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

Abstract

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.

Keywords: Cervical carcinogenesis; HPV; HPV research model; Prevention; Recurrent disease; Reserve cells; Treatment.

Fig. 1

Overview of the prenatal development of uterine cervix (adapted from: Fritsch H., et al., The development of the human vaginal fornix and the portio cervicis. Clin. Anat. 2020; 34:1059-1067). Fig. 1a Early embryologic development: Two different cell lineages meet at the utero-vaginal anlagen. Schematic drawing indicating the border of urogenital sinus structures (blue) and Müllerian structures (yellow). Fig. 1b Late prenatal development: Schematic drawing indicating endocervical epithelium capable of squamous metaplasia (red line) with urogenital sinus derived Ck17 positive reserve cells (blue) and Müllerian derived Ck7 positive reserve cells (yellow).

Fig. 2

Overview of the epithelial situation of the adult uterine cervix (adapted from: Fritsch H., et al., The development of the human vaginal fornix and the portio cervicis. Clin. Anat. 2020; 34:1059-1067). Blue line: The vagina, the fornices and the ectocervix are covered by a thick stratified mature glycogenated squamous epithelium referred to as original squamous epithelium. The original squamous epithelium is a low-risk area for squamous cervical cancer. Black line: Manifest metaplastic squamous epithelium of the transformation zone resembling the original squamous epithelium. It is derived from p63/CK17-positive reserve cells. As glycogenated squamous epithelium (original or metaplastic) represents a permissive environment for completion of a full HPV-life cycle, this area is also a low-risk area for squamous cervical cancer. By contrast, endocervical tall columnar epithelium with subcolumnar reserve cells with beginning immature squamous metaplasia is a high-risk area for squamous cervical cancer. A transforming HPV-infection of proliferating reserve cells and HPV-transformed immature metaplastic squamous epithelium is characterized by high-level expression of E6 and E7 HPV genes. These developing high-grade intraepithelial lesions are thin full-thickness lesions up to 9 cell layers in thickness. Red line: Endocervical columnar epithelium with urogenital sinus derived p63/CK17-positive reserve cells (blue cells) and Müllerian-derived CK7-positive reserve cells (yellow cells). These reserve cells may serve as reservoir of HPV infection. A transforming HPV infection of these (residual) reserve cells are causal for recurrent HSIL after destruction / treatment of HSIL. Yellow line: Isthmic mucosa as part of Müllerian derived endometrium. The last CK7 positive endocervical reserve cell represents the upper border of the uterine epithelium that is sensitive for HPV.