A Candidate Cell of Origin for Cervical Cancer
Michael Herfs, Yusuke Yamamoto, Anna R Laury, Wa Xian, Frank D McKeon, Christopher P Crum. University of Liege, Liege, Belgium; Institute of Medical Biology, A*STAR, Singapore; UCLA Medical Center, Los Angeles, CA; Harvard Medical School, Boston, MA; Brigham and Women's Hospital, Boston, MA
Background: Squamous cell carcinoma of the cervix and its precursor (cervical intraepithelial neoplasia) are thought to develop either within, or in close proximity to, the squamo-columnar junction (SCJ) of the ecto and endocervix. Despite this assumption, one issue unresolved in cervical cancer research is the identity of the normal cervical cell type in the SCJ in which tumorigenesis begins.
Design: We discovered an immunophenotypically unique cell population at the SCJ. Using microarray analysis, we compared the gene expression profiles of the ecto and endocervical epithelia with the squamo-columnar junctional cells. Embryo and adult mouse cervical specimens were studied in situ to identify, characterize and determine the dynamics of junctional cell development. Candidate biomarkers targeting the junctional population were applied to 90 cases of CIN and 10 cervical squamous and adenocarcinomas. In addition, cervical SCJs following cervical LEEP/conization were analyzed for retention of the SCJ-specific cells.
Results: Human adult cervices contained a immunohistochemically unique population of cuboidal cells at the SCJ. Analysis of embryonic and postnatal mouse tissues revealed specific lining cells in the lower genital tract that over time become exclusive to the region of the SCJ. Expression analysis of laser-captured cells from the ecto and endocervix and the SCJ revealed a panel of markers unique to the junctional cells; this biomarker panel consistently immunostained both low and high grade CINs associated with carcinogenic human papillomaviruses (HPV) via strong expression of p16ink4. A second population of low grade CINs were identified that arose caudal to the SCJ. This group was negative for the SCJ-specific biomarkers. New SCJs following LEEP/conization did not display the immunophenotype of the SCJ cells.
Conclusions: This study establishes, for the first time, the presence of a unique cell population in the cervix that is selectively retained at the SCJ at birth, possesses an immunophenotype identical to carcinogenic HPV-associated neoplasms, and may be lost or reduced following surgical excision of the SCJ. Moreover, it suggests that low grade CINs can be subdivided immunophenotypically into putative ectocervical and SCJ origins. The attributes of the junctional epithelium described above are consistent with a cell of origin for cervical cancer at the SCJ.
Category: Gynecologic & Obstetrics
Tuesday, March 20, 2012 1:45 PM
Platform Session: Section B, Tuesday Afternoon