Sensitivity of the cervical transformation zone to estrogen-induced squamous carcinogenesis.
Sensitivity of the cervical transformation zone to estrogen-induced squamous carcinogenesis.
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发表时间：
2000-03
期刊：
影响因子：
11.2
通讯作者：
D. Elson;Rebeccah R. Riley;Ama Lacey;G. Thordarson;Frank Talamantes;J. Arbeit
中科院分区：
文献类型：
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作者：
D. Elson;Rebeccah R. Riley;Ama Lacey;G. Thordarson;Frank Talamantes;J. Arbeit
其中一种上皮替代另一种上皮（化生）的区域具有癌症形成的倾向。环境因素与化生性癌变密切相关。特别是，与人乳头瘤病毒（HPV）感染相关的宫颈癌主要发生在转化区，在该区域，在另外的柱状上皮衬里的宫颈内腺中检测到化生鳞状细胞。以前，我们报道了在基底鳞状上皮细胞中表达HPV 16癌基因的转基因小鼠中雌激素诱导的多阶段阴道和宫颈癌发生。在目前的研究中，探讨阈值肿瘤反应外源性雌激素，我们处理组的转基因小鼠与较低的激素剂量。与其他生殖道部位相比，雌激素剂量减少5倍仅在宫颈转化区诱导鳞状细胞癌发生。进一步的研究描绘了转化区癌变的阶段，包括增生性子宫下腺的形成和单个干细胞样腺储备细胞出现多个鳞状化生灶，随后是化生到异型增生和鳞状细胞癌的肿瘤进展。我们认为，低剂量雌激素和低水平HPV癌基因表达的组合偏向鳞状上皮，而不是柱状上皮的命运决定的转化区腺储备细胞。通过病毒癌蛋白细胞周期失调和雌激素受体信号传导协同激活增殖，以及改变的旁分泌基质-上皮相互作用，可能共同支持和促进肿瘤进展和癌症形成。
Regions where one type of epithelium replaces another (metaplasia) have a predilection for cancer formation. Environmental factors are closely linked to metaplastic carcinogenesis. In particular, cervical cancers associated with human papillomavirus (HPV) infection develop primarily at the transformation zone, a region where metaplastic squamous cells are detected in otherwise columnar epithelial-lined endocervical glands. Previously, we reported estrogen-induced multistage vaginal and cervical carcinogenesis in transgenic mice expressing HPV16 oncogenes in basal squamous epithelial cells. In the present study to investigate the threshold neoplastic response to exogenous estrogen, we treated groups of transgenic mice with lower hormone doses. A 5-fold reduction in estrogen dose induced squamous carcinogenesis solely at the cervical transformation zone compared with other reproductive tract sites. Further study delineated stages of transformation zone carcinogenesis, including formation of hyperplastic lower uterine glands and emergence of multiple foci of squamous metaplasia from individual stem-like glandular reserve cells, followed by neoplastic progression of metaplasia to dysplasia and squamous cancer. We propose that a combination of low-dose estrogen and low-level HPV oncogene expression biases transformation zone glandular reserve cells toward squamous rather than columnar epithelial fate decisions. Synergistic activation of proliferation by viral oncoprotein cell cycle dysregulation and estrogen receptor signaling, together with altered paracrine stromal-epithelial interactions, may conspire to support and promote neoplastic progression and cancer formation.