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Jun 14, 2012

Scientists Say Discrete Population of Cells Gives Rise to High-Grade CIN, Cervical Cancer

  • Scientists have identified a discrete population of cells in the cervix that appears to be solely responsible for giving rise to precancerous cervical intraepithelial neoplasia (CIN) and cervical cancer triggered by carcinogenic HPV infection. The cervical squamocolumnar (SC) junction cells demonstrate a unique morphology and gene expression profile and, critically, don’t regenerate after surgical excision, which makes them a potential target for cervical cancer prevention, claims the Brigham and Women’s Hospital-led team.

    The researchers hope that the newly discovered SC junction cells will also provide new insights into cervical lesion risk assessment, and represent a model for investigating the pathway by which HPV infection leads to cervical cancer. Christopher P. Crum, M.D., and colleagues report their discovery in PNAS, in a paper titled “A discrete population of squamocolumnar junction cells implicated in the pathogenesis of cervical cancer.”

    Infection with HPV is necessary for the development of CIN, but what hasn’t yet been worked out is why cervical cancers are restricted to the SC junction. A clue, however, has emerged with the recent report that Barrett oesophagus, a precursor of esophageal cancer, occurs in a discrete population of embryonic cells sited at the gastroesophageal SC junction.

    The Brigham and Women’s team and collaborators have now found a discrete population of cuboidal epithelial cells that make up a single layer at the SC junction of the cervix. The cells are morphologically different to the most common cells of the stratified squamous epithelium, and in healthy women without HPV infection display a distinct gene-expression profile when compared with squamous and columnar cells in the ecto- and endocervical epithelia. In fact, the researchers showed that 77 genes were up-regulated twofold or more in the SC junction cells.

    The team established a panel of five SC junction cell-specific transcripts (keratin (Krt)7, anterior gradient (AGR)2, cluster differentiation (CD)63, matrix metalloproteinase (MMP)7, guanine deaminase (GDA)) that could be used to identify SC cells using antibodies. They found that this panel of markers was displayed by every carcinogenic HPV-infected high-grade CIN (CIN2 and CIN3), squamous carcinoma, and adenocarcinoma evaluated. In each case the high-grade CIN lesions and carcinomas were located at the SC junction.

    In contrast, 34 of 42 low-grade CINs (CIN1) evaluated were located either in the ectocervix or transformation zone (TZ),  and didn’t express the junction-specific markers. Of these 34 CIN1s, 10 had noncarcinogenic HPVs, while 24 harbored carcinogenic or "probably carcinogenic" HPVs. The remaining eight low-grade CIN1s were located at the SC junction, and all stained positive for junction-specific markers and harbored carcinogenic HPV, supporting the putative causal link between the SC cell population, carcinogenic HPV, and cervical cancer.

    In a subsequent set of in vitro experiments the team ruled out the possibility that SC junction cells were generated as a result of the transformation of basal keratinocytes by carcinogenic HPVs, indicating that the cells were truly a distinct population. Fetal studies confirmed that at 16 weeks the Krt7-positive cells are widely distributed throughout the cervix before the onset of squamous (Krt5) differentiation, but by about 20 weeks of gestation as basal Krt5 expression emerges, the Krt7-positive epithelial cells are found above the stratifying squamous epithelium, and in the adult, Krt7-positive cells are confined to the SC junction.

    Crucially, the examination of tissue from patients who had undergone hysterectomy 1–23 months after cone biopsy or loop electrical excision confirmed that once removed, the SC junction cells don’t get replaced. “The overlap in immunophenotypic identity between SC junction cells and HPV-induced squamous and columnar neoplasms suggest that this unique population of cells at the SC junction forms a core group that can spawn multiple tumor phenotypes,” the authors conclude.

    They suggest the panel of immunological markers may provide new opportunities to study cancer risk in early cervical neoplasia, given their presence in all high-grade CINs and cancers, absence in most low-grade CINs irrespective of HPV type, and presence in the minority of low-grade CINs that are located at the SC junction and harbor carcinogenic HPV. “Thus, in nearly all of the cases that we studied, the SC junction markers described in this report precisely predicted the cervical cancer precursors with the highest likelihood of harboring the most carcinogenic HPV (HPV16), irrespective of their histologic grade.”

    The team admits that the mechanisms by which viral–host cell interactions lead to malignancy in the SC junction cells has yet to be determined. However, they state, “the SC junction expression data provide a unique template to study SC junction-specific transgenic models of HPV carcinogenesis ... A final question is whether similar populations of SC junctional cells are responsible for neoplasms tied to carcinogenic HPV infections in other sites, such as the anus and oropharynx.”


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