Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2012 Jun 26;109(26):10516-21. doi: 10.1073/pnas.1202684109. Epub 2012 Jun 11.
Infection by carcinogenic human papillomaviruses (HPV) results in precancers [cervical intraepithelial neoplasia (CIN)] and cancers near the ectoendocervical squamocolumnar (SC) junction of the cervix. However, the specific cells targeted by HPV have not been identified and the cellular origin of cervical cancer remains elusive. In this study, we uncovered a discrete population of SC junctional cells with unique morphology and gene-expression profile. We also demonstrated that the selected junctional biomarkers were expressed by a high percentage of high-grade CIN and cervical cancers associated with carcinogenic HPVs but rarely in ectocervical/transformation zone CINs or those associated with noncarcinogenic HPVs. That the original SC junction immunophenotype was not regenerated at new SC junctions following excision, not induced by expression of viral oncoproteins in foreskin keratinocytes, and not seen in HPV-related precursors of the vagina, vulva, and penis further support the notion that junctional cells are the source of cervical cancer. Taken together, our findings suggest that carcinogenic HPV-related CINs and cervical cancers are linked to a small, discrete cell population that localizes to the SC junction of the cervix, expresses a unique gene expression signature, and is not regenerated after excision. The findings in this study uncover a potential target for cervical cancer prevention, provide insight into the risk assessment of cervical lesions, and establish a model for elucidating the pathway to cervical cancer following carcinogenic HPV infection.
致癌型人乳头瘤病毒 (HPV) 的感染会导致癌前病变（宫颈上皮内瘤变 [CIN]）和宫颈外内口柱状移行区（SC）交界处附近的癌症。然而，尚未确定 HPV 靶向的特定细胞，宫颈癌的细胞起源仍然难以捉摸。在这项研究中，我们发现了具有独特形态和基因表达谱的离散 SC 交界处细胞群。我们还证明，所选的交界标志物在与致癌型 HPV 相关的高级别 CIN 和宫颈癌中表达的比例较高，但在宫颈外口/转化区 CIN 或与非致癌型 HPV 相关的 CIN 中很少表达。在切除后，原始 SC 交界处免疫表型不会在新的 SC 交界处再生，在包皮角质形成细胞中表达病毒癌蛋白不会诱导，也不会在 HPV 相关的阴道、外阴和阴茎前体中看到，这进一步支持了交界细胞是宫颈癌来源的观点。总之，我们的研究结果表明，致癌型 HPV 相关的 CIN 和宫颈癌与定位于宫颈 SC 交界处的一小部分离散细胞群有关，这些细胞表达独特的基因表达特征，并且在切除后不会再生。本研究的发现为宫颈癌的预防提供了潜在的靶点，深入了解了宫颈病变的风险评估，并为阐明致癌型 HPV 感染后宫颈癌的发生途径建立了模型。
