Yoshida Norio, Ino Kazuhiko, Ishida Yoshiyuki, Kajiyama Hiroaki, Yamamoto Eiko, Shibata Kiyosumi, Terauchi Mikio, Nawa Akihiro, Akimoto Hidetoshi, Takikawa Osamu, Isobe Ken-ichi, Kikkawa Fumitaka
Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Clin Cancer Res. 2008 Nov 15;14(22):7251-9. doi: 10.1158/1078-0432.CCR-08-0991.
Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme that induces immune tolerance in mice. Our prior study showed that high tumoral IDO expression in endometrial cancer tissues correlates with disease progression and impaired patient survival. The purpose of the present study was to clarify the functional role of IDO in human endometrial cancer cells and to investigate the therapeutic potential of IDO inhibitors.
IDO cDNA was transfected into the human endometrial carcinoma cell line AMEC, resulting in the establishment of stable clones of IDO-overexpressing AMEC cells (AMEC-IDO). AMEC-IDO cells were characterized in vitro as well as in vivo using a mouse xenograft model.
There was no significant difference in in vitro cell proliferation, migration, or chemosensitivity to paclitaxel between AMEC-IDO and control vector-transfected cells (AMEC-pcDNA). However, in vivo tumor growth was markedly enhanced in AMEC-IDO-xenografted nude mice when compared with AMEC-pcDNA-xenografted mice. Splenic natural killer (NK) cell counts in AMEC-IDO-xenografted mice were significantly decreased when compared with control mice. Furthermore, conditioned medium obtained from AMEC-IDO cell cultures markedly reduced the NK lysis activity of nude mice. Finally, oral administration of the IDO inhibitor 1-methyl-D-tryptophan in combination with paclitaxel in AMEC-IDO-xenografted mice strongly potentiated the antitumor effect of paclitaxel, resulting in significantly prolonged survival.
This is the first evidence showing that IDO overexpression in human cancer cells contributes to tumor progression in vivo with suppression of NK cells. Our data suggest that targeting IDO may be a novel therapeutic strategy for endometrial cancer.
吲哚胺2,3-双加氧酶（IDO）是一种色氨酸分解代谢酶，可诱导小鼠产生免疫耐受。我们之前的研究表明，子宫内膜癌组织中肿瘤IDO高表达与疾病进展及患者生存率降低相关。本研究的目的是阐明IDO在人子宫内膜癌细胞中的功能作用，并研究IDO抑制剂的治疗潜力。
将IDO cDNA转染到人子宫内膜癌细胞系AMEC中，从而建立IDO过表达的AMEC细胞稳定克隆（AMEC-IDO）。使用小鼠异种移植模型对AMEC-IDO细胞进行体外和体内特性分析。
AMEC-IDO细胞与对照载体转染细胞（AMEC-pcDNA）在体外细胞增殖、迁移或对紫杉醇的化学敏感性方面无显著差异。然而，与AMEC-pcDNA异种移植小鼠相比，AMEC-IDO异种移植裸鼠体内肿瘤生长明显增强。与对照小鼠相比，AMEC-IDO异种移植小鼠脾脏自然杀伤（NK）细胞计数显著降低。此外，从AMEC-IDO细胞培养物中获得的条件培养基显著降低了裸鼠的NK裂解活性。最后，在AMEC-IDO异种移植小鼠中口服IDO抑制剂1-甲基-D-色氨酸联合紫杉醇可强烈增强紫杉醇的抗肿瘤作用，从而显著延长生存期。
这是首个证据表明人癌细胞中IDO过表达通过抑制NK细胞促进体内肿瘤进展。我们的数据表明，靶向IDO可能是子宫内膜癌的一种新型治疗策略。
