Aiyenuro Ademola, Griffin Heather, Schichl Konstanze, Omar Tanvier, Ordi Jaume, Kelly Helen, Walker Caroline, Pino Marta Del, Desai Kanan, de Sanjosé Silvia, Schiffman Mark, Doorbar John
Department of Pathology, University of Cambridge, United Kingdom.
Department of Anatomical Pathology, Faculty of Health Sciences, University of the Witwatersrand, Charlotte Maxeke Academic Hospital, Johannesburg, South Africa.
Lab Invest. 2025 Jul;105(7):104166. doi: 10.1016/j.labinv.2025.104166. Epub 2025 Apr 9.
Squamous cervical cancers generally arise as a result of persistent infection with high-risk human papillomaviruses (hrHPVs) and occur near the squamocolumnar junction (SCJ) and within the transformation zone (TZ). The susceptibility of the TZ to HPV-related carcinogenesis appears linked to epithelial cell plasticity, with squamous metaplasia originating from a specialized stem cell population at this site. Two alternative cell populations have been implicated: keratin (K)7+ve cuboidal cells located at the SCJ vs a more broadly distributed K17+ve cervical reserve cell population. To distinguish between the hypotheses, we utilized multiplex immunofluorescence and large-scale digital imaging to map cell populations at the TZ of 165 women with and without hrHPV infections. Our results did not reveal a distinct population of K7+ cuboidal cells at the SCJ but found instead that the cuboidal and columnar cells of the TZ express K7 and K8 throughout and lack the p63 transcription factor required for epithelial stratification. Squamous metaplasia and reserve cells, which are defined by their subcolumnar location and pattern of biomarker expression (K5/K17/P63), were conspicuous at cervical crypt entrances within the TZ extending proximally toward the endocervix. In HPV-infected tissue, crypt-entrance regions with thin high-grade squamous intraepithelial lesion pathology showed prominent expression of hrHPV E6/E7 mRNA, as detected by fluorescence in situ hybridization, and p16/MCM expression, with infection also apparent in neighboring reserve cells. In some instances, normal/uninfected reserve cells (E6/E7 mRNA-ve) and squamous metaplasia were not only seen close to these regions of hrHPV infection but also extended well beyond the infected area both laterally and by depth. Our results confirm that the reserve cells underneath the columnar epithelia at TZ have the potential to undergo malignant squamous transformation via reserve cell proliferation, in agreement with previous histopathological studies. These translational findings highlight the importance of understanding the molecular biology of the epithelial sites where HPV cancers develop and suggest that in high-risk individuals, treatment strategies should target a wider area than previously thought.
宫颈鳞状细胞癌通常是由高危型人乳头瘤病毒（hrHPV）持续感染引起的，发生在鳞柱交界（SCJ）附近和转化区（TZ）内。TZ对HPV相关致癌作用的易感性似乎与上皮细胞可塑性有关，鳞状化生起源于该部位的一种特殊干细胞群。有两种替代细胞群被认为与此有关：位于SCJ的角蛋白（K）7阳性立方形细胞与分布更广泛的K17阳性宫颈储备细胞群。为了区分这两种假设，我们利用多重免疫荧光和大规模数字成像技术，对165名有或无hrHPV感染的女性的TZ细胞群进行了定位。我们的结果并未在SCJ处发现明显的K7阳性立方形细胞群，而是发现TZ的立方形和柱状细胞全程表达K7和K8，并且缺乏上皮分层所需的p63转录因子。鳞状化生细胞和储备细胞由其柱状上皮下位置和生物标志物表达模式（K5/K17/P63）定义，在TZ内宫颈隐窝入口处很明显，这些隐窝入口向宫颈管近端延伸。在HPV感染的组织中，荧光原位杂交检测显示，具有薄的高级别鳞状上皮内病变病理特征的隐窝入口区域显示hrHPV E6/E7 mRNA的显著表达以及p16/MCM表达，在邻近的储备细胞中也明显存在感染。在某些情况下，不仅在这些hrHPV感染区域附近可以看到正常/未感染的储备细胞（E6/E7 mRNA阴性）和鳞状化生细胞，而且它们在横向和深度上都延伸到感染区域之外。我们的结果证实，TZ柱状上皮下的储备细胞有可能通过储备细胞增殖发生恶性鳞状转化，这与之前的组织病理学研究一致。这些转化研究结果突出了了解HPV癌症发生上皮部位分子生物学的重要性，并表明在高危个体中，治疗策略应针对比以前认为的更广泛的区域。
