Stromal cartilage oligomeric matrix protein as a tumorigenic driver in ovarian cancer via Notch3 signaling and epithelial-to-mesenchymal transition
Abstract Background Cartilage oligomeric matrix protein (COMP), an extracellular matrix glycoprotein, is vital in preserving cartilage integrity. Further, its overexpression is associated with the aggressiveness of several types of solid cancers. This study investigated COMP’s role in ovarian cancer...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-04-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-024-05083-0 |
| _version_ | 1797209062998278144 |
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| author | Gilar Gorji-Bahri B. Madhu Krishna Catharina Hagerling Akira Orimo Karin Jirström Konstantinos S. Papadakos Anna M. Blom |
| author_facet | Gilar Gorji-Bahri B. Madhu Krishna Catharina Hagerling Akira Orimo Karin Jirström Konstantinos S. Papadakos Anna M. Blom |
| author_sort | Gilar Gorji-Bahri |
| collection | DOAJ |
| description | Abstract Background Cartilage oligomeric matrix protein (COMP), an extracellular matrix glycoprotein, is vital in preserving cartilage integrity. Further, its overexpression is associated with the aggressiveness of several types of solid cancers. This study investigated COMP’s role in ovarian cancer, exploring clinicopathological links and mechanistic insights. Methods To study the association of COMP expression in cancer cells and stroma with clinicopathological features of ovarian tumor patients, we analyzed an epithelial ovarian tumor cohort by immunohistochemical analysis. Subsequently, to study the functional mechanisms played by COMP, an in vivo xenograft mouse model and several molecular biology techniques such as transwell migration and invasion assay, tumorsphere formation assay, proximity ligation assay, and RT-qPCR array were performed. Results Based on immunohistochemical analysis of epithelial ovarian tumor tissues, COMP expression in the stroma, but not in cancer cells, was linked to worse overall survival (OS) of ovarian cancer patients. A xenograft mouse model showed that carcinoma-associated fibroblasts (CAFs) expressing COMP stimulate the growth and metastasis of ovarian tumors through the secretion of COMP. The expression of COMP was upregulated in CAFs stimulated with TGF-β. Functionally, secreted COMP by CAFs enhanced the migratory capacity of ovarian cancer cells. Mechanistically, COMP activated the Notch3 receptor by enhancing the Notch3-Jagged1 interaction. The dependency of the COMP effect on Notch was confirmed when the migration and tumorsphere formation of COMP-treated ovarian cancer cells were inhibited upon incubation with Notch inhibitors. Moreover, COMP treatment induced epithelial-to-mesenchymal transition and upregulation of active β-catenin in ovarian cancer cells. Conclusion This study suggests that COMP secretion by CAFs drives ovarian cancer progression through the induction of the Notch pathway and epithelial-to-mesenchymal transition. |
| first_indexed | 2024-04-24T09:48:44Z |
| format | Article |
| id | doaj.art-70cd2d9352ca489783d89fb5d55c6172 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-04-24T09:48:44Z |
| publishDate | 2024-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-70cd2d9352ca489783d89fb5d55c61722024-04-14T11:27:40ZengBMCJournal of Translational Medicine1479-58762024-04-0122111910.1186/s12967-024-05083-0Stromal cartilage oligomeric matrix protein as a tumorigenic driver in ovarian cancer via Notch3 signaling and epithelial-to-mesenchymal transitionGilar Gorji-Bahri0B. Madhu Krishna1Catharina Hagerling2Akira Orimo3Karin Jirström4Konstantinos S. Papadakos5Anna M. Blom6Department of Translational Medicine, Lund UniversityDepartment of Translational Medicine, Lund UniversityDepartment of Experimental Medical Science, Lund UniversityDepartment of Pathology and Oncology, Juntendo UniversityDepartment of Clinical Sciences Lund, Lund UniversityDepartment of Translational Medicine, Lund UniversityDepartment of Translational Medicine, Lund UniversityAbstract Background Cartilage oligomeric matrix protein (COMP), an extracellular matrix glycoprotein, is vital in preserving cartilage integrity. Further, its overexpression is associated with the aggressiveness of several types of solid cancers. This study investigated COMP’s role in ovarian cancer, exploring clinicopathological links and mechanistic insights. Methods To study the association of COMP expression in cancer cells and stroma with clinicopathological features of ovarian tumor patients, we analyzed an epithelial ovarian tumor cohort by immunohistochemical analysis. Subsequently, to study the functional mechanisms played by COMP, an in vivo xenograft mouse model and several molecular biology techniques such as transwell migration and invasion assay, tumorsphere formation assay, proximity ligation assay, and RT-qPCR array were performed. Results Based on immunohistochemical analysis of epithelial ovarian tumor tissues, COMP expression in the stroma, but not in cancer cells, was linked to worse overall survival (OS) of ovarian cancer patients. A xenograft mouse model showed that carcinoma-associated fibroblasts (CAFs) expressing COMP stimulate the growth and metastasis of ovarian tumors through the secretion of COMP. The expression of COMP was upregulated in CAFs stimulated with TGF-β. Functionally, secreted COMP by CAFs enhanced the migratory capacity of ovarian cancer cells. Mechanistically, COMP activated the Notch3 receptor by enhancing the Notch3-Jagged1 interaction. The dependency of the COMP effect on Notch was confirmed when the migration and tumorsphere formation of COMP-treated ovarian cancer cells were inhibited upon incubation with Notch inhibitors. Moreover, COMP treatment induced epithelial-to-mesenchymal transition and upregulation of active β-catenin in ovarian cancer cells. Conclusion This study suggests that COMP secretion by CAFs drives ovarian cancer progression through the induction of the Notch pathway and epithelial-to-mesenchymal transition.https://doi.org/10.1186/s12967-024-05083-0Ovarian cancerStromaCOMPCAFEpithelial-to-mesenchymal transition |
| spellingShingle | Gilar Gorji-Bahri B. Madhu Krishna Catharina Hagerling Akira Orimo Karin Jirström Konstantinos S. Papadakos Anna M. Blom Stromal cartilage oligomeric matrix protein as a tumorigenic driver in ovarian cancer via Notch3 signaling and epithelial-to-mesenchymal transition Journal of Translational Medicine Ovarian cancer Stroma COMP CAF Epithelial-to-mesenchymal transition |
| title | Stromal cartilage oligomeric matrix protein as a tumorigenic driver in ovarian cancer via Notch3 signaling and epithelial-to-mesenchymal transition |
| title_full | Stromal cartilage oligomeric matrix protein as a tumorigenic driver in ovarian cancer via Notch3 signaling and epithelial-to-mesenchymal transition |
| title_fullStr | Stromal cartilage oligomeric matrix protein as a tumorigenic driver in ovarian cancer via Notch3 signaling and epithelial-to-mesenchymal transition |
| title_full_unstemmed | Stromal cartilage oligomeric matrix protein as a tumorigenic driver in ovarian cancer via Notch3 signaling and epithelial-to-mesenchymal transition |
| title_short | Stromal cartilage oligomeric matrix protein as a tumorigenic driver in ovarian cancer via Notch3 signaling and epithelial-to-mesenchymal transition |
| title_sort | stromal cartilage oligomeric matrix protein as a tumorigenic driver in ovarian cancer via notch3 signaling and epithelial to mesenchymal transition |
| topic | Ovarian cancer Stroma COMP CAF Epithelial-to-mesenchymal transition |
| url | https://doi.org/10.1186/s12967-024-05083-0 |
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