{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T02:07:37Z","timestamp":1790215657739,"version":"4.1.0"},"reference-count":22,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2013,1,25]],"date-time":"2013-01-25T00:00:00Z","timestamp":1359072000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2013,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:bold>The cervical squamocolumnar (<jats:styled-content style=\"fixed-case\">SC<\/jats:styled-content>) junction is the site of a recently discovered \u2018embryonic\u2019 cell population that was proposed as the cell of origin for cervical cancer and its precursors. How this population participates in cervical remodelling and neoplasia is unclear. In the present study, we analysed the <jats:styled-content style=\"fixed-case\">SC<\/jats:styled-content> junction immunophenotype during pre\u2010 and post\u2010natal human and mouse development and in the adult, processes of metaplastic evolution of the <jats:styled-content style=\"fixed-case\">SC<\/jats:styled-content> junction, microglandular change, and early cervical neoplasia. Early in life, embryonic cervical epithelial cells were seen throughout the cervix and subsequently diminished in number to become concentrated at the <jats:styled-content style=\"fixed-case\">SC<\/jats:styled-content> junction in the adult. In all settings, there was a repetitive scenario in which cuboidal embryonic\/<jats:styled-content style=\"fixed-case\">SC<\/jats:styled-content> junction cells gave rise to subjacent metaplastic basal\/reserve cells with a switch from the <jats:styled-content style=\"fixed-case\">SC<\/jats:styled-content> junction positive to negative immunophenotype. This downward or basal (rather than upward or apical) evolution from progenitor cell to metaplastic progeny was termed reverse or \u2018top down\u2019 differentiation. A similar pattern was noted in high\u2010grade squamous intraepithelial lesions (<jats:styled-content style=\"fixed-case\">HSILs<\/jats:styled-content>), suggesting that <jats:styled-content style=\"fixed-case\">HPV<\/jats:styled-content> infection of the cuboidal <jats:styled-content style=\"fixed-case\">SC<\/jats:styled-content> junction cells initiated outgrowth of basally\u2010oriented neoplastic progeny. The progressive loss of the embryonic\/<jats:styled-content style=\"fixed-case\">SC<\/jats:styled-content> junction markers occurred with \u2018top down\u2019 differentiation during development, remodelling, and early neoplasia. Interestingly, most low\u2010grade <jats:styled-content style=\"fixed-case\">SILs<\/jats:styled-content> were <jats:styled-content style=\"fixed-case\">SC<\/jats:styled-content> junction\u2010negative, implying infection of metaplastic progeny rather than the original <jats:styled-content style=\"fixed-case\">SC<\/jats:styled-content> junction cells. This proposed model of \u2018top down\u2019 differentiation resolves the mystery of how <jats:styled-content style=\"fixed-case\">SC<\/jats:styled-content> junction cells both remodel the cervix and participate in neoplasia and provides for a second population of metaplastic progeny (including basal and reserve cells), the infection of which is paradoxically less likely to produce a biologically aggressive precursor. It also provides new targets in animal models to determine why the <jats:styled-content style=\"fixed-case\">SC<\/jats:styled-content> junction is uniquely susceptible to carcinogenic <jats:styled-content style=\"fixed-case\">HPV<\/jats:styled-content> infection. Copyright \u00a9 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:bold><\/jats:p>","DOI":"10.1002\/path.4110","type":"journal-article","created":{"date-parts":[[2012,9,24]],"date-time":"2012-09-24T10:21:07Z","timestamp":1348482067000},"page":"460-468","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":88,"title":["A novel blueprint for \u2018top down\u2019 differentiation defines the cervical squamocolumnar junction during development, reproductive life, and neoplasia"],"prefix":"10.1002","volume":"229","author":[{"given":"Michael","family":"Herfs","sequence":"first","affiliation":[{"name":"Division of Women's and Perinatal Pathology, Department of Pathology Brigham and Women's Hospital  Boston MA USA"},{"name":"Department of Pathology, GIGA\u2010Cancer University of Li\u00e8ge  Li\u00e8ge Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara O","family":"Vargas","sequence":"additional","affiliation":[{"name":"Department of Pathology Children's Hospital  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Genome Institute of Singapore, A\u2010STAR  Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brooke E","family":"Howitt","sequence":"additional","affiliation":[{"name":"Division of Women's and Perinatal Pathology, Department of Pathology Brigham and Women's Hospital  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisa R","family":"Nucci","sequence":"additional","affiliation":[{"name":"Division of Women's and Perinatal Pathology, Department of Pathology Brigham and Women's Hospital  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason L","family":"Hornick","sequence":"additional","affiliation":[{"name":"Division of Women's and Perinatal Pathology, Department of Pathology Brigham and Women's Hospital  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank D","family":"Mckeon","sequence":"additional","affiliation":[{"name":"Genome Institute of Singapore, A\u2010STAR  Singapore"},{"name":"Department of Cell Biology Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wa","family":"Xian","sequence":"additional","affiliation":[{"name":"Division of Women's and Perinatal Pathology, Department of Pathology Brigham and Women's Hospital  Boston MA USA"},{"name":"Institute of Medical Biology, A\u2010STAR  Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher P","family":"Crum","sequence":"additional","affiliation":[{"name":"Division of Women's and Perinatal Pathology, Department of Pathology Brigham and Women's Hospital  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,1,25]]},"reference":[{"key":"e_1_2_7_2_1","first-page":"444","article-title":"Original site of cervical carcinoma; 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