Elimination of reserve cells for prevention of HPV-associated cervical cancer

Human papilloma viruses (HPV), that are causative for most squamous cell cervical cancers (SCC), have a simple structure with only a few genes (six early and two late genes). Two of the early HPV genes (E6 and E7) are capable of transforming normal squamous epithelium into cancer. In the last 10 years, a controversial discussion arose as to which cells are primarily involved in cervical carcinogenesis. Virologists traditionally use a research model of stratified squamous epithelium, a permissive environment for completion of a full HPV-life cycle. Basic insights on HPV tropism, HPV life cycle, HPV-uptake, HPV-replication, HPV-gene expression were gained from this model. Stratified squamous epithelium, however, is a low-risk area for SCC. Most SCC develop in an area of endocervical columnar epithelium that undergoes squamous metaplasia. SCC arise after infection of immature squamous metaplasia, proliferating reserve cells/reserve cell hyperplasia and reserve cells of the endocervical columnar epithelium. Study models investigating this pathway of carcinogenesis do not exist and therapeutic consequences deduced from this knowledge are lacking. This review describes in detail cervical carcinogenesis after HPV infection of subcolumnar reserve cells and discusses new intervention strategies for patients. The WHO-launched global strategy to eliminate HPV-associated cervical cancer builds primarily on prophylactic vaccination, screening and treatment. New insights in cervical pathogenesis, may assist in reaching this ambitious WHO goal.