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BACKGROUND: Glioblastomas (GBM) are highly aggressive brain tumors commonly treated with a combination of surgery, radiation therapy, and systemic chemotherapy. However, despite recent improvement in the multimodality approach, patient median survival times range between 3 and 30 months. New data by genomic approaches have allowed the subdivision of GBM into molecular subtypes, allowing us, in this way, to identify new targets. An important role in carcinogenesis is played by Dickkopf protein-related 3, which is involved in embryonic development through its interaction and modulation of the Wnt pathway. 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. The mutations of Wnt pathway are of clinical importance, because they lead to the onset of several cancers, including brain tumors, being also involved in tumor angiogenesis. The Wnt signaling contributes also to activity of the claudins, that are critical components of tight junctions (TJ), implicated in blood-brain barrier (BBB) formation, whose expression was altered in cerebral microvessels of human GBM. MATERIAL AND METHODS: In the present study we investigated the Wnt-signaling-mediated role of Dkk-3 and claudin-5 in vitro on GBM cell lines, and in the histopathological study on tissues of 30 WHO grade IV GBM patients. RESULTS: We evidenced that the expression of Dkk-3 was higher in normal human astrocytes cell line (NHA) used as control compared to human GBM tissues. Similarly, intracellular claudin-5 expression was significantly lower in U-138MG, A-172, LN-18 and LN-229 cell lines, while NHA cells significantly expressed claudin-5. CONCLUSION: Dkk-3 is able to regulate the WNT pathway, while the claudin-5 appears to interfere in maintaining the integrity of BBB permeability. By molecular analysis, our findings suggest a key role of Dkk-3 protein in GBM, as a potential tumor suppressor, evidenced by its reduced expression in tumor tissues. In addition, the down-regulation of claudin-5 observed confirms the protective role of BBB to maintain its integrity. Our research clearly demonstrated that Dkk-3 in GBM had pro-apoptotic effects up-regulating both intrinsic and extrinsic apoptotic pathways. The restoration of the levels of these proteins could induce a slowdown in tumor progression. We hypothesize that a more complete evaluation of the role of these proteins might suggest interesting new molecular targets for future therapeutic protocols.

Introduction: Meningiomas are the most common tumors of the CNS, where the incidence is around 25% of all primary brain tumors. The optimal treatment is total resection with removal of the dura mater and bone when infiltrated. The histological grading is the most important prognostic factor. Meningiomas may recur after total surgical resection. WHO grade I meningiomas show a recurrence rate between 7-25%. Atypical meningiomas (WHO grade II) between 29-52%. Anaplastic meningiomas (WHO grade III) between 50-94%. From recent studies the Wnt pathway is emerging as involving in growth and progression of meningioma. However, molecular mechanism driving meningioma invasion are not completely clarified. The gene Dkk-3 (Dickkopf WNT signaling pathway inhibitor 3) encodes one of Dickkopf-related protein family of proteins. The activity of this gene is a tumor-suppressive type. The Dkk-3 protein (Dickkopf-related protein 3) is involved in embryonic development through its interactions with the WNT. The REIC/Dkk-3 expression has been shown to be down-regulated in various cancer cell lines. Aim of our study was to study the role of Dkk-3 expression and claudin-5 in meningiomas of different histotype and histological grade. Material and METHODS: We evaluated how meningiomas modify DKK-3 expression in 20 tumors biopsies assessing both immunohistochemistry and western blotting. The tissue samples were embedded in paraffin for immunohistochemical analysis. The expression strength was analyzed and graded based on the positive ratio and intensity of immunoreactivity. The molecular analyses were performed on frozen sections of tumor tissue, by Western Blot method. Statistical analysis was also performed. Results: The expression of Dkk-3 protein and claudin-5 were significantly reduced in meningioma samples compared to controls. These results were confirmed by immunohistochemistry that reveals a slight expression of Dkk-3 protein in meningioma samples examined. It was also highlighted an irregular positivity of claudin-5 protein, on vascular localization. Claudin-5 levels were inversely regulated in meningiomas proteic extract with decreased levels compared to controls. Conclusions: Overexpression of Dkk-3 has been shown to mediate potent anti-tumor effects including reduced cell proliferation, independent growth, invasion and metastasis, and induced cancer cell specific apoptosis.Our preliminary results can suggest that in meningiomas Dkk-3 and Claudin-5 are downregulated. There is an alteration of the BBB. There is a decreasing of apoptotic susceptibility. The immunoreactivity of vascular neoplastic endothelium can suggest a role in angiogenesis. We suggest that the re-establishment of Dkk-3 expression can represent a new potential therapeutic approach in meningiomas treatment also by modulation of blood-brain barrier permeability.

The prognosis of patients with cerebral gliomas remains noticeably poor. Total surgical resection is almost unachievable due to considerable infiltrative ability of glial cells. Furthermore, adjuvant treatments are burdened by considerable limitations. Angiogenesis is the mechanism by which new blood vessels are formed from preexisting ones, thus supporting neoplasm progression. Gliomas are characterized by extensive microvascular proliferation. The extent of neovascularization in brain tumor correlates directly with the biological aggressiveness, degree of malignancy, and clinical recurrence of the tumor. Although a plethora of molecules can act as inducers of angiogenesis, the major growth factors include members of the vascular endothelium growth factor family. The new therapeutic approaches envisage the identification of specific biomarkers involved in this process and try to inhibit them, thus slowing down the neoplastic progression. Nanoparticles (NPs) show the ability to pass the blood–brain barrier, and moreover, when suitably modified, they can bind to specific overexpressed receptors in the glial cells. As carriers, they are able to protect the therapeutic agent and allow their sustained release. In this review, we describe some NP delivery systems which target specific biomarkers to intervene in the process of angiogenesis.