化疗可诱导上皮性卵巢癌中死亡受体5的表达。

Chemotherapy induces death receptor 5 in epithelial ovarian carcinoma.

作者信息

Arts H J G, de Jong S, Hollema H, ten Hoor K, van der Zee A G J, de Vries E G E

机构信息

Department of Gynecological Oncology, University Hospital, Groningen, The Netherlands.

出版信息

Gynecol Oncol. 2004 Mar;92(3):794-800. doi: 10.1016/j.ygyno.2003.11.054.

DOI:10.1016/j.ygyno.2003.11.054

PMID:14984943

Abstract

OBJECTIVES

Defects in the apoptotic pathway are a general cause for drug resistance. Chemotherapy in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has proven to be an effective strategy to induce apoptosis in vitro in ovarian tumor cells. Systemic TRAIL administration might be a therapeutic option, since no toxicity was observed in nonhuman primates. In the present study, expression of TRAIL and its apoptosis-inducing death receptors (DR4 and DR5) and inhibitory decoy receptor (DcR1) was studied in normal ovaries and in malignant ovarian tumors before and after chemotherapy to investigate the therapeutic potential of TRAIL.

METHODS

DR4, DR5, DcR1, and TRAIL were studied immunohistochemically in 5 normal ovaries, 15 stages I/II, and 26 stages III/IV primary ovarian cancers, including 19 paired tumor samples (pre- and post-chemotherapy).

RESULTS

Surface epithelium of normal ovaries expressed TRAIL and its receptors; ovarian stromal cells expressed only DcR1. Of the ovarian cancers, 73% expressed DR4, 51% DR5, 46% DcR1, and 34% TRAIL. Most primary ovarian cancers (88%) expressed at least one death receptor. TRAIL expression was lower in stage III/IV than in stage I/II tumors (P<0.05). In paired samples, DR5 immunostaining was more frequently (P=0.05) and stronger (P<0.01) expressed in residual tumors.

CONCLUSION

Early stage tumors expressed TRAIL more frequently than advanced stage tumors. Most primary and residual ovarian tumors expressed at least one TRAIL death receptor, while in residual tumors following chemotherapy, DR5 was more frequently expressed. Therefore, human recombinant TRAIL administration might be an interesting treatment option.

摘要

目的

凋亡途径缺陷是耐药的常见原因。化疗联合肿瘤坏死因子相关凋亡诱导配体（TRAIL）已被证明是在体外诱导卵巢肿瘤细胞凋亡的有效策略。全身给予TRAIL可能是一种治疗选择，因为在非人类灵长类动物中未观察到毒性。在本研究中，研究了TRAIL及其凋亡诱导死亡受体（DR4和DR5）和抑制性诱饵受体（DcR1）在正常卵巢以及化疗前后的恶性卵巢肿瘤中的表达，以研究TRAIL的治疗潜力。

方法

采用免疫组织化学方法研究了5例正常卵巢、15例Ⅰ/Ⅱ期和26例Ⅲ/Ⅳ期原发性卵巢癌中的DR4、DR5、DcR1和TRAIL，其中包括19对肿瘤样本（化疗前后）。

结果

正常卵巢的表面上皮表达TRAIL及其受体；卵巢基质细胞仅表达DcR1。在卵巢癌中，73%表达DR4，51%表达DR5，46%表达DcR1，34%表达TRAIL。大多数原发性卵巢癌（88%）表达至少一种死亡受体。TRAIL在Ⅲ/Ⅳ期肿瘤中的表达低于Ⅰ/Ⅱ期肿瘤（P<0.05）。在配对样本中，DR5免疫染色在残留肿瘤中更频繁（P=0.05）且更强（P<0.01）表达。