宫颈癌发生中的死亡受体和配体：一项免疫组织化学研究。

Death receptors and ligands in cervical carcinogenesis: an immunohistochemical study.

作者信息

Reesink-Peters N, Hougardy B M T, van den Heuvel F A J, Ten Hoor K A, Hollema H, Boezen H M, de Vries E G E, de Jong S, van der Zee A G J

机构信息

Department of Gynecologic Oncology, University Hospital Groningen, PO Box 30001, 9700 RB, Groningen, The Netherlands.

出版信息

Gynecol Oncol. 2005 Mar;96(3):705-13. doi: 10.1016/j.ygyno.2004.10.046.

DOI:10.1016/j.ygyno.2004.10.046

PMID:15721415

Abstract

OBJECTIVE

Increasing imbalance between proliferation and apoptosis is important in cervical carcinogenesis. The death ligands FasL and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induce apoptosis by binding to their cognate cell-surface death receptors Fas or death receptor (DR) 4 and DR5. This study aims to examine if changes in death ligand and death receptor expression during different stages of cervical carcinogenesis are related to an imbalance between proliferation and apoptosis.

METHODS

The immunohistochemical expression and localization of Fas/FasL and DR4/DR5/TRAIL were assessed in 11 normal cervices, 15 cervical intraepithelial neoplasia (CIN) grade I, 15 CIN II, 13 CIN III, and 25 (microinvasive) squamous cell cervical cancers. The number of apoptotic cells was determined by morphological criteria and the number of proliferating cells by counting Ki-67-positive cells.

RESULTS

A marked increase in proliferation as well as apoptosis percentage was found with increasing severity of neoplasia. In normal cervix and CIN I samples, FasL, DR4, DR5, and TRAIL staining was mainly observed in the basal/parabasal layer, whereas Fas staining was localized in the superficial, more differentiated epithelial layer. Frequency of Fas-positive staining decreased with increasing severity of CIN. In contrast, homogeneous FasL, DR4, DR5, and TRAIL expression throughout the lesions was more frequently observed in CIN III and cervical cancer. FasL, DR4, DR5, and TRAIL staining patterns were correlated, although TRAIL expression was more intense in low-grade lesions. No association was found between death receptor or ligand expression with the percentage of apoptosis or proliferation.

CONCLUSION

The loss of Fas and the deregulation of FasL, DR4, DR5, and TRAIL in the CIN-cervical cancer sequence suggest a possible functional role of these death ligands and receptors during cervical carcinogenesis. The frequent expression of DR4 and DR5 presents these receptors as promising targets for innovative therapy modalities in cervical cancer.

摘要

目的

增殖与凋亡之间日益加剧的失衡在宫颈癌发生过程中具有重要意义。死亡配体FasL和肿瘤坏死因子相关凋亡诱导配体（TRAIL）通过与其同源的细胞表面死亡受体Fas或死亡受体（DR）4和DR5结合来诱导凋亡。本研究旨在探讨宫颈癌发生不同阶段死亡配体和死亡受体表达的变化是否与增殖和凋亡之间的失衡有关。

方法

对11例正常宫颈组织、15例宫颈上皮内瘤变（CIN）I级、15例CIN II级、13例CIN III级以及25例（微浸润）宫颈鳞状细胞癌组织进行Fas/FasL和DR4/DR5/TRAIL的免疫组化表达及定位评估。通过形态学标准确定凋亡细胞数量，通过计数Ki-67阳性细胞确定增殖细胞数量。

结果

随着肿瘤形成严重程度的增加，增殖以及凋亡百分比显著升高。在正常宫颈和CIN I样本中，FasL、DR4、DR5和TRAIL染色主要见于基底/副基底层，而Fas染色定位于浅表、分化程度更高的上皮层。Fas阳性染色频率随CIN严重程度增加而降低。相反，在CIN III和宫颈癌中更频繁地观察到病变部位FasL、DR4、DR5和TRAIL的均匀表达。FasL、DR4、DR5和TRAIL染色模式相关，尽管TRAIL在低级别病变中表达更强。未发现死亡受体或配体表达与凋亡或增殖百分比之间存在关联。