7 gene products are active in transformed tissue culture and are essential for the maintenance of the transformed state. The HPV-DNA consists of a small circular genome of around 8 KB. Under normal conditions, the genome is usually episomal, whereas in cancer, the DNA genome is integrated. The process of integration involves a breakpoint at the E1 and E2 region. One of the functions of the E1 region is to repress the E6 and E7 genes. In the presence of the breakage, the repressor function is lost and E6 and E7 became continuously expressed.

There is cumulating evidence that E6 and E7 genes are involved in oncogenesis. E6 and E7 genes were introduced (transfected) into cell cultures. It was shown that the expression of E7 can transformed established immortalized cell lines such as NIH 3T3. With primary cells transfected with ras (a transforming gene), expression of E7, in cooperation with ras, resulted in full transformation. Using primary human foreskin keratinocytes, E6 or E7 alone did not have any effects. Only with both E6 and E7, does immortalization took place. However that was not sufficient to express full tumourigenic potential.

E6 and E7 are small proteins. Both have been shown to bind to specific cellular anti-oncogenes: p53 in the case of E6 and Rb in the case of E7. p53 and RB are involved in suppressing cell division. As a result of this binding, these cellular anti-oncogenes are inactivated and cell division is not inhibited. Besides cervical carcinoma, abnormalities of the Rb and p53 genes have been found in many other tumours such as colon and breast.

However it must be borne in mind that other factors are involved in the tumourigenesis of cervical Ca ;-

(1) The actual site in the body

(2) The HPV type

(3) The immune status of the patient ; immunocompromised patients have a much higher risk of developing Ca.Cervix.

(4) Smoking

(5) Hormones

(6) Vitamin A deficiency

Cancer is a multi-step and multi-factorial process which involves the interplay of many factors. The presence of HPV alone is insufficient to cause cancer. However, there is now compelling evidence which suggest that certain HPV types are involved in causing cervical carcinoma. The final proof can only be demonstrated if effective vaccination become available against these HPV types and that as a direct result, the incidence of cervical carcinoma is reduced.