Cadherin composition and multicellular aggregate invasion in organotypic models of epithelial ovarian cancer intraperitoneal metastasis
| Autor: | Yuliya Klymenko, Jing Yang, Oleg Kim, M. S. Stack, Elizabeth Loughran, Rachel Lombard, Mark Alber |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research extracellular matrix Biology Matrix metalloproteinase Carcinoma Ovarian Epithelial Matrix Metalloproteinase Inhibitors Article Metastasis Mesoderm 03 medical and health sciences Mice Organ Culture Techniques mesothelium Cell Line Tumor Genetics medicine Cell Adhesion Matrix Metalloproteinase 14 Animals Humans metastasis Neoplasm Invasiveness Neoplasms Glandular and Epithelial Cell adhesion Molecular Biology Peritoneal Neoplasms Cell Aggregation Ovarian Neoplasms Cadherin Mesenchymal stem cell Dipeptides medicine.disease Cadherins invasion Cell aggregation Gene Expression Regulation Neoplastic Mice Inbred C57BL Disease Models Animal 030104 developmental biology ovarian cancer Cell culture Immunology Cancer research Female Mesothelial Cell |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 |
| Popis: | During epithelial ovarian cancer (EOC) progression, intraperitoneally disseminating tumor cells and multi-cellular aggregates (MCAs) present in ascites fluid adhere to the peritoneum and induce retraction of the peritoneal mesothelial monolayer prior to invasion of the collagen-rich sub-mesothelial matrix and proliferation into macro-metastases. Clinical studies have shown heterogeneity among EOC metastatic units with respect to cadherin expression profiles and invasive behavior, however the impact of distinct cadherin profiles on peritoneal anchoring of metastatic lesions remains poorly understood. In the current study, we demonstrate that metastasis-associated behaviors of ovarian cancer cells and MCAs are influenced by cellular cadherin composition. Our results show that mesenchymal N-cadherin expressing (Ncad+) cells and MCAs invade much more efficiently than E-cadherin expressing (Ecad+) cells. Ncad+ MCAs exhibit rapid lateral dispersal prior to penetration of three-dimensional collagen matrices. When seeded as individual cells, lateral migration and cell-cell junction formation precede matrix invasion. Neutralizing the Ncad extracellular domain with the monoclonal antibody GC-4 suppresses lateral dispersal and cell penetration of collagen gels. In contrast, use of a broad spectrum matrix metalloproteinase (MMP) inhibitor (GM6001) to block endogenous membrane type 1 matrix metalloproteinase (MT1-MMP) activity does not fully inhibit cell invasion. Using intact tissue explants, Ncad+ MCAs were also shown to efficiently rupture peritoneal mesothelial cells, exposing the sub-mesothelial collagen matrix. Acquisition of Ncad by E-cadherin expressing cells (Ecad+) increased mesothelial clearance activity, but was not sufficient to induce matrix invasion. Furthermore, co-culture of Ncad+ with Ecad+ cells did not promote a “leader-follower” mode of collective cell invasion, demonstrating that matrix remodeling and creation of invasive micro-tracks are not sufficient for cell penetration of collagen matrices in the absence of Ncad. Collectively, our data emphasize the role of Ncad in intraperitoneal seeding of EOC and provide the rationale for future studies targeting Ncad+ in pre-clinical models of EOC metastasis. |
| Databáze: | OpenAIRE |
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