Refining our understanding of cervical neoplasia and its cellular origins

Human papillomaviruses (HPV) cause cancer at a number of vulnerable epithelial sites, including the cervix, the anus and the oropharynx, with cervical cancer being the most significant in terms of numbers. The cervix has a complex epithelial organisation, and comprises the stratified epithelium of the ectocervix, the columnar epithelium of the endocervix, and the cervical transformation zone (TZ). Most cervical cancers arise at the TZ, which is a site where a stratified squamous epithelium can develop via metaplasia from a simple columnar epithelium. It is thought that this process is mediated by the cervical reserve cell, a specialised type of stem cell that is located at the TZ, which has been proposed as the target cell for HPV infection. Reserve cells may be derived from the basal cells of the ectocervix, or may originate from the cuboidal cells found at the squamo columnar junction. It appears that HPV infection of these diverse cell types, including the columnar cells of the endocervix, facilitates deregulated viral gene expression and the development of neoplasia, with different epithelial sites having different cancer risk. It is envisaged that these concepts may explain the vulnerability of the oropharynx, and other TZ regions where HPV-associated cancers arise.