Oncogenicity And Role Of Hpv In Human Cancers

Common warts and plantar warts never become malignant. Direct conversion of condylomas to carcinomas has been described anecdotally but is extremely rare. In addition to experimental evidence, large-scale epidemiological studies performed during recent years have established HPV infections as the major risk factor for cervical cancer. Skin cancers arising in immunosuppressed patients are also increasingly found to contain HPV DNA. Since the matter of causality is being elucidated, the focus is at present, and in the years to come, being shifted towards the mechanisms by which the interplay between certain HPV genotypes, the infected host cells, their environment and other factors may initiate, establish and maintain oncogenic processes in the cervix as well as other locations. HPVs associated with anogenital lesions have been divided into 'low-risk' types (6, 11, 34, 40, 42, 43) or 'high-risk' types (16, 18, 31, 33, 35,

Figure 38.1 HUMAN PAPILLOMAVIRUS. Bar, 50 nm (Electron micrograph courtesy of G. Haukenes)

39, 45, 51, 52, 54, 56, 58) based on the preneoplastic character of the lesions. Low-risk HPVs such as types 6 and 11 are generally associated with venereal warts or condylomas acuminata, which only rarely progress to malignancy. High-risk HPVs include types 16 and 18 and are associated with CIN. Both these HPVs were originally isolated from human cervical carcinomas, and approximately 70% of all cervical cancers contain either HPV16 or 18. In CIN lesions the HPV genomes are found extrachromosomally, while in cervical cancers viral DNA is found integrated. Integration may confer a relative growth or survival advantage to the host cell, and hence contribute to an oncogenic process. Continued expression of the E6 and E7 genes is, however, necessary for maintained proliferation of cervical carcinoma cells. The mechanisms by which the E6 and E7 proteins of high-risk HPVs contribute to cellular transformation and carcinogenesis are not known in detail but, similarly to oncoproteins of other DNA tumour viruses, these HPV proteins interact with and change the activities of cellular regulatory proteins. The best known examples are the complex formations with and functional neutralization of the tumour suppressor proteins p53 (E6) and pRB, the product of the retinoblastoma susceptibility gene (E7). The E6 and E7 proteins of low-risk HPVs are less transforming, and bind the tumour suppressor proteins with lower affinity than their counterparts from high-risk types.

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