We previously reported that indoleamine-2,3dioxygenase (IDO) is associated with paclitaxel resistance and that IDO serves as a marker of poor prognosis in ovarian serous adenocarcinomas (SA). In this study, to explore the role of IDO in the development of various histological types of ovarian cancer, we further examined IDO expression not only in SA but also in other types of ovarian cancers. Expression of IDO protein was analyzed by immunohistochemistry for a total of 122 ovarian cancers including 40 SA, 67 clear cell adenocarcinomas (CCA), and 15 endometrioid adenocarcinomas (EA) with informed consent. Among these cases, there were 11 CCA accompanied with endometriosis and 60 cases with lymph node metastasis. We classified the samples into four categories by IDO staining pattern. IDO staining was positive in 57.5% of SA, 49.2% of CCA, and 73.3% of EA, respectively. The Kaplan-Meier survival curve showed a clear relationship between staining score and overall survival for patients with advanced (stages III and IV) SA (n=33) who underwent optimal surgery and paclitaxelcarboplatin (TC) chemotherapy as a first-line regimen. There was no association between IDO staining score and overall survival in the CCA cases. Eight of 11 cases (72.7%) of CCA accompanied by endometriosis presented identical staining patterns of IDO between CCA and endometriosis. In 43 of 60 cases (71.6%) with lymph node metastasis, the staining patterns of IDO showed a correspondence between the primary lesion and metastatic site. These results suggested that the increased synthesis of IDO protein was positively associated with impaired survival only in the serous type of ovarian cancer.

Abstract. Most ovarian cancers arise from the mesothelial surface lining of the ovaries or from invaginations of this lining into the superficial ovarian cortex that form cortical inclusion cysts. Thus, these cysts are thought to be precursor lesions of ovarian carcinoma. Epithelial-mesenchymal transition, which is a transcriptional program for inducing maintenance of the mesenchymal phenotype, acts in tumor progression and metastasis. Little is known about the mechanisms involved in mesenchymal-epithelial transition (MET). We aimed to characterize the human ovarian surface epithelium (OSE) and inclusion cysts by immunohistochemical analysis to examine whether MET occurs during inclusion cyst formation in the OSE. We used specimens from 9 endometrial cancer patients who had undergone hysterectomy and bilateral salpingo-oophorectomy. Immunohistochemical analysis was performed in 10 normal ovaries containing 92 inclusion cysts and in 4 normal tubes to examine the expression of antigen markers including calretinin, podoplanin, D2-40, thrombomodulin, HBME-1, vimentin, EMA, WT1, CA125, MOC31, TAG-72, Ber-EP4 and E-cadherin. The positive staining rates for mesothelial markers in normal OSE were 100% (10/10) for calretinin, 80% (8/10) for podoplanin, 80% (8/10) for D2-40, 70% (7/10) for thrombomodulin, 100% (10/10) for HBME-1, 100% (10/10) for vimentin. The positive staining rates for epithelial markers in tubal epithelium were 100% (4/4) for HBME-1, 100% (4/4) for vimentin, 100% (4/4) for EMA, 75% (3/4) for TAG-72, 100% (4/4) for Ber-EP4. Inclusion cysts showed positive staining for both markers with an incidence of 51% (47/92) for HBME-1, 44% (41/92) for vimentin, 65% (60/92) for TAG-72, 88% (81/92) for Ber-EP4. The OSE showed the characteristics of both mesenchymal and epithelium cells. In contrast, inclusion cysts gained epithelial characteristics, but lost mesenchymal characteristics. These findings support that MET occurs during the inclusion cyst formation from OSE.

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