Functional Expression Analysis of TLR-4 and MYD88 in Epithelial Ovarian Neoplasia
CJ d'Adhemar, MF Gallagher, S O'Toole, C Murphy, PC Smyth, C Martin, O Sheils, JJ O'Leary. Trinity College Dublin, Dublin 2, Ireland; Coombe Women's Hospital, Dublin 8, Ireland
Background: Toll-like receptors, key parts of the innate immune system, are being increasingly studied in cancer pathogenesis, influencing both tumour proliferation and chemoresistance. The expression of TLR-4 and its adaptor protein MyD88 have recently been analysed in epithelial ovarian neoplasia (EON). However, to date, this work has been limited to serous carcinomas. The aim of this study was to evaluate TLR-4/MyD88 expression in all common subtypes of EON (benign, borderline and malignant), to analyse its effect on patient survival and to assess its expression in ovarian cancer stem cells (CSCs).
Design: Archival tissue samples were obtained from 129 patients with EON and 50 with histologically normal ovaries, and were evaluated for TLR-4 and MyD88 by immunohistochemistry (IHC). Results were correlated with histologic subtype, grade and clinical disease progression. p53 and BRAF mutation analysis was performed on samples of borderline serous tumours (BSTs), using IHC and Taqman® SNP detection, respectively. TLR-4/MyD88 expression in CSC cell lines 2102Ep and NTera2 was determined using IHC, with and without differentiation in retinoic acid.
Results: While some degree of TLR-4 expression was observed in all ovarian epithelium, MyD88 expression was confined to serous neoplasms and was greatest in borderline and malignant tumours. MyD88 staining was positive in 46% of malignant tumours (n=40), all of which were serous carcinomas. No direct correlation was observed between tumour grade and TLR-4/MyD88 expression, or with p53/BRAF status in BSTs. MyD88 expression was associated with both shorter progression-free and overall survival (50 vs. 16 months and 78 vs. 36 months, respectively; p < 0.05). TLR-4 and MyD88 were expressed in both CSC lines in their undifferentiated state. However, MyD88 expression was significantly decreased in NTera2 cells following differentiation with retinoic acid.
Conclusions: Our findings suggest that MyD88 expression is restricted to serous ovarian neoplasms, independent of histologic grade and associated with significantly shorter patient survival. Furthermore ex vivo manipulation of ovarian CSC differentiation can significantly decrease MyD88 expression. These results suggest that MyD88 expression may be more important than histologic subtype or grade in epithelial ovarian cancers.
Category: Gynecologic & Obstetrics
Wednesday, March 24, 2010 1:00 PM
Poster Session VI # 163, Wednesday Afternoon