Microenvironmental regulation of ovarian cancer dissemination via activation of the Wnt signaling pathway

Abstract

Disseminating single cells and multicellular aggregates (MCAs) and experience compressive forces exerted upon them by ascites fluid and are exposed to lysophosphatidic acid, aberrantly adhesive mesothelium and a collagen-rich submesothelial matrix. This work investigates the hypothesis that microenvironmental forces (increased fluid pressure/compressive force, lysophosphatidic acid, and integrin engagement) facilitate successful metastasis via Wnt signaling activation. Short-term (8-hour) increased fluid pressure, applied using an Instron 8215, enhances cell proliferation and up-regulates expression of Wnt target genes. Integrin engagement and LPA signaling down-regulate Ecadherin leading to dissolution of MCAs and initiating the epithelial to mesenchymal transition (EMT), characteristic of disseminating EOCs at this stage. β1 integrin engagement, modeled using anti-β1 integrin antibody adsorbed on 3-micron microspheres, leads to accumulation of free cytoplasmic β-catenin. And subsequent activation β-catenin target genes. These data suggest a novel Wnt ligand-independent mechanism for activation of the Wnt signaling pathway in ovarian carcinoma, and correlates with research and clinical observations of alterations in Wnt signaling by addressing mutation-independent activation of the signaling pathway.