Carcinogenic HPV infection in the cervical squamo‐columnar junction

Abstract

Recent studies have suggested the involvement of a unique population of cells at the cervical squamo-columnar junction (SCJ) in the pathogenesis of early (squamous intraepithelial lesion or SIL) and advanced (squamous cell and adeno-carcinomas) cervical neoplasia. However, there is little evidence to date showing that SCJ cells harbour carcinogenic HPV or are instrumental in the initial phases of neoplasia. This study was designed to 1) determine if normal-appearing SCJ cells contained evidence of carcinogenic HPV infection and 2) trace their transition to early SIL. Sections of cervix from high-risk reproductive age women were selected and SCJ cells were analyzed by using several techniques which increasingly implicated HPV infection: HPV DNA (genotyping and in situ hybridization)/RNA (PCR), immunostaining for HPV16 E2 (an early marker of HPV infection), p16ink4, Ki67 and HPV L1 protein. In 22 cases with a history of SIL and no evidence of preneoplastic lesion in the excision specimen, HPV DNA was isolated from 8 of 10 with visible SCJ cells, 6 of which were HPV16/18 DNA positive. In 5 of these latter cases, the SCJ cells were positive for p16ink4 and/or HPV E2. Transcriptionally active HPV infection (E6/E7 mRNAs) was also detected in micro-dissected SCJ cells. Early squamous atypia associated with the SCJ cells demonstrated in addition diffuse p16ink4 immunoreactivity, elevated proliferative index and rare L1 antigen positivity. We present for the first time direct evidence that normal-appearing SCJ cells can be infected by carcinogenic HPV. They initially express HPV E2 and their progression to SIL is heralded by an expanding metaplastic progeny with increased proliferation and p16ink4 expression. Whether certain SCJs are more vulnerable than others to carcinogenic HPV genotypes and what variables determine transition to high grade SIL remain unresolved, but the common event appears to be a vulnerable cell at the SCJ.

Upsetting the Balance: When Viruses Manipulate Cell Polarity Control

“…or are they cells that do not stratify, such as the columnar cells of the simple epithelium of the endocervix? It is clear that the majority of cervical (N 99%) and anal (N 90%) tumors occur at the transformation zone between the stratified and columnar epithelia [82], and many cervical tumor cells have an embryonic stem cell expression signature [83]. It has been suggested that many cervical tumors may have their origin in the cuboidal cells of the squamocolumnar junction: these cells are more accessible than the endocervical cells; they are highly susceptible to infection by HPV, but are unable to stratify and permit a productive infection; and they are located in an anatomical site that appears to be somewhat immuneprivileged.…”

The CXCL12/CXCR4 Signaling Pathway: A New Susceptibility Factor in Human Papillomavirus Pathogenesis

“…Many reports have described HPVs as commensal viruses that can persist on healthy skin [2–4]. HPVs selectively infect basal keratinocytes of stratified epithelia and other discrete populations, including the cells located in the squamocolumnar junction of the cervix [5, 6]. These viruses undergo productive replication strictly in the terminally differentiated layers of the infected epithelium, and in most cases, cause no tissue damage or only benign warts [7].…”

Functional Roles of E6 and E7 Oncoproteins in HPV-Induced Malignancies at Diverse Anatomical Sites

“…It is unclear why this region is particularly susceptible to HPV-induced transformation, but it could be due to mis-regulation of viral gene expression, resulting in failure of the productive life cycle [156,157]. The cervical transformation zone contains specialized cells known as reserve cells [158] and also has a population of cuboidal cells at the squamo-columnar junction [159,160].…”