Papillomavirus infections--a major cause of human cancers

Abstract

The papillomavirus family represents a remarkably heterogeneous group of viruses. At present, 77 distinct genotypes have been identified in humans and partial sequences have been obtained from more than 30 putative novel genotypes. Geographic differences in base composition of individual genotypes are generally small and suggest a low mutation rate and thus an ancient origin of today's prototypes. The relatively small size of the genome permitted an analysis of individual gene functions and of interactions of viral proteins with host cell components. Proliferating cells contain the viral genome in a latent form, large scale viral DNA replication, as well as translation and functional activity of late viral proteins, and viral particle assembly are restricted to differentiating layers of skin and mucosa. In humans papillomavirus infections cause a variety of benign proliferations: warts, epithelial cysts, intraepithelial neoplasias, anogenital, oro-laryngeal and -pharyngeal papillomas, keratoacanthomas and other types of hyperkeratoses. Their involvement in the etiology of some major human cancers is of particular interest: specific types (HPV 16, 18 and several others) have been identified as causative agents of at least 90% of cancers of the cervix and are also linked to more than 50% of other anogenital cancers. These HPV types are considered as 'high risk' infections. Their E6/E7 oncoproteins stimulate cell proliferation by activating cyclins E and A, and interfere with the functions of the cellular proteins RB and p53. The latter interaction appears to be responsible for their mutagenic and aneuploidizing activity as an underlying principle for the progression of these HPV-containing lesions and the role of high risk HPV types as solitary carcinogens. In non-transformed human keratinocytes transcription and function of viral oncoproteins is controlled by intercellular and intracellular signalling cascades, their interruption emerges as a precondition for immortalization and malignant growth. Recently, novel and known HPV types have also been identified in a high percentage of non-melanoma skin cancers (basal and squamous cell carcinomas). Similar to observations in patients with a rare hereditary condition, epidermodysplasia verruciformis, characterized by an extensive verrucosis and development of skin cancer, basal and squamous cell carcinomas develop preferentially in light-exposed sites. This could suggest an interaction between a physical carcinogen (UV-part of the sunlight) and a 'low risk' (non-mutagenic) papillomavirus infection. Reports on the presence of HPV infections in cancers of the oral cavity, the larynx, and the esophagus further emphasize the importance of this virus group as proven and suspected human carcinogens.