ABSTRACT
Vasculogenic Mimicry (VM) refers to the capacity to form a blood network from aggressive cancer cells in an independent way of endothelial cells, to provide nutrients and oxygen leading to enhanced microenvironment complexity and treatment failure. In a previous study, we demonstrated that VE-Cadherin and its phosphorylation at Y658 modulated kaiso-dependent gene expression (CCND1 and Wnt 11) through a pathway involving Focal Adhesion kinase (FAK). In the present research, using a proteomic approach, we have found that ß-catenin/TCF-4 is associated with nuclear VE-cadherin and enhances the capacity of malignant melanoma cells to undergo VM in cooperation with VE-Cadherin; in addition, preventing the phosphorylation of Y658 of VE-cadherin upon FAK disabling resulted in VE-Cadherin/ß-catenin complex dissociation, increased ß-catenin degradation while reducing TCF-4-dependent genes transcription (C-Myc and Twist-1). Uveal melanoma cells knockout for VE-Cadherin loses ß-catenin expression while the rescue of VE-Cadherin (but not of the phosphorylation defective VE-Cadherin Y658F mutant) permits stabilization of ß-catenin and tumor growth reduction in vivo experiments. In vivo, the concomitant treatment with the FAK inhibitor PF-271 and the anti-angiogenic agent bevacizumab leads to a strong reduction in tumor growth concerning the single treatment. In conclusion, the anomalous expression of VE-Cadherin in metastatic melanoma cells (from both uveal and cutaneous origins), together with its permanent phosphorylation at Y658, favors the induction of the aggressive VM phenotype through the cooperation of ß-catenin with VE-Cadherin and by enhancing TCF-4 genes-dependent transcription.
Subject(s)
Endothelial Cells , Melanoma , Uveal Neoplasms , beta Catenin , beta Catenin/genetics , beta Catenin/metabolism , Cadherins/genetics , Cadherins/metabolism , Endothelial Cells/metabolism , Melanoma/pathology , Proteomics , Uveal Neoplasms/pathology , Transcription Factor 4/metabolismABSTRACT
Varying amounts of bone resorption can occur following tooth loss, and this can lead to implant placement problems due to a lack of an alveolar ridge with suitable osseous dimensions. There are many techniques for bone regeneration and many types of barriers, including polytetrafluoroethylene, collagen, and titanium meshes. The present case report describes the use of a customized CAD/CAM zirconia barrier for vertical ridge augmentation. A bone height gain of 12 mm was observed, as well as 8 mm of width. Subsequent histologic analysis revealed an excellent bone quality, allowing successful implant placement.
