Kaufmann A M, Backsch C, Schneider A, Dürst M
Gynäkologische Molekularbiologie, Frauenklinik, Friedrich-Schiller-Universität Jena.
Zentralbl Gynakol. 2002 Nov;124(11):511-24. doi: 10.1055/s-2002-39579.
Association of infection with papillomavirus and dysplasia of the cervix uteri has been firmly established. There are only few cervical cancers where no HPV DNA is detectable. The mechanism of epithelial cell immortalization by interaction with tumour suppressor genes p53 and pRb by viral oncogenes E6 and E7 is elucidated. Progression of the HPV infected cell to a malignant phenotype involves further modification of host gene expression and/or mutations. The appearance of chromosomal aberrations can lead to mutational inactivation or loss of tumour suppressor genes (TSG), activation and amplification of oncogenes, with importance for the process of carcinogenesis. Oncogene amplification, with exception of few reports, seems not to be a major mechanism in cervical carcinogenesis. In contrast, cytogenetic and loss of heterozygosity (LOH) results from CIN and invasive cancer demonstrate alterations at specific chromosomal regions, pointing at localisation of TSG. Genetic alterations at chromosomes 3p, 6p, 1lq were frequently found early in tumour development Primary invasive carcinoma showed additional allelic losses at chromosome arms 6q, 17p and 18q. Useful biological diagnostic and prognostic markers for high-risk HPV infection and malignant progression may be p16NK4 p27Kip, and NET-I/C4.8. Putative senescence genes relevant for HPV-induced carcinogenesis are localized on chromosomes 2, 4 and 10. Genes for Telomerase suppression are presumably located on chromosomes 3, 4 and 6. Natural immune responses to HPV infection exist Therefore, immune therapy is an attractive possibility for prevention and therapy of HPV infection. To date, vaccine development has reached clinical evaluation. Prophylaxis aims at the induction of virus neutralizing antibodies to capsid proteins. Virus-like particle vaccines are currently tested in clinical trials. Due to the long lag period between infection and clinical manifestation trials will take a long time until conclusive results are obtained. Mandatory expression of viral and perhaps certain cellular genes in infected epithelial and tumour cells offers targets for therapeutic approaches. Since most dysplasia clears spontaneously the viral infection is immunogenic to some extent. However, in some individuals the immune response has to be stimulated by vaccination in order to be effective. Several strategies are being tested in clinical trials and others are in preclinical development The task will be to circumvent immunosuppressive features of the HPV infected cells.
乳头瘤病毒感染与子宫颈发育异常之间的关联已得到确凿证实。仅有少数宫颈癌病例检测不到人乳头瘤病毒（HPV）DNA。病毒癌基因E6和E7通过与肿瘤抑制基因p53和pRb相互作用使上皮细胞永生化的机制已得到阐明。HPV感染细胞向恶性表型的进展涉及宿主基因表达的进一步改变和/或突变。染色体畸变的出现可导致肿瘤抑制基因（TSG）的突变失活或缺失、癌基因的激活和扩增，这对致癌过程具有重要意义。除少数报道外，癌基因扩增似乎不是子宫颈癌发生的主要机制。相比之下，来自宫颈上皮内瘤变（CIN）和浸润性癌的细胞遗传学和杂合性缺失（LOH）结果显示特定染色体区域存在改变，提示肿瘤抑制基因的定位。在肿瘤发生早期经常发现染色体3p、6p、11q的基因改变。原发性浸润性癌在染色体臂6q、17p和18q显示额外的等位基因缺失。p16NK4、p27Kip和NET-I/C4.8可能是高危HPV感染和恶性进展有用的生物学诊断和预后标志物。与HPV诱导的致癌作用相关的假定衰老基因定位于染色体2、4和10。端粒酶抑制基因可能位于染色体3、4和6。对HPV感染存在天然免疫反应。因此，免疫疗法是预防和治疗HPV感染颇具吸引力的选择。迄今为止，疫苗研发已进入临床评估阶段。预防旨在诱导针对衣壳蛋白的病毒中和抗体。病毒样颗粒疫苗目前正在临床试验中进行测试。由于感染与临床表现之间的间隔期较长，试验将需要很长时间才能获得确凿结果。病毒以及可能某些细胞基因在受感染上皮细胞和肿瘤细胞中的强制表达为治疗方法提供了靶点。由于大多数发育异常会自发消退，病毒感染在一定程度上具有免疫原性。然而，在一些个体中，免疫反应必须通过接种疫苗来刺激才能有效。几种策略正在临床试验中进行测试，其他一些则处于临床前开发阶段。任务将是规避HPV感染细胞的免疫抑制特性。
