Elson D A, Riley R R, Lacey A, Thordarson G, Talamantes F J, Arbeit J M
Cancer Genetics Program, University of California San Francisco Cancer Center, 94143-0808, USA.
Cancer Res. 2000 Mar 1;60(5):1267-75.
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.
一种上皮组织被另一种上皮组织取代（化生）的区域易发生癌症。环境因素与化生致癌密切相关。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，在这个区域，原本柱状上皮内衬的宫颈内膜腺体中可检测到化生的鳞状细胞。此前，我们报道了在基底鳞状上皮细胞中表达HPV16癌基因的转基因小鼠中雌激素诱导的阴道和宫颈多阶段致癌作用。在本研究中，为了探究对外源性雌激素的阈值肿瘤反应，我们用较低剂量的激素处理了几组转基因小鼠。与其他生殖道部位相比，雌激素剂量降低5倍仅在宫颈转化区诱导了鳞状细胞癌发生。进一步的研究描绘了转化区致癌的各个阶段，包括增生性子宫下段腺体的形成以及单个干细胞样腺储备细胞出现多个鳞状化生灶，随后化生进展为发育异常和鳞状细胞癌。我们提出，低剂量雌激素和低水平HPV癌基因表达的组合使转化区腺储备细胞倾向于鳞状而非柱状上皮命运决定。病毒癌蛋白细胞周期失调和雌激素受体信号协同激活增殖，以及旁分泌基质 - 上皮相互作用的改变，可能共同支持和促进肿瘤进展和癌症形成。
