Modulation of Dkk-3 and claudin-5 as new therapeutic strategy in the treatment of meningiomas

Abstract

Meningiomas are the most common tumors of the central nervous system, where the incidence is around 25% of all primary brain tumors. The optimal treatment is represented by total resection accompanied by the removal of the dura mater and bone when infiltrated by the tumor. The histological grading is the most important prognostic factor in the outcome. However, recurrences do occur in a significant proportion (10–25%) of cases, representing the most relevant clinical complication. Molecular therapies are providing to give different opportunities in the development of new treatments. The Dickkopf-related family of proteins includes four secretory proteins. The expression of the REIC/Dkk-3 gene is down-regulated in many tumor cell lines and could contribute to the immunomodulatory properties of the tissue microenvironment. An important role in carcinogenesis is played by Dickkopf protein-related protein 3, which is involved in embryonic development through its interaction and modulation of the pathway of the Wnt signal transduction. The mutations of this pathway are of clinical importance, because they lead to the onset of several cancers, including brain tumors, being also involved in tumor angiogenesis. The claudin-5, is an integral membrane protein, which regulate the permeability of the blood-brain barrier. In various pathological processes, including inflammation, trauma and tumor, claudin 5 regulate the change in endothelial or epithelial permeability, therefore, modification in claudin-5 expression may play a role in malignant transformation. The aim of our study is to demonstrate the role of Dkk-3 and claudin-5 in the pathogenesis of meningiomas. A more correct identification of the role of these proteins might suggest interesting and new molecular targets for future therapeutic protocols.

TLR-4/Wnt modulation as new therapeutic strategy in the treatment of glioblastomas

“…Malignant gliomas present a therapeutic challenge because they are protected from cytotoxic chemotherapy by a heterogeneously permeable BBB. claudin-5, in various pathological tumor processes, regulated the change in endothelial or epithelial permeability, exercising a protective role of BBB to maintain its integrity [29]. In our work we observed, for the first time, a significantly reduction of claudin-5 expression levels in GBM human cell lines, further confirmed in GBM tissues.…”

Effect of tryptase on mouse brain microvascular endothelial cells via protease-activated receptor 2

“…Reports have found that degradation of claudin-5 and occludin can increase the permeability and contribute to brain oedema in ischaemic stroke [ 30 ]. And claudin-5 regulates the permeability and integrity of the BBB by changing endothelial or epithelial cell permeability [ 31 ]. Our current observation suggests that moderate stimulation of PAR-2 on mouse brain microvascular endothelial cell may regulate tight junction proteins and supply a new option for the management of CNS functions.…”

Wnt Signaling in the Tumor Microenvironment

“…There have been a tremendous number of studies that identify how Wnt signaling is involved in the formation and regulation of CAFs in different tumor types. In contrast to the expression in cancer cells as a Wnt antagonist to suppress various cancers progression [69][70][71], the stromal expression of Dickkopf-3 (DKK3), a HSF1 effector, regulated the pro-turnorigenic behavior of CAFs via Wnt signaling and the activation of Hippo pathway transducers YAP/TAZ [72]. CAFs also promoted the stemness, metastasis, and chemoresistance of colorectal cancer cells by secreting exosomes to increase miR-92a-3p, a microRNA, activating the Wnt/β-catenin pathway and inhibiting mitochondrial apoptosis by directly inhibiting FBXW7 and MOAP1 [73].…”