58 SYNDECAN-1 Inhibition reverses the pre-malignant phenotype of endometrioma through TGF-BETA signalling: potential implications in endometriosis associated ovarian cancer. (18th September 2019)

• Record Type: Journal Article
• Authors: Ponandai-Srinivasan, S; Saare, M; Boggavarapu, NR; Ehström, S; Garcìa-Uribe, PA; Salumets, A; Götte, M; Lalitkumar, PG; Gemzell-Danielsson, K
• Is Part Of: International journal of gynecological cancer. Volume 29(2019)Supplement 3
• Page Start: A32
• Page End: A32
• Publication Date: 2019-09-18
• Subjects: Generative organs, Female -- Cancer -- Periodicals; 616.99465
• DOI: 10.1136/ijgc-2019-IGCS.58
• Languages: English
• ISSNs: 1048-891X

Abstract

Abstract : Objectives: Transforming growth factor-beta (TGF-β) is abundantly expressed in peritoneal fluid and endometrioma of women with endometriosis. Similarly, transmembrane proteoglycans of the Syndecan family (SDC), act as co-receptors for growth signalling factors and are aberrantly expressed in endometriotic tissues. Here, we aim to investigate the regulation of SDC-1 upon induced activation with TGF-β in vitro, to better understand their interactions and involvement in the pathophysiology of endometriosis. Methods: Endometrioma biopsies (n=15) were obtained from women diagnosed with endometriosis and not received any hormonal treatment. Tissue biospies were investigated for intra-patient heterogeneity using pre-validated panel of stem- and cancer- cell signalling genes. Simultaneously, patient-derived endometriotic stem/stromal cells (CD90 + CD73 + CD105 +, SC + ) were allowed to generate 3D-spheroids in absence or presence of rhTGF-β or TGFBRI/II inhibitor Ly2109761 in vitro ; assessed for its influence on SDC-1 expression, proliferation and invasive behaviour. Further, transcriptomic signatures after 3D-spheroid invasion was evaluated upon combining SDC-1 gene silencing with rhTGF-β treatment. Results: Clustering analysis from endometriotic tissue gene expression revealed in 2/15 samples (referred to as Endo-hi) aberrant expression of molecules of TGF-β signalling ( TGF-β1, ESR1, CTNNB1, SNAI1, BMI1) which grouped separately from low expression samples (Endo-lo) by >95% CI. 3D-spheroids from Endo-hi SC+ exposed to rhTGF-β treatment showed increased SDC-1 expression and higher 3D-spheroid invasion compared to Endo-lo SC+. However, rhTGFβ treatment following SDC-1 gene silencing reversed the higher 3D-invasion potential and exhibited downregulation of cancer associated pathways. Conclusions: Modulation of SDC-1 reverses the pre-malignant phenotype of endometrioma and may reduce the potential risk for endometriosis associated ovarian cancer.