Role of the immunosuppressive enzyme indoleamine 2,3-dioxygenase in the progression of ovarian carcinoma
Role of the immunosuppressive enzyme indoleamine 2,3-dioxygenase in the progression of ovarian carcinoma
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DOI：
10.1016/j.ygyno.2009.07.015
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发表时间：
2009-11-01
影响因子：
4.7
通讯作者：
Kikkawa, Fumitaka
中科院分区：
文献类型：
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作者：
Inaba, Tomoko;Ino, Kazuhiko;Kikkawa, Fumitaka
objective.吲哚胺2，3-双加氧酶（IDO）是一种诱导免疫耐受的聚糖分解酶。本研究的目的是研究IDO在卵巢癌细胞中的表达及其功能作用。在卵巢切除的卵巢癌组织（n = 60）中对IDO表达进行化学评分，并分析其与肿瘤浸润淋巴细胞（TIL）计数或患者存活率的相关性。接着，将IDO cDNA转染到人卵巢癌细胞系SKOV 3中，建立IDO过表达细胞（SK-IDO）的稳定克隆。SK-IDO细胞在体外以及在体内使用裸鼠异种移植模型进行表征。34例（56.7%）肿瘤细胞中发现IDO高表达，并与CD8 + TIL数量减少相关。与无IDO表达或低IDO表达的患者相比，高IDO表达的患者的总体和进展无离子生存期显著受损。SK-IDO和对照载体转染（SK-pcDNA）细胞在体外细胞增殖、迁移、侵袭或对紫杉醇的化学敏感性方面没有显著差异。然而，与SK-pcDNA异种移植小鼠相比，SK-IDO异种移植小鼠中的肿瘤腹膜播散显著增加。通过口服IDO抑制剂1-甲基-色氨酸（1-MT）消除了SK-IDO异种移植小鼠中的这种肿瘤进展效应。最后，每周腹腔注射紫杉醇联合每日给予1-MT治疗与单独使用紫杉醇治疗相比，显著延长了SK-IDO异种移植小鼠的生存期。这些结果表明，IDO参与了卵巢癌的体内进展，并可能成为晚期卵巢癌的一个有前途的治疗靶点。(C)2009 Elsevier Inc. All rights reserved.
Objective. Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme that induces immune tolerance. The purpose of the present study is to investigate IDO expression and its functional role in ovarian cancer cells in vitro and in vivo.Methods. IDO expression was immunohistochemically scored in surgically-resected ovarian cancer tissues (n = 60), and its association with tumor-infiltrating lymphocyte (TIL) count or patient survival was analyzed. Next, IDO cDNA was transfected into the human ovarian carcinoma cell line SKOV3, establishing stable clones of IDO-overexpressing cells (SK-IDO). SK-IDO cells were characterized in vitro as well as in vivo using a nude mouse xenograft model.Results. High IDO expression in tumor cells was found in 34 (56.7%) cases and was correlated with a reduced number of CD8+ TIL. Patients with high IDO expression had significantly impaired overall and progress ion-free survival compared to patients with no or low IDO expression. There were no significant differences in in vitro cell proliferation, migration, invasion, or chemosensitivity to paclitaxel between the SK-IDO and control vector-transfected (SK-pcDNA) cells. However, tumor peritoneal dissemination was significantly increased in SK-IDO-xenografted mice compared to SK-pcDNA-xenografted mice. This tumor-progressive effect in SK-IDO-xenografted mice was abrogated by oral administration of the IDO inhibitor 1-methyl-tryptophan (1-MT). Finally, treatment with weekly i.p. paclitaxel combined with daily administration of 1-MT significantly prolonged the survival of the SK-IDO-xenografted mice compared to treatment with paclitaxel alone.Conclusions. These results suggest that IDO is involved in ovarian cancer progression in vivo and may be a promising therapeutic target for advanced ovarian cancer. (C) 2009 Elsevier Inc. All rights reserved.